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Heparanase is the possible link between monkeypox and Covid-19: robust candidature in the mystic and present perspective

Heparanase is the possible link between monkeypox and Covid-19: robust candidature in the mystic... Heparanase (HPSE) is an endoglycosidase cleaves heparan sulfate (HS) and this contributes to the degradation and remodeling of the extracellular matrix. HS cleaved by HPSE induces activation of autophagy and formation of autophagosommes which facilitate binding of HPSE to the HS and subsequent release of growth factors. The inter‑ action between HPSE and HS triggers releases of chemokines and cytokines which affect inflammatory response and cell signaling pathways with development of hyperinflammation, cytokine storm (CS) and coagulopathy. HPSE expression is induced by both SARS‑ CoV‑2 and monkeypox virus (MPXV ) leading to induction release of pro ‑inflam‑ matory cytokines, endothelial dysfunction and thrombotic events. Co‑infection of MPX with SARS‑ CoV‑2 may occur as we facing many outbreaks of MPX cases during Covid‑19 pandemic. Therefore, targeting of HPSE by specific inhibi‑ tors may reduce the risk of complications in both SARS‑ CoV‑2 and MPXV infections. Taken together, HPSE could be a potential link between MPX with SARS‑ CoV‑2 in Covid‑19 era. Keywords Heparanase, SARS‑ CoV‑2, Monkeypox Introduction Heparanase (HPSE) is an endoglycosidase cleaves hep- *Correspondence: aran sulfate (HS) and this contributes to the degrada- ‏Helal F. Hetta tion and remodeling of the extracellular matrix. HPSE helalhetta@aun.edu.eg Marios Papadakis is synthesized as 68  kDa in the endoplasmic reticulum. marios_papadakis@yahoo.gr In the Goli apparatus, HPSE is processed into proHPSE Gaber El‑Saber Batiha (65  kDa) and the proHPSE is secreted into the extracel- gaberbatiha@gmail.com Department of Clinical Pharmacology and Therapeutic Medicine, lular space (Fux et al. 2009). College of Medicine, ALmustansiriyiah University, Baghdad, Iraq Outside the cell, HPSE binds different molecules Department of Medical Microbiology and Immunology, Faculty including HS and mannose-6-phosphate (low density of Medicine, Assiut University, Assiut 71515, Egypt Department of Science and Engineering, Novel Global Community lipoprotein receptor related protein) leading to endocyto- Educational Foundation, Hebersham, NSW 2770, Australia sis and transport of these molecules. Within the lysosome AFNP Med, 1030 Vienna, Austria 5 and by action of L-cathepsin the 6 kDa subunit is cleaved Department of Surgery II, University Hospital Witten‑Herdecke, University of Witten‑Herdecke, Heusnerstrasse 40, 42283 Wuppertal, with formation of heterodimer form of HPSE (Vlodavsky Germany et  al. 2012). HPSE induces activation of autophagy and Department of Pharmacology and Therapeutics, Faculty of Veterinary formation of autophagosommes which facilitate bind- Medicine, Damanhour University, AlBeheira, Damanhour 22511, Egypt ing of HPSE to the HS and subsequent release of growth © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Al‑Kuraishy et al. AMB Express (2023) 13:13 Page 2 of 13 factors like epidermal growth factor (EGF) and vascu- (Alakunle et  al. 2020). Recently, it has been shown that lar endothelial growth factor (VEGF) (Jayatilleke and HS severs as a co-receptor for spike protein of severe Hulett 2020). The interaction between HPSE and HS trig - acute respiratory syndrome coronavirus type 2 (SARS- gers releases of chemokines and cytokines which affect CoV-2) to binds angiotensin converting enzyme 2 (ACE2) inflammatory response and cell signaling pathways (Jaya - (Fig. 1) (Yu et al. 2021). tilleke and Hulett 2020). HPSE is involved in progression In this bargain, due to involvement of HS proteoglycan of many diseases including viral infections and cancer. in both MPXV and SARS-CoV-2 infections, this study Expression of HPSE is link with propagation of angiogen- aimed to find the potential link between SARS-CoV-2 esis, metastasis and enhancement of tumor progression infection and MPXV infection regarding HPSE level. (Masola et al. 2018). HS is consisting of a core protein and glycosaminogly- Heparanase in viral infections can (GAG), like syndecan and perlecan. HS proteoglycans HPSE is regarded as a connection between HS and viral are mainly expressed on the cell membrane (Masola et al. infections, since HS represents a first line of interac - 2018; Qiao et al. 2020). HS is degraded by HPSE, and HS tion between host cells and viral particles. Direct regu- promotes cell adhesion and motility as well; it binds and lation of HS by HPSE increases risk of viral binding and prevents degradation of chemokines, cytokines, morpho- entry (Agelidis and Shukla 2020). As well, expression of gens and growth factors (Qiao et  al. 2020). Of note, HS HPSE is induced and up-regulated during viral infec- acts as an endocytosis receptor regulates degradation of tions resulting in degradation of HS and release of pro- extracellular molecules, and increasing trans-endothelial inflammatory cytokines. For example herpes simplex transmission of chemokines. Through proteolytic shed - virus (HSV) increases expression of HPSE with subse- ding of perlecan and syndecan, HS promotes regulation quent development of inflammatory changes (Agelidis of intracellular stress which maintains development of and Shukla 2020). Koganti et  al., revealed that higher stem cell (Zhang et al. 2014). expression of HPSE induced by HSV infection in mice Notably, the negatively charged HS can interacts and resulted in worsening ocular symptoms (Gross-Cohen acts as a receptor for the positively charged viral glyco- et  al. 2021). Similarly, human papilloma viruses (HPV) proteins of different viruses. In this state, the viruses use block p53 which limit HPSE activation and expression. these interactions to augment their load and increase Release of chemokines, cytokines and growth factors in their chance to bind more entry receptors (Rusnati HPV infection is augmented due to degradation of HS by et  al. 2009). Moreover, HS acts as specific receptor for HPSE, thus p53 activators like pyranoside decrease HPSE Orthopoxviruses including monkeypox virus (MPXV) activation (Hirshoren et al. 2014; Song et al. 2016). Fig. 1 Role of heparan sulfate (HS) in the entry of SARS‑ CoV‑2: HS serves as a co ‑receptor for spike protein of SARS‑ CoV‑2 to binds angiotensin converting enzyme 2 (ACE2). HS binding compounds may compete with the viral particles for attachment to the HSPGs, thus inhibiting the viral engagement of HS chains and the subsequent access to the ACE2 receptor. Consequently, the viral entry by either fusion or endocytosis may be impaired A l‑Kuraishy et al. AMB Express (2023) 13:13 Page 3 of 13 Furthermore, respiratory syncytial virus (RSV) up- macrophage activation and release of pro-inflamma - regulates expression of HPSE during acute respiratory tory cytokines (Takeda and Akira 2004). Furthermore, infection with exaggeration of respiratory inflammation activated macrophages can secret pro-inflammatory (Tao et al. 2014. Su et al., revealed that HS is involved in cytokines like TNF-α which increase expression of HPSE. the pathogenesis of Japanese encephalitis virus (JEV) (Su As well, activated macrophages release cathepsin L which et  al. 2001). However, highly sulfated dextran, heparin also activates expression and activation of HPSE with and GAGs inhibit binding and entry of JEV in BHK-21 subsequent propagation of hyperinflammation state cell line (Su et al. 2001). Thus, heparin could be effective which promote neovascularization and tumorigenesis against development of infection by JEV (Su et al. 2001). (Lerner et al. 2011). As well, human immune deficiency virus 1 (HIV-1) It has been reported that activated T cells can release interacts with HS before to be recognized by CD4, caus- HPSE which increase binding of T cells to the extracel- ing augmentation of infection (Connell and Lortat-Jacob lular matrix proteins (Goldshmidt et  al. 2003). This 2013). HS acts as co-receptor for binding of HIV-1 to mechanism is depending on presence of β1 integrin and pg120. Thus, HS mimetic may inhibit the interaction vascular cell adhesion molecule 1 (VCAM-1) on T lym- between HIV-1 and pg120 (Connell and Lortat-Jacob phocytes and endothelial cells respectively (Goldshmidt 2013). HS is also used by many pathogens including plas- et  al. 2003). Furthermore, HPSE can stimulate activation modium falciparum, pseudomonas aeruginosa, mycobac- of natural killer (NK) cells through activation of natural terium tuberculosis, borrelia budrdorferi and hepatitis cytotoxic receptors which increase expression of pro- viruses (Spillmann 2001; Liu and Thorp 2002; Vivès et al. inflammatory cytokines. In this state HPSE has ability to 2006; Bartlett and Park 2010; Tiwari et al. 2012). Different remove HS which act as a co-ligand in preventing activa- studies illustrated that elimination of HS augments cell tion of NK cells (Mayes et al. 2017). resistance to the many viral infections. However, soluble Notably, HPSE increases activation and release of HS like heparin and dextran bind the circulating viruses VEGF which normally sequestered by HS (Elkin et  al. and prevent their binding to the cell membrane HS 2001). It has been reported that VEGF is activated during (Urbinati et al. 2008; Walker et al. 2002). The interaction viral infections (Fleming et  al. 2015). Releasing of VEGF between HS and viral molecules may cause adaptation by HPSE-dependent mechanism is occurs via degrada- changes with increasing affinity to HS (Bear et al. 2006). tion of HS bounded to the VEGF(Elkin et  al. 2001). In Taken together, HS increases entry and pathogenesis addition, HPSE encourage release of EGF and TGF-α via of viruses but HS derived molecules may have antiviral activation of ERK and MAPK signaling pathways (Koro- effects, thus these molecules could be effective thera - glu et al. 2010). peutic tools (Hu et al. 2011). These observations suggest Interestingly, HPSE assists in egress of various viruses that HS plays a critical role in the pathogenesis of viral like HSV from host immune response by releasing of infections. bounded HS from invading virus. HPSE increases shed- ding of syndecan from host cell membrane through Heparanase and immune response activation release of matrix metalloproteinase (MMP) HPSE has a crucial role in the activation of macrophage (Surviladze et al. 2015). As well, virus binding to HS can and release of pro-inflammatory cytokines during viral be released outside the infected cells without immune infections (Wagner et  al. 2021). Non-enzymatic activa- recognition (Surviladze et  al. 2015). Cleaving of HS by tion of HPSE promotes cytokine expression, suggesting HPSE increases viral release and infectivity, herein phar- that HS is not necessary in HPSE-induced macrophage macological inhibition of HPSE may reduce viral release activation (Wagner et  al. 2021). Besides, in  vitro study and pathogenesis of viral infections (Surviladze et  al. demonstrated that macrophage inflammatory protein 2 2015). Activation of HPSE during viral infection may (MIP-2) can induces activation of HPSE (Wagner et  al. increase disease severity by inhibiting release of type 1 2021). Notably, HPSE increases polarization of mac- interferon which has potent antiviral effect (Agelidis et al. rophage to tumorigenic phenotype (Fig.  2) (Bhattacha- 2017). rya et  al. 2020). Furthermore, HS HS fragments cleaved These verdicts pointed out that HPSE has important by HPSE induces activation of toll-like receptor 4 (TLR- immunological effects through activation of macrophage, 4) which promote activation of inflammatory signal - T cell and NK cells with stimulation of inflammatory ing pathways including JNK, ERK and p38 trigger some signaling pathways and growth factors during viral infec- cytokines necessary for macrophage activation (Wag- tions. These changes may increase disease severity during ner et  al. 2021). Likewise, activation of TLR-4 by HS viral infections. So, targeting of HPSE by specific antag - and HPSE stimulate a series of inflammatory signaling onists may reduce immunological overreaction during pathways like NF-κB, PI3K and MAPK which provoke viral infections. Al‑Kuraishy et al. AMB Express (2023) 13:13 Page 4 of 13 Fig. 2 Heparanase (HPSE) and macrophage activation: HPSE activates resting macrophage to be converted to activated macrophage with activation of cytokine receptors. HPSE via HPSE receptors increases expression of Fgr1 and NF‑κB which induces expression and release of pro‑inflammatory cytokines like IL ‑6 and IL ‑2. HPSE and pro ‑inflammatory cytokines also stimulate the activated macrophage to release more of pro‑inflammatory cytokines Heparanase in Covid‑19 that Covid-19 may cause extra-pulmonary manifesta- Coronavirus disease 2019 (Covid-19) is an existing tions including acute kidney injury, thromboembolic pandemic disease caused by severe acute respiratory disorders, gastrointestinal and neurological complica- syndrome coronavirus virus respiratory type 2 (SARS- tions (Al-Kuraishy et  al. 2020a, Al-Kuraishy et  al. 2022, CoV-2) (Al-Kuraishy et  al. 2021a, Al-Kuraishy et  al. 2021e). Generally, Covid-19 is typically asymptomatic 2022c). SARS-CoV-2 is a single strand RNA virus from in about 85% of affected patients. Though, 15% of the Betacoronavireadae family, which has a close-up genetic affected patients presented with severe dyspnea and criti - correspondence with other coronaviruses like bat coro- cal respiratory symptoms due to promulgation of acute navirus, SARS-CoV and Middle East Respiratory Syn- lung injury (ALI). Additionally, 5% of Covid-19 patients drome coronavirus virus (MERS-CoV) (Al-Kuraishy et al. require hospitalization and intensive care unit (ICU) 2021b,2022c). SARS-CoV-2 was originally appeared in admission due to progression of acute respiratory dis- Wuhan, China, led to unrecognized pneumonia named tress syndrome (ARDS) (Al-Kuraishy, Al-Gareeb, Qusty, Wuhan pneumonia (Al-Kuraishy et  al. 2021c). Further, et  al. 2021f, Al-Kuraishy et  al. 2022). Severely affected this virus was renamed as a novel coronavirus virus 2019 Covid-19 patients may necessitate invasive oxygen sup- (nCov2019). Then the world health organization (WHO) plementation and mechanical ventilation (Al-Kuraishy declared this disease as a pandemic and renamed this et al. 2021f, Al-Kuraishy et al. 2022g). virus to SARS-CoV-2 (Al-Kuraishy et al. 2021d). Covid-19 Management of Covid-19 patients is mostly supportive is considered as a respiratory disease causing respiratory and symptomatic alleviate as explicit anti-SARS-CoV-2 symptoms similar to the flue like illness characterized by was not build up till now in spite of advance of effective fever, headache, dry cough, dyspnea, myalgia, joint pain, vaccines. Noteworthy, numerous repurposed agents like and anosmia (Al-Kuraishy et al. 2021e, Al-Kuraishy et al. ivermectin, remdesivir, and favipiravir were incorporated 2022 2021d). Further scrutinized researches exposed in dissimilar therapeutic protocols in the management of A l‑Kuraishy et al. AMB Express (2023) 13:13 Page 5 of 13 Covid-19 (Carlotti et  al. 2020, Al-Kuraishy et  al. 2022h). and syndecanes are increased during sepsis-induced Though, these agents did not fashioned to be effectual endothelial dysfunction (Iba and Levy 2019). In SARS- therapeutic agents in the eradication of SARS-CoV-2, CoV-2 infection degradation of HS by HPSE induces thus prolong searching for novel anti-SARS-CoV-2 activation of bradykinin with development of pulmonary agents is a type of brave nowadays (Carlotti et al. 2020). inflammation and ARDS. Normally, HS inhibits brady - In SARS-CoV-2 infection, HPSE is increased leading kinin activation so over-activation of HPSE in Covid-19 to degradation of endothelial glycocalyx with increment with degradation of HS provokes activation of bradykinin of vascular inflammation and leakage with subsequent (Liu et  al. 2020). Besides, deregulation of renin-angio- development of endothelial dysfunction (ED) a hallmark tensin system (RAS) due to downregulation of ACE2 of Covid-19 (Buijsers et  al. 2020). A prospective study increases circulating level of angiotensin II (AngII) with involved 48 Covid-19 patients compared to 10 healthy subsequent development and propagation of endothelial controls illustrated that HPSE and HS serum levels were dysfunction (Al-Kuraishy et  al. 2020b, Al-Kuraishy, Al- increased in Covid-19 patients as compared to the con- Niemi, et  al. 2020; Al-Kuraishy, Al-Gareeb, Alzahrani, trols (Buijsers et al. 2020). Higher HPSE level was linked Alexiou, et al. 2021). Different studies showed that AngII with Covid-19 severity and ICU admission (Buijsers et al. had ability to induce expression of HPSE and endothe- 2020). Nadir and colleagues found that higher expression lin-1 (ET-1) which also promote HPSE expression (Van of HPSE and HS are correlated with Covid-19 severity den Hoven et  al. 2009; Hong et  al. 2004). As well, AngII (Nadir and Brenner 2021). HPSE is increased in elderly enhances bradykinin activation and development of ED subjects by whom pulmonary HS and other GAGs are (Hasan et al. 2021). reduced with increasing risk of SARS-CoV-2 infection in Over-activation of HPSE and releases of HS in severe elderly (Nadir and Brenner 2021). It has been proposed SARS-CoV-2 infection induce activation of macrophage that increasing HPSE in older age individuals enhances through TLR-4 with subsequent release of pro-inflam - degradation of HS in lung and endothelial cells with matory cytokines (Buijsers et al. 2020). Free HS acts as a more risk for development of ARDS and ED in Covid-19 pro-inflammatory agent provokes immune cells stimula - patients (Nadir and Brenner 2021). tion (Buijsers et  al. 2020). In turn, exaggerated immune Notably, endothelial glycocalyx which cover the response and hypercytokinemia in severe SARS-CoV-2 endothelial cells has an important role in maintaining of infection promote HPSE expression in a positive feed- vascular endothelial homeostasis. Disruption of endothe- back loop (Buijsers et  al. 2020, Al-kuraishy et  al. 2022). lial glycocalyx is associated with poor clinical outcome Therefore, inhibition of HPSE by low molecular weight in severely affected Covid-19 patients (Stahl et al. 2020). heparin (LMWH) may reduce endothelial injury and A clinical study included severely affected Covid-19 exaggeration of immune response by inhibiting release of patients at ICU showed that biomarkers of endothelial pro-inflammatory cytokines (Shen et  al. 2022). In addi - glycocalyx injury like HPSE and HS were increased as tion, prophylactic use of LMWH in Covid-19 patients compared to healthy controls (Stahl et  al. 2020). Thus, can decrease HPSE expression and activation (Shen et al. HPSE inhibitors may reduce development of ED by sup- 2022). However, HPSE level remains elevated in severely pressing injury of endothelial glycocalyx in Covid-19 affected Covid-19 patients despite use of LMWH (Bui - patients (Fig. 3) (Rus et al. 2022). jsers et  al. 2020). This feature suggest that early use of Of note, ED is associated with development of Covid- LMWH may reduce HPSE level by preventing endothe- 19 complications including ARDS and acute kidney lial glycocalx injury but use of LMWH in the late phase of injury (AKI) (Al-Kuraishy et  al. 2022). HS is the main Covid-19 may not reduce HPSE level as it released in the GAG present in the endothelial cells glycocalyx. HS early stage mainly in severely affected Covid-19 patients. due to its negative charge can play an important role in These observations proposed that HPSE and HS are maintaining of charge-dependent endothelial barrier highly deranged in Covid-19 leading to activation release function(Talsma et  al. 2018). Degradation of endothelial of pro-inflammatory cytokines and increase risk for HS by HPSE impairs glycocalyx barrier and endothe- development of cytokine storm. As well, HPSE and HS lial function. This interaction promotes generation serum levels could be potential biomarkers for assess- of pro-inflammatory glycocalyx which trigger bind - ment of Covid-19 severity. ing of pro-inflammatory cytokines to the endothelial cells (McDonald et  al. 2016). La Riviere and Schmidt Heparanase and coagulopathy in Covid‑19 observed that injury of pulmonary endothelial glycoca- It has been shown that severe SARS-CoV-2 infection lyx during sepsis promotes development of ALI, ARDS is associated with development of thrombotic lead- and alveolar micro-vascular dysfunction (LaRivière and ing to pulmonary micro-thrombosis and development Schmidt 2018). Biomarkers of glycocalyx injury like HS of ARDS. As well, Covid-19 may induce progression of Al‑Kuraishy et al. AMB Express (2023) 13:13 Page 6 of 13 Fig. 3 Glycocalyx injury in Covid‑19 and systemic complications: Co ‑morbidities like old age, diabetes and cardiovascular disorders together with SARS‑ CoV‑2 induce glycocalyx injury with development of endothelial dysfunction, blood vessel leakage and coagulation disorders. These changes lead to organ damage, multi‑ organ failure, and death. Covid‑19‑induced glycocalyx injury is mediated by cytokine storm, immune cell infiltration, and direct cellular injury systemic thrombosis and disseminated intravascular HPSE and degradation of HS can cause coagulopathy coagulopathy (DIC). These changes are developed due to through induction expression of TF and TFPI (Kinaneh SARS-CoV-2 infection-induced ED [Fig. 4]. (Asakura and et  al. 2021). In addition, HPSE facilitates the interaction Ogawa 2021; Al-Kuraishy et al. 2021e). between TF and activated VII with consequent escalation Activation of HS and HPSE may be implicated in the of thrombosis (Kinaneh et  al. 2021). As well, activated pathogenesis of coagulopathy. Normally, tissue fac- platelets produce and release HPSE with further throm- tor (TF) is the chief initiator of coagulation; it is not botic development (Kinaneh et al. 2021). expressed by endothelial cells under physiological condi- Of note, HS enhances SARS-CoV-2 and other coronavi- tion (Reeves et al. 2018). Though, during systemic inflam - rus infections to bind ACE2 with further viral entry (Hao mation and dysregulation of RAS, the expression of TF et al. 2021). Likewise; SARS-CoV-2 induces expression of by the endothelial cells is augmented (Reeves et al. 2018). HPSE with more degradation of HS in endothelial glyco- TF induces coagulation cascade as it act as a receptor calyx (Buijsers et al. 2020). Interestingly, up-regulation of for clotting factor VII (Zhao et  al. 2021). TF is modu- HPSE in SARS-CoV-2 infection could the potential cause lated by many endogenous proteinases expressed on for development of coagulopathy and fatal complications the endothelial cells, called TF pathway inhibitor (TFPI) (Buijsers et  al. 2020). u Th s, administration of LMWH in (Zhao et  al. 2021). Therefore, activation of TF and TFPI severely affected Covid-19 patients may decrease risk of trigger development of thrombosis in severe viral infec- thrombotic complications by inhibiting HPSE expression tions and cancer (Zhao et  al. 2021). Over-expression of and activation of TF/TFIP axis (Grandone et  al. 2021). A l‑Kuraishy et al. AMB Express (2023) 13:13 Page 7 of 13 Fig. 4 Coagulopathy in Covid‑19: SARS‑ CoV‑2 infection leads to inflammatory reactions, endothelial dysfunction, platelet dysfunction and increase release of histone and nucleosomes. These changes trigger activation of coagulation cascade with thrombotic disorders and increase D‑ dimer. Fibrinogen and D‑ dimer activate release of pro‑inflammatory cytokines Furthermore, HS mimetic compounds like pixatimod activated HPSE increases activation and polarization which is a potent inhibitor of HPSE might be of value of macrophages, T cells and NK cells with induction in the management of Covid-19 by inhibiting HPSE- expression of TLR4 (Wagner et al. 2021) (Bhattacharya induced inflammation and coagulopathy (Guimond et al. et  al. 2020; Goldshmidt et  al. 2003; Mayes et  al. 2017). 2022). Besides, activation of HPSE promotes expression of These findings indicate that activated HS/HPSE in inflammatory signaling pathways including NF-κB, SARS-CoV-2 infection may participate in the progres- PI3K and MAPK which increase macrophage activation sion of coagulopathy. u Th s, LMWH and HS mimetic and release of pro-inflammatory cytokines (Takeda and can reduce HPSE in SARS-CoV-2 infection with further Akira 2004). In addition, activated macrophages can attenuation of thrombotic complications. secret pro-inflammatory cytokines like TNF-α which increase expression of HPSE (Takeda and Akira 2004). Additionally activated macrophages release cathepsin L Heparanase and cytokine storm in Covid‑19 which also increases HPSE expression with propagation Cytokine storm (CS) in Covid-19 is propagated due of hyperinflammation state (Lerner et  al. 2011). Differ - to complex immunological response characterized by ent studies observed that higher expression of inflam - over-activation of T1h immune response and weak matory signaling pathways in severe Covid-19 may IFN response with subsequent stimulation of inflam - increase risk for development of CS by inducing release matory signaling pathways and excessive release of of pro-inflammatory cytokines and chemokines (Kim pro-inflammatory cytokines (Hu et  al. 2021). Develop - et al. 2021; Yang et al. 2021). ment of CS is correlated with Covid-19 severity due These judgements proposed that higher HPSE expres - to hypercytokinemia-induced organ injury (Hu et  al. sion in Covid-19 may linked with development of CS and 2021). Remarkably, activation of HPSE with subse- disease severity. Targeting of HPSE in the early stage of quent release of pro-inflammatory HS promotes release Covid-19 may reduce propagation of CS and associated of pro-inflammatory cytokines with development life-threatening complications. of CS during sepsis (Vlodavsky et  al. 2021). Of note, Al‑Kuraishy et al. AMB Express (2023) 13:13 Page 8 of 13 Heparanase in Monkeypox Transmission of MPXV is frequently occurring through Monkeypox (MPX) is one of common zoonotic disease direct contact and respiratory droplets. Sexual contact caused by a double strand DNA MPX virus (MPXV) with animals could be a probable cause (Organization belonging of Orthopoxvirus genus/ Poxviridae family. 2022). The skin rashes go in various stages before form - MPXV is extremely pathogenic for human subsequent to ing scab which finally fall out. Two third of patients have the eradication of smallpox in 1980 (Alkhalil et  al. 2010; skin lesions on the palms and soles (Organization 2022). Di Giulio and Eckburg 2004). The natural host of MPXV Diagnosis of human MPX is done depending on the is not certainly identified, though it infects a wide-spec - clinical features and history for contacts with animals. trum of animal and mammalian species. MPX is mostly Polymerase chain reaction (PCR) of samples from skin endemic in Democratic Republic of Congo (DRC) and lesions is definitive for the final diagnosis. Blood PCR some area of Ivory Coast (Alkhalil et  al. 2010; Di Giulio is not a definitive since MPXV is no longer persisting in and Eckburg 2004). Particularly, there are two clades of the blood (Organization 2022). Human MPX in severe MPXV that vary clinically and epidemiologically. Central conditions may lead to various complications including African clade (Congo Basin clade) characterized by ele- bronchopneumonia, acute respiratory distress, sepsis, vated case fatality rate (CFR) about 11% with confirmed gastrointestinal complications, dehydration, encephali- person-to-person transmission. Though, West African tis, and visual loss due to involvement of cornea. Human clade is characterized by low CFR about 1% without per- MPX may be misdiagnosed with chickenpox, small- son- to- person transmission (Likos et al. 2005). pox, anthrax and HIV-induced skin lesion (Adalja and MPX was initially documented in 1958 as smallpox-like Inglesby 2022). disease in the laboratory monkeys in Denmark by Preben von Magnus (Xiang and White 2022). The first reported Pathogenesis and immunological response case of human MPX was in 1970, and on 1972 a case of of MPXV human MPX was recognized a 9-month neonate in DRC Human MPX is caused by an enveloped dsDNA MPXV (Xiang and White 2022). A sum number of 50 reported which has 250 nm width and 170–250 kb in size of DNA cases of human MPX were established from 1970 to genome. MPXV consist of surface tubules, outer enve- 1979, two thirds of these cases being from DRC (Breman lope of extracellular virion, lateral bodies, plasid layer, et  al. 1980). Meyer et  al., reported that by end of 1986 core fibrils, and outer membrane of intracellular and more than 400 cases of human MPX characterized by extracellular virions (Fig. 5). 10% CFR were identified in West and Central Africa that MPXV enters the mucous membrane of mouth, eye was design as a first outbreak (Meyer et  al. 2002). The and respiratory tracts (Guarner et al. 2004). Similar to the second outbreak of human MPX was identified in DRC other Orthopoxviruses, entry of MPXV into host cells is in a period between 1996 and 1997 (Qiao et al. 2020). In a achieved by binding to the glycosaminoglycan (GAGs) period from 1991 to 1999 a 511 reported cases of human on the cell membrane, which mediate viral endocyto- MPX were celebrated in DRC (Meyer et al. 2002). sis (Guarner et  al. 2004). In the cytoplasm the viral core The clinical picture of human MPX is highly identical and genomes are released with succeeding replication to that of smallpox, nevertheless early lymphadenopa- of viral proteins by viral DNA polymerase. Indeed, viral thy in human MPX is the distinguishing sign not present structural proteins are produced within 48  h post-infec- in smallpox. The incubation period is 1–3  weeks, fever, tion with subsequent assembly into mature virions in the headache, joint pain, myalgia and nausea for about 3 days Golgi apparatus. From Golgi apparatus, the mature viri- (Minhaj et al. 2022). Skin lesions which appear 1–3 days ons are transported by microtubules to the plasma mem- subsequent fever and lymphadenopathy are typically brane and released outside the infected cells to infect appearing at the same time on the face and periphery other cells in the same manner (Likos et al. 2005). (Weinstein et al. 2005) (Adler et al. 2022). Lymphadenop- There are four types of GAGs including HS, chondrio - athy characterized by lymph node enlargement mainly in tin/dermatan sulfate, keratin sulfate and hayluronic acid the neck, groin, and submandibular area. The skin lesions (Bartlett and Park 2010; Gandhi and Mancera 2008; Sodhi cover all the body in severe cases. The skin lesions started and Panitch 2020). GAGs are complex carbohydrate as a small flat spot which become small bumps (papules) ubiquitously expressed on cell surface and extracellular which later filled with clear fluid and then with yellow matrix. The interactions between GAGs and microbial fluid, sometimes merge to form large lesions. The lesions pathogens represent a defense line against invasion (Lin progress in the same time similar to that of smallpox, fol- et  al. 2020). Several pathogens including MPXV induce lowing healing the lesions leaves pale marks which finally release of GAGs with formation of soluble GAGs which become darks (Adalja and Inglesby 2022). coat the pathogen to escape immune detection (Akhtar A l‑Kuraishy et al. AMB Express (2023) 13:13 Page 9 of 13 Fig. 5 Structure of monkeypox virus: Human MPX is an enveloped dsDNA MPXV which has 250 nm width and 170–250 kb in size of DNA genome. MPXV consist of surface tubules, outer envelope of extracellular virion, lateral bodies, plasid layer, core fibrils, and outer membrane of intracellular and extracellular virions and Shukla 2009; Hughes et  al. 2014). HS together with immunosuppressive effect of MPXV as evident by reduc - sialic acid are highly expressed in dermal and epidermal tion of T lymphocytes in MPX (Townsend et  al. 2013; cells that enhance binding and entry of MPXV to the skin Hammarlund et al. 2008). (Hughes et al. 2014). Different studies showed that binding of MPXV to the In MPXV like other Orthopoxviruses there is activa- HS may induce activation of HPSE and release of pro- tion of genes concerned in activation expression of pro- inflammatory cytokines (Khanna et  al. 2017; Bhatt et  al. inflammatory cytokines and chemokines like IL-6 and 2021; Kindrachuk et  al. 2012). In severe MPXV infec- CCL-2 respectively (Bourquain et  al. 2013). As well, tion, activation of inflammatory signaling pathways with MAPK and ERK are activated by MPXV which encour- release of pro-inflammatory cytokines may lead to the age viral entry, viral replication and augment expression development of CS. It has been shown that MPX may of viral proteins needed for viral replication (DuShane causes fatal complications like sepsis, bronchopneumo- and Maginnis 2019). Furthermore, heat shock protein 1 nia and ALI (Stittelaar et  al. 2005) which might develop (HSP-1) is necessary for replication of MPXV so it highly due to propagation of CS. Stanford et  al. observed that induced during infection with MPXV (Filone et al. 2014). severity of MPX and smallpox was related to the direct Notably, MPXV induces activation of NF-κB through cytopathic effect and immunopathological changes due suppression of signal transducer and activator of tran- to release of immunomodulatory molecules. Invasion of scription (STAT) which has antiviral effects (Filone injured tissues by immune and inflammatory cells due to et  al. 2014). Besides, MPXV activates NK cells to release exaggerated immune response may cause extensive tissue interferon gamma (INF-γ) and TNF-α which stimulate damage due to propagation of CS (Stanford et al. 2007). Th1 immune response (Filone et  al. 2014). Overall, due to selective tropism of lymphoid tissues, MPXV can The potential link between MPX and Covid‑19 induce lymphopenia and lymphadenopathy (Townsend In both Covid-19 and MPX, lymphopenia is developed et  al. 2013). Inhibition of CD4 and CD8 as well as main- by different mechanisms. Direct injury of lymphocyte taining of major histocompatibility complex 1 (MHC1) by SARS-CoV-2, lymphocyte exhaustion and sequestra- could be the probable mechanism for immune evasion tion of lymphocytes in the lymphoid tissues could be the of MPXV (Hammarlund et  al. 2008). MPXV can evade possible cause of lymphopenia in Covid-19 (Fathi and the immune response through release of viroceptors Rezaei 2020). Similarly, exaggeration immune response and virokines which are like to the host cytokines. These and development of CS may induce lymphocyte apopto- annotations may clarify the immunosuppressive effect of sis inhibit bone marrow proliferation and production of MPXV as evident by reduction of T lymphocytes in MPX lymphocytes (Fathi and Rezaei 2020). Of note, lympho- (Hammarlund et  al. 2008). Consequently, the immune penia is associated with Covid-19 severity due to loss of response unlike other viral infections is complex and anti-inflammatory function of lymphocytes (Fathi and need further attention. These verdicts may explain the Rezaei 2020). A systematic review and meta-analysis Al‑Kuraishy et al. AMB Express (2023) 13:13 Page 10 of 13 from 24 studies included 3099 Covid-19 patients showed that lymphopenia at time of admission is linked with poor clinical outcomes and high mortality (Huang and Pranata 2020). In MPX, lymphopenia is a characteristic pathognomic feature due to lymphotropism of MPXV with inhibition release of lymphocytes (Mucker et  al. 2015). As well, abnormal immune response and hypercy- tokinemia in MPX exhausts circulating lymphocytes with development of lymphopenia (Stanford et al. 2007). Furthermore, over-expression of HPSE in both Covid- 19 and MPX with higher immune response may induce propagation of lymphopenia (Digre et al. 2017). Of note, inflammatory signaling pathways and pro-inflammatory cytokines are exaggerated in both Covid-19 and MPX leading to hyperinflammation and development of CS (Buijsers et al. 2020; DuShane and Maginnis 2019). Inter- estingly, degradation and release of pro-inflammatory HS is triggered by HPSE. SARS-CoV-2 and MPXV are impli- cated to induce HPSE expression and dissociation of HS Fig. 6 The possible link between SARS‑ CoV‑2 and MPXV infections: SARS‑ CoV‑2 and MPXV infections activate heparanase (HPSE) leading from cell membrane GAGs (Buijsers et al. 2020; Lin et al. to lymphpenia which cause complications 2020). Pro-inflammatory HS and activated HPSE pro - mote release of pro-inflammatory cytokines which also trigger stimulation of HPSE in a positive loop manner pandemic. Further studies are required to find the magic in SARS-CoV-2 and MPXV infections (Kindrachuk et al. link between MPX and Covid-19. 2012; Yang et al. 2021; Kim et al. 2021). The present review had many limitations like rareness Up-regulation of HPSE in SARS-CoV-2 infection might of clinical studies concerning role MPX in propagation be the potential cause for progression of coagulopa- of thrombotic events and CS which are the hallmark of thy (Buijsers et  al.2020). Though, HPSE expression and Covid-19. As well, HS level and HPSE activity in relation development of coagulopathy was not precisely reported to pro-inflammatory cytokines and inflammatory sign - in MPX (Hutson and Damon 2010). The underlying aling pathways were not listed from previous studies in mechanism of coagulopathy and thrombotic events in both MPX and Covid-19. Though the present review sug - Covid-19 and MPX could in part relate to HPSE expres- gests that HPSE could be the latent link between MPX sion. u Th s, administration of LMWH in severely affected and Covid-19. Covid-19 or MPX patients may reduce risk of thrombotic complications by inhibiting HPSE expression and activa- tion of TF/TFIP axis (Hutson and Damon 2010) (Gran- Conclusions done et  al. 2021). What’s more, HS mimetic compounds HPSE is an endoglycosidase cleaves heparin sulfate (HS) like pixatimod which is a potent inhibitor of HPSE could and this contributes to the degradation and remodeling be of value in the management of Covid-19 and MPX by of the  extracellular matrix. HS cleaved by HPSE induces inhibiting HPSE-induced inflammation and coagulopa - activation of autophagy and formation of autophago- thy (Hutson and Damon 2010; Guimond et al. 2022). somes which facilitate binding of HPSE to the HS and These findings and observations proposed that HPSE consequent release of growth factors and pro-inflam - expression which involved in the progression hyperin- matory cytokines. The interface between HPSE and HS flammation, CS, and coagulopathy could be the poten - triggers releases of chemokines and cytokines which tial link between Covid-19 and MPX (Fig.  6). Targeting influence inflammatory response and cell signaling of HPSE by treatment with LMWH in severely affected pathways with propagation of hyperinflammation, CS, Covid-19 or MPX patients may reduce risk of thrombotic and thrombotic events. HPSE expression is induced and inflammatory complications. In addition, MPX- by both SARS-CoV-2 and MPXV in severely affected induced immunosuppressant effects (Hammarlund et  al. patients leading to induction release of pro-inflammatory 2008) may increase risk of SARS-CoV-2 infection. Co- cytokines, endothelial dysfunction, and coagulopathy. infection of MPX with SARS-CoV-2 may occur as we Co-infection of MPX with SARS-CoV-2 may occur as we facing many outbreaks of MPX cases during Covid-19 facing many outbreaks of MPX cases during Covid-19 A l‑Kuraishy et al. AMB Express (2023) 13:13 Page 11 of 13 Al‑Kuraishy HM, Al‑ Gareeb AI, Alblihed M, Cruz‑Martins N, Batiha GE (2021) pandemic. Therefore, targeting of HPSE by specific inhib - COVID‑19 and risk of acute ischemic stroke and acute lung injury in itors like LMWH may reduce risk of complications in patients with type ii diabetes mellitus: the anti‑inflammatory role of both SARS-CoV-2 and MPXV infections. Taken together, metformin. Front Med. 1:110 Al‑Kuraishy HM, Al‑ Gareeb AI, Alblihed M, Guerreiro SG, Cruz‑Martins N, Batiha HPSE could be a potential link between MPX with SARS- GE (2021) COVID‑19 in relation to hyperglycemia and diabetes mellitus. CoV-2 in Covid-19 era. In this regards, various experi- Front Cardiovasc Med. 8:644095 mental, preclinical, and clinical studies are warranted to Al‑Kuraishy HM, Al‑ Gareeb AI, Alzahrani KJ, Alexiou A, Batiha GE (2021) Niclosa‑ mide for Covid‑19: bridging the gap. Mol Biol Rep. 48(12):8195–202 explore and confirm the possible role in the pathogenesis Al‑Kuraishy HM, Al‑ Gareeb AI, Alzahrani KJ, Cruz‑Martins N, Batiha GE (2021) of SARS-CoV-2 and MPXV infections. The potential role of neopterin in Covid‑19: a new perspective. Mol Cell Biochem. 476(11):4161–6 Acknowledgements Al‑Kuraishy HM, Al‑ Gareeb AI, Faidah H, Al‑Maiahy TJ, Cruz‑Martins N, Batiha Not applicable. GE (2021) The looming effects of estrogen in Covid‑19: a rocky rollout. Front Nutr. 8:649128 Author contributions Al‑Kuraishy HM, Al‑ Gareeb AI, Qusty N, Cruz‑Martins N, Batiha GE (2021) Conceptualization, HMA, AIA, HFH, GEB; methodology, HMA, AIA, HFH, GEB; Sequential doxycycline and colchicine combination therapy in Covid‑ formal analysis, HMA, AIA, HFH, GEB.; writing original draft, HMA, AIA, HFH, GEB; 19: The salutary effects. Pulm Pharmacol Ther. 67:102008 AA, MP, writing the revised manuscript and critical revision. All authors have Al‑Kuraishy HM, Al‑ Gareeb AI, Al‑Hussaniy HA, Al‑Harcan NA, Alexiou A, Batiha read and approved the final manuscript. GE (2022) Neutrophil Extracellular Traps (NETs) and Covid‑19: A new frontiers for therapeutic modality. Int Immunopharmacol 6:108516 Funding Al‑Kuraishy HM, Al‑ Gareeb AI, Onohuean H, El‑Saber Batiha G (2022) COVID ‑19 Open Access funding enabled and organized by Projekt DEAL. and erythrocrine function: the roller coaster and danger. Int J Immuno‑ pathol Pharmacol. 4:36 Availability of data and materials Al‑Kuraishy HM, Batiha GE, Faidah H, Al‑ Gareeb AI, Saad HM, Simal‑ Gandara All generated data are included in this manuscript. J (2022) Pirfenidone and post‑ Covid‑19 pulmonary fibrosis: invoked again for realistic goals. Inflammopharmacology. 31:1 Al‑Kuraishy HM, Al‑ Gareeb AI, Kaushik A, Kujawska M, Batiha GE (2022) Hemo‑ Declarations lytic anemia in COVID‑19. Ann Hematol. 8:1–9 Al‑Kuraishy HM, Al‑ Gareeb AI, Al‑Niemi MS, Alexiou A, Batiha GE (2022) Calpro ‑ Ethics approval and consent to participate tectin: the link between acute lung injury and gastrointestinal injury in Not applicable. Covid‑19: Ban or boon. Curr Prot Pept Sci. 23(5):310–20 Al‑Kuraishy HM, Al‑ Gareeb AI, Alexiou A, Batiha GE (2022) Central effects of Consent for publication ivermectin in alleviation of Covid‑19‑induced dysautonomia. Curr Drug Not applicable. Targets. 23(13):1277–87 Al‑Kuraishy HM, Al‑Fakhrany OM, Elekhnawy E, Al‑ Gareeb AI, Alorabi M, De Competing interests Waard M, Albogami SM, Batiha GE (2022) Traditional herbs against The authors declare no conflict of interest. COVID‑19: back to old weapons to combat the new pandemic. Eur J Med Res. 27(1):1–1 Al‑kuraishy HM, Al‑ Gareeb AI, Elekhnawy E, Batiha GE (2022) Dipyridamole and Received: 17 August 2022 Accepted: 18 January 2023 adenosinergic pathway in Covid‑19: a juice or holy grail. Egypt J Med Hum Genet. 23(1):1–6 Al‑Kuraishy HM, Al‑Niemi MS, Hussain NR, Al‑ Gareeb AI, Al‑Harchan NA, Al‑ Kurashi AH. The potential role of renin angiotensin system (RAS) and dipeptidyl peptidase‑4 (DPP ‑4) in COVID ‑19: navigating the uncharted. References Selected chapters from the reninangiotensin system, Kibel A (Ed). Adalja A, Inglesby T (2022) A novel international monkeypox outbreak. In.: IntechOpen, London. 2020a;1:151–65. 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Cancer Micro ‑ environt 5(2):115–132 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AMB Express Springer Journals

Heparanase is the possible link between monkeypox and Covid-19: robust candidature in the mystic and present perspective

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Abstract

Heparanase (HPSE) is an endoglycosidase cleaves heparan sulfate (HS) and this contributes to the degradation and remodeling of the extracellular matrix. HS cleaved by HPSE induces activation of autophagy and formation of autophagosommes which facilitate binding of HPSE to the HS and subsequent release of growth factors. The inter‑ action between HPSE and HS triggers releases of chemokines and cytokines which affect inflammatory response and cell signaling pathways with development of hyperinflammation, cytokine storm (CS) and coagulopathy. HPSE expression is induced by both SARS‑ CoV‑2 and monkeypox virus (MPXV ) leading to induction release of pro ‑inflam‑ matory cytokines, endothelial dysfunction and thrombotic events. Co‑infection of MPX with SARS‑ CoV‑2 may occur as we facing many outbreaks of MPX cases during Covid‑19 pandemic. Therefore, targeting of HPSE by specific inhibi‑ tors may reduce the risk of complications in both SARS‑ CoV‑2 and MPXV infections. Taken together, HPSE could be a potential link between MPX with SARS‑ CoV‑2 in Covid‑19 era. Keywords Heparanase, SARS‑ CoV‑2, Monkeypox Introduction Heparanase (HPSE) is an endoglycosidase cleaves hep- *Correspondence: aran sulfate (HS) and this contributes to the degrada- ‏Helal F. Hetta tion and remodeling of the extracellular matrix. HPSE helalhetta@aun.edu.eg Marios Papadakis is synthesized as 68  kDa in the endoplasmic reticulum. marios_papadakis@yahoo.gr In the Goli apparatus, HPSE is processed into proHPSE Gaber El‑Saber Batiha (65  kDa) and the proHPSE is secreted into the extracel- gaberbatiha@gmail.com Department of Clinical Pharmacology and Therapeutic Medicine, lular space (Fux et al. 2009). College of Medicine, ALmustansiriyiah University, Baghdad, Iraq Outside the cell, HPSE binds different molecules Department of Medical Microbiology and Immunology, Faculty including HS and mannose-6-phosphate (low density of Medicine, Assiut University, Assiut 71515, Egypt Department of Science and Engineering, Novel Global Community lipoprotein receptor related protein) leading to endocyto- Educational Foundation, Hebersham, NSW 2770, Australia sis and transport of these molecules. Within the lysosome AFNP Med, 1030 Vienna, Austria 5 and by action of L-cathepsin the 6 kDa subunit is cleaved Department of Surgery II, University Hospital Witten‑Herdecke, University of Witten‑Herdecke, Heusnerstrasse 40, 42283 Wuppertal, with formation of heterodimer form of HPSE (Vlodavsky Germany et  al. 2012). HPSE induces activation of autophagy and Department of Pharmacology and Therapeutics, Faculty of Veterinary formation of autophagosommes which facilitate bind- Medicine, Damanhour University, AlBeheira, Damanhour 22511, Egypt ing of HPSE to the HS and subsequent release of growth © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Al‑Kuraishy et al. AMB Express (2023) 13:13 Page 2 of 13 factors like epidermal growth factor (EGF) and vascu- (Alakunle et  al. 2020). Recently, it has been shown that lar endothelial growth factor (VEGF) (Jayatilleke and HS severs as a co-receptor for spike protein of severe Hulett 2020). The interaction between HPSE and HS trig - acute respiratory syndrome coronavirus type 2 (SARS- gers releases of chemokines and cytokines which affect CoV-2) to binds angiotensin converting enzyme 2 (ACE2) inflammatory response and cell signaling pathways (Jaya - (Fig. 1) (Yu et al. 2021). tilleke and Hulett 2020). HPSE is involved in progression In this bargain, due to involvement of HS proteoglycan of many diseases including viral infections and cancer. in both MPXV and SARS-CoV-2 infections, this study Expression of HPSE is link with propagation of angiogen- aimed to find the potential link between SARS-CoV-2 esis, metastasis and enhancement of tumor progression infection and MPXV infection regarding HPSE level. (Masola et al. 2018). HS is consisting of a core protein and glycosaminogly- Heparanase in viral infections can (GAG), like syndecan and perlecan. HS proteoglycans HPSE is regarded as a connection between HS and viral are mainly expressed on the cell membrane (Masola et al. infections, since HS represents a first line of interac - 2018; Qiao et al. 2020). HS is degraded by HPSE, and HS tion between host cells and viral particles. Direct regu- promotes cell adhesion and motility as well; it binds and lation of HS by HPSE increases risk of viral binding and prevents degradation of chemokines, cytokines, morpho- entry (Agelidis and Shukla 2020). As well, expression of gens and growth factors (Qiao et  al. 2020). Of note, HS HPSE is induced and up-regulated during viral infec- acts as an endocytosis receptor regulates degradation of tions resulting in degradation of HS and release of pro- extracellular molecules, and increasing trans-endothelial inflammatory cytokines. For example herpes simplex transmission of chemokines. Through proteolytic shed - virus (HSV) increases expression of HPSE with subse- ding of perlecan and syndecan, HS promotes regulation quent development of inflammatory changes (Agelidis of intracellular stress which maintains development of and Shukla 2020). Koganti et  al., revealed that higher stem cell (Zhang et al. 2014). expression of HPSE induced by HSV infection in mice Notably, the negatively charged HS can interacts and resulted in worsening ocular symptoms (Gross-Cohen acts as a receptor for the positively charged viral glyco- et  al. 2021). Similarly, human papilloma viruses (HPV) proteins of different viruses. In this state, the viruses use block p53 which limit HPSE activation and expression. these interactions to augment their load and increase Release of chemokines, cytokines and growth factors in their chance to bind more entry receptors (Rusnati HPV infection is augmented due to degradation of HS by et  al. 2009). Moreover, HS acts as specific receptor for HPSE, thus p53 activators like pyranoside decrease HPSE Orthopoxviruses including monkeypox virus (MPXV) activation (Hirshoren et al. 2014; Song et al. 2016). Fig. 1 Role of heparan sulfate (HS) in the entry of SARS‑ CoV‑2: HS serves as a co ‑receptor for spike protein of SARS‑ CoV‑2 to binds angiotensin converting enzyme 2 (ACE2). HS binding compounds may compete with the viral particles for attachment to the HSPGs, thus inhibiting the viral engagement of HS chains and the subsequent access to the ACE2 receptor. Consequently, the viral entry by either fusion or endocytosis may be impaired A l‑Kuraishy et al. AMB Express (2023) 13:13 Page 3 of 13 Furthermore, respiratory syncytial virus (RSV) up- macrophage activation and release of pro-inflamma - regulates expression of HPSE during acute respiratory tory cytokines (Takeda and Akira 2004). Furthermore, infection with exaggeration of respiratory inflammation activated macrophages can secret pro-inflammatory (Tao et al. 2014. Su et al., revealed that HS is involved in cytokines like TNF-α which increase expression of HPSE. the pathogenesis of Japanese encephalitis virus (JEV) (Su As well, activated macrophages release cathepsin L which et  al. 2001). However, highly sulfated dextran, heparin also activates expression and activation of HPSE with and GAGs inhibit binding and entry of JEV in BHK-21 subsequent propagation of hyperinflammation state cell line (Su et al. 2001). Thus, heparin could be effective which promote neovascularization and tumorigenesis against development of infection by JEV (Su et al. 2001). (Lerner et al. 2011). As well, human immune deficiency virus 1 (HIV-1) It has been reported that activated T cells can release interacts with HS before to be recognized by CD4, caus- HPSE which increase binding of T cells to the extracel- ing augmentation of infection (Connell and Lortat-Jacob lular matrix proteins (Goldshmidt et  al. 2003). This 2013). HS acts as co-receptor for binding of HIV-1 to mechanism is depending on presence of β1 integrin and pg120. Thus, HS mimetic may inhibit the interaction vascular cell adhesion molecule 1 (VCAM-1) on T lym- between HIV-1 and pg120 (Connell and Lortat-Jacob phocytes and endothelial cells respectively (Goldshmidt 2013). HS is also used by many pathogens including plas- et  al. 2003). Furthermore, HPSE can stimulate activation modium falciparum, pseudomonas aeruginosa, mycobac- of natural killer (NK) cells through activation of natural terium tuberculosis, borrelia budrdorferi and hepatitis cytotoxic receptors which increase expression of pro- viruses (Spillmann 2001; Liu and Thorp 2002; Vivès et al. inflammatory cytokines. In this state HPSE has ability to 2006; Bartlett and Park 2010; Tiwari et al. 2012). Different remove HS which act as a co-ligand in preventing activa- studies illustrated that elimination of HS augments cell tion of NK cells (Mayes et al. 2017). resistance to the many viral infections. However, soluble Notably, HPSE increases activation and release of HS like heparin and dextran bind the circulating viruses VEGF which normally sequestered by HS (Elkin et  al. and prevent their binding to the cell membrane HS 2001). It has been reported that VEGF is activated during (Urbinati et al. 2008; Walker et al. 2002). The interaction viral infections (Fleming et  al. 2015). Releasing of VEGF between HS and viral molecules may cause adaptation by HPSE-dependent mechanism is occurs via degrada- changes with increasing affinity to HS (Bear et al. 2006). tion of HS bounded to the VEGF(Elkin et  al. 2001). In Taken together, HS increases entry and pathogenesis addition, HPSE encourage release of EGF and TGF-α via of viruses but HS derived molecules may have antiviral activation of ERK and MAPK signaling pathways (Koro- effects, thus these molecules could be effective thera - glu et al. 2010). peutic tools (Hu et al. 2011). These observations suggest Interestingly, HPSE assists in egress of various viruses that HS plays a critical role in the pathogenesis of viral like HSV from host immune response by releasing of infections. bounded HS from invading virus. HPSE increases shed- ding of syndecan from host cell membrane through Heparanase and immune response activation release of matrix metalloproteinase (MMP) HPSE has a crucial role in the activation of macrophage (Surviladze et al. 2015). As well, virus binding to HS can and release of pro-inflammatory cytokines during viral be released outside the infected cells without immune infections (Wagner et  al. 2021). Non-enzymatic activa- recognition (Surviladze et  al. 2015). Cleaving of HS by tion of HPSE promotes cytokine expression, suggesting HPSE increases viral release and infectivity, herein phar- that HS is not necessary in HPSE-induced macrophage macological inhibition of HPSE may reduce viral release activation (Wagner et  al. 2021). Besides, in  vitro study and pathogenesis of viral infections (Surviladze et  al. demonstrated that macrophage inflammatory protein 2 2015). Activation of HPSE during viral infection may (MIP-2) can induces activation of HPSE (Wagner et  al. increase disease severity by inhibiting release of type 1 2021). Notably, HPSE increases polarization of mac- interferon which has potent antiviral effect (Agelidis et al. rophage to tumorigenic phenotype (Fig.  2) (Bhattacha- 2017). rya et  al. 2020). Furthermore, HS HS fragments cleaved These verdicts pointed out that HPSE has important by HPSE induces activation of toll-like receptor 4 (TLR- immunological effects through activation of macrophage, 4) which promote activation of inflammatory signal - T cell and NK cells with stimulation of inflammatory ing pathways including JNK, ERK and p38 trigger some signaling pathways and growth factors during viral infec- cytokines necessary for macrophage activation (Wag- tions. These changes may increase disease severity during ner et  al. 2021). Likewise, activation of TLR-4 by HS viral infections. So, targeting of HPSE by specific antag - and HPSE stimulate a series of inflammatory signaling onists may reduce immunological overreaction during pathways like NF-κB, PI3K and MAPK which provoke viral infections. Al‑Kuraishy et al. AMB Express (2023) 13:13 Page 4 of 13 Fig. 2 Heparanase (HPSE) and macrophage activation: HPSE activates resting macrophage to be converted to activated macrophage with activation of cytokine receptors. HPSE via HPSE receptors increases expression of Fgr1 and NF‑κB which induces expression and release of pro‑inflammatory cytokines like IL ‑6 and IL ‑2. HPSE and pro ‑inflammatory cytokines also stimulate the activated macrophage to release more of pro‑inflammatory cytokines Heparanase in Covid‑19 that Covid-19 may cause extra-pulmonary manifesta- Coronavirus disease 2019 (Covid-19) is an existing tions including acute kidney injury, thromboembolic pandemic disease caused by severe acute respiratory disorders, gastrointestinal and neurological complica- syndrome coronavirus virus respiratory type 2 (SARS- tions (Al-Kuraishy et  al. 2020a, Al-Kuraishy et  al. 2022, CoV-2) (Al-Kuraishy et  al. 2021a, Al-Kuraishy et  al. 2021e). Generally, Covid-19 is typically asymptomatic 2022c). SARS-CoV-2 is a single strand RNA virus from in about 85% of affected patients. Though, 15% of the Betacoronavireadae family, which has a close-up genetic affected patients presented with severe dyspnea and criti - correspondence with other coronaviruses like bat coro- cal respiratory symptoms due to promulgation of acute navirus, SARS-CoV and Middle East Respiratory Syn- lung injury (ALI). Additionally, 5% of Covid-19 patients drome coronavirus virus (MERS-CoV) (Al-Kuraishy et al. require hospitalization and intensive care unit (ICU) 2021b,2022c). SARS-CoV-2 was originally appeared in admission due to progression of acute respiratory dis- Wuhan, China, led to unrecognized pneumonia named tress syndrome (ARDS) (Al-Kuraishy, Al-Gareeb, Qusty, Wuhan pneumonia (Al-Kuraishy et  al. 2021c). Further, et  al. 2021f, Al-Kuraishy et  al. 2022). Severely affected this virus was renamed as a novel coronavirus virus 2019 Covid-19 patients may necessitate invasive oxygen sup- (nCov2019). Then the world health organization (WHO) plementation and mechanical ventilation (Al-Kuraishy declared this disease as a pandemic and renamed this et al. 2021f, Al-Kuraishy et al. 2022g). virus to SARS-CoV-2 (Al-Kuraishy et al. 2021d). Covid-19 Management of Covid-19 patients is mostly supportive is considered as a respiratory disease causing respiratory and symptomatic alleviate as explicit anti-SARS-CoV-2 symptoms similar to the flue like illness characterized by was not build up till now in spite of advance of effective fever, headache, dry cough, dyspnea, myalgia, joint pain, vaccines. Noteworthy, numerous repurposed agents like and anosmia (Al-Kuraishy et al. 2021e, Al-Kuraishy et al. ivermectin, remdesivir, and favipiravir were incorporated 2022 2021d). Further scrutinized researches exposed in dissimilar therapeutic protocols in the management of A l‑Kuraishy et al. AMB Express (2023) 13:13 Page 5 of 13 Covid-19 (Carlotti et  al. 2020, Al-Kuraishy et  al. 2022h). and syndecanes are increased during sepsis-induced Though, these agents did not fashioned to be effectual endothelial dysfunction (Iba and Levy 2019). In SARS- therapeutic agents in the eradication of SARS-CoV-2, CoV-2 infection degradation of HS by HPSE induces thus prolong searching for novel anti-SARS-CoV-2 activation of bradykinin with development of pulmonary agents is a type of brave nowadays (Carlotti et al. 2020). inflammation and ARDS. Normally, HS inhibits brady - In SARS-CoV-2 infection, HPSE is increased leading kinin activation so over-activation of HPSE in Covid-19 to degradation of endothelial glycocalyx with increment with degradation of HS provokes activation of bradykinin of vascular inflammation and leakage with subsequent (Liu et  al. 2020). Besides, deregulation of renin-angio- development of endothelial dysfunction (ED) a hallmark tensin system (RAS) due to downregulation of ACE2 of Covid-19 (Buijsers et  al. 2020). A prospective study increases circulating level of angiotensin II (AngII) with involved 48 Covid-19 patients compared to 10 healthy subsequent development and propagation of endothelial controls illustrated that HPSE and HS serum levels were dysfunction (Al-Kuraishy et  al. 2020b, Al-Kuraishy, Al- increased in Covid-19 patients as compared to the con- Niemi, et  al. 2020; Al-Kuraishy, Al-Gareeb, Alzahrani, trols (Buijsers et al. 2020). Higher HPSE level was linked Alexiou, et al. 2021). Different studies showed that AngII with Covid-19 severity and ICU admission (Buijsers et al. had ability to induce expression of HPSE and endothe- 2020). Nadir and colleagues found that higher expression lin-1 (ET-1) which also promote HPSE expression (Van of HPSE and HS are correlated with Covid-19 severity den Hoven et  al. 2009; Hong et  al. 2004). As well, AngII (Nadir and Brenner 2021). HPSE is increased in elderly enhances bradykinin activation and development of ED subjects by whom pulmonary HS and other GAGs are (Hasan et al. 2021). reduced with increasing risk of SARS-CoV-2 infection in Over-activation of HPSE and releases of HS in severe elderly (Nadir and Brenner 2021). It has been proposed SARS-CoV-2 infection induce activation of macrophage that increasing HPSE in older age individuals enhances through TLR-4 with subsequent release of pro-inflam - degradation of HS in lung and endothelial cells with matory cytokines (Buijsers et al. 2020). Free HS acts as a more risk for development of ARDS and ED in Covid-19 pro-inflammatory agent provokes immune cells stimula - patients (Nadir and Brenner 2021). tion (Buijsers et  al. 2020). In turn, exaggerated immune Notably, endothelial glycocalyx which cover the response and hypercytokinemia in severe SARS-CoV-2 endothelial cells has an important role in maintaining of infection promote HPSE expression in a positive feed- vascular endothelial homeostasis. Disruption of endothe- back loop (Buijsers et  al. 2020, Al-kuraishy et  al. 2022). lial glycocalyx is associated with poor clinical outcome Therefore, inhibition of HPSE by low molecular weight in severely affected Covid-19 patients (Stahl et al. 2020). heparin (LMWH) may reduce endothelial injury and A clinical study included severely affected Covid-19 exaggeration of immune response by inhibiting release of patients at ICU showed that biomarkers of endothelial pro-inflammatory cytokines (Shen et  al. 2022). In addi - glycocalyx injury like HPSE and HS were increased as tion, prophylactic use of LMWH in Covid-19 patients compared to healthy controls (Stahl et  al. 2020). Thus, can decrease HPSE expression and activation (Shen et al. HPSE inhibitors may reduce development of ED by sup- 2022). However, HPSE level remains elevated in severely pressing injury of endothelial glycocalyx in Covid-19 affected Covid-19 patients despite use of LMWH (Bui - patients (Fig. 3) (Rus et al. 2022). jsers et  al. 2020). This feature suggest that early use of Of note, ED is associated with development of Covid- LMWH may reduce HPSE level by preventing endothe- 19 complications including ARDS and acute kidney lial glycocalx injury but use of LMWH in the late phase of injury (AKI) (Al-Kuraishy et  al. 2022). HS is the main Covid-19 may not reduce HPSE level as it released in the GAG present in the endothelial cells glycocalyx. HS early stage mainly in severely affected Covid-19 patients. due to its negative charge can play an important role in These observations proposed that HPSE and HS are maintaining of charge-dependent endothelial barrier highly deranged in Covid-19 leading to activation release function(Talsma et  al. 2018). Degradation of endothelial of pro-inflammatory cytokines and increase risk for HS by HPSE impairs glycocalyx barrier and endothe- development of cytokine storm. As well, HPSE and HS lial function. This interaction promotes generation serum levels could be potential biomarkers for assess- of pro-inflammatory glycocalyx which trigger bind - ment of Covid-19 severity. ing of pro-inflammatory cytokines to the endothelial cells (McDonald et  al. 2016). La Riviere and Schmidt Heparanase and coagulopathy in Covid‑19 observed that injury of pulmonary endothelial glycoca- It has been shown that severe SARS-CoV-2 infection lyx during sepsis promotes development of ALI, ARDS is associated with development of thrombotic lead- and alveolar micro-vascular dysfunction (LaRivière and ing to pulmonary micro-thrombosis and development Schmidt 2018). Biomarkers of glycocalyx injury like HS of ARDS. As well, Covid-19 may induce progression of Al‑Kuraishy et al. AMB Express (2023) 13:13 Page 6 of 13 Fig. 3 Glycocalyx injury in Covid‑19 and systemic complications: Co ‑morbidities like old age, diabetes and cardiovascular disorders together with SARS‑ CoV‑2 induce glycocalyx injury with development of endothelial dysfunction, blood vessel leakage and coagulation disorders. These changes lead to organ damage, multi‑ organ failure, and death. Covid‑19‑induced glycocalyx injury is mediated by cytokine storm, immune cell infiltration, and direct cellular injury systemic thrombosis and disseminated intravascular HPSE and degradation of HS can cause coagulopathy coagulopathy (DIC). These changes are developed due to through induction expression of TF and TFPI (Kinaneh SARS-CoV-2 infection-induced ED [Fig. 4]. (Asakura and et  al. 2021). In addition, HPSE facilitates the interaction Ogawa 2021; Al-Kuraishy et al. 2021e). between TF and activated VII with consequent escalation Activation of HS and HPSE may be implicated in the of thrombosis (Kinaneh et  al. 2021). As well, activated pathogenesis of coagulopathy. Normally, tissue fac- platelets produce and release HPSE with further throm- tor (TF) is the chief initiator of coagulation; it is not botic development (Kinaneh et al. 2021). expressed by endothelial cells under physiological condi- Of note, HS enhances SARS-CoV-2 and other coronavi- tion (Reeves et al. 2018). Though, during systemic inflam - rus infections to bind ACE2 with further viral entry (Hao mation and dysregulation of RAS, the expression of TF et al. 2021). Likewise; SARS-CoV-2 induces expression of by the endothelial cells is augmented (Reeves et al. 2018). HPSE with more degradation of HS in endothelial glyco- TF induces coagulation cascade as it act as a receptor calyx (Buijsers et al. 2020). Interestingly, up-regulation of for clotting factor VII (Zhao et  al. 2021). TF is modu- HPSE in SARS-CoV-2 infection could the potential cause lated by many endogenous proteinases expressed on for development of coagulopathy and fatal complications the endothelial cells, called TF pathway inhibitor (TFPI) (Buijsers et  al. 2020). u Th s, administration of LMWH in (Zhao et  al. 2021). Therefore, activation of TF and TFPI severely affected Covid-19 patients may decrease risk of trigger development of thrombosis in severe viral infec- thrombotic complications by inhibiting HPSE expression tions and cancer (Zhao et  al. 2021). Over-expression of and activation of TF/TFIP axis (Grandone et  al. 2021). A l‑Kuraishy et al. AMB Express (2023) 13:13 Page 7 of 13 Fig. 4 Coagulopathy in Covid‑19: SARS‑ CoV‑2 infection leads to inflammatory reactions, endothelial dysfunction, platelet dysfunction and increase release of histone and nucleosomes. These changes trigger activation of coagulation cascade with thrombotic disorders and increase D‑ dimer. Fibrinogen and D‑ dimer activate release of pro‑inflammatory cytokines Furthermore, HS mimetic compounds like pixatimod activated HPSE increases activation and polarization which is a potent inhibitor of HPSE might be of value of macrophages, T cells and NK cells with induction in the management of Covid-19 by inhibiting HPSE- expression of TLR4 (Wagner et al. 2021) (Bhattacharya induced inflammation and coagulopathy (Guimond et al. et  al. 2020; Goldshmidt et  al. 2003; Mayes et  al. 2017). 2022). Besides, activation of HPSE promotes expression of These findings indicate that activated HS/HPSE in inflammatory signaling pathways including NF-κB, SARS-CoV-2 infection may participate in the progres- PI3K and MAPK which increase macrophage activation sion of coagulopathy. u Th s, LMWH and HS mimetic and release of pro-inflammatory cytokines (Takeda and can reduce HPSE in SARS-CoV-2 infection with further Akira 2004). In addition, activated macrophages can attenuation of thrombotic complications. secret pro-inflammatory cytokines like TNF-α which increase expression of HPSE (Takeda and Akira 2004). Additionally activated macrophages release cathepsin L Heparanase and cytokine storm in Covid‑19 which also increases HPSE expression with propagation Cytokine storm (CS) in Covid-19 is propagated due of hyperinflammation state (Lerner et  al. 2011). Differ - to complex immunological response characterized by ent studies observed that higher expression of inflam - over-activation of T1h immune response and weak matory signaling pathways in severe Covid-19 may IFN response with subsequent stimulation of inflam - increase risk for development of CS by inducing release matory signaling pathways and excessive release of of pro-inflammatory cytokines and chemokines (Kim pro-inflammatory cytokines (Hu et  al. 2021). Develop - et al. 2021; Yang et al. 2021). ment of CS is correlated with Covid-19 severity due These judgements proposed that higher HPSE expres - to hypercytokinemia-induced organ injury (Hu et  al. sion in Covid-19 may linked with development of CS and 2021). Remarkably, activation of HPSE with subse- disease severity. Targeting of HPSE in the early stage of quent release of pro-inflammatory HS promotes release Covid-19 may reduce propagation of CS and associated of pro-inflammatory cytokines with development life-threatening complications. of CS during sepsis (Vlodavsky et  al. 2021). Of note, Al‑Kuraishy et al. AMB Express (2023) 13:13 Page 8 of 13 Heparanase in Monkeypox Transmission of MPXV is frequently occurring through Monkeypox (MPX) is one of common zoonotic disease direct contact and respiratory droplets. Sexual contact caused by a double strand DNA MPX virus (MPXV) with animals could be a probable cause (Organization belonging of Orthopoxvirus genus/ Poxviridae family. 2022). The skin rashes go in various stages before form - MPXV is extremely pathogenic for human subsequent to ing scab which finally fall out. Two third of patients have the eradication of smallpox in 1980 (Alkhalil et  al. 2010; skin lesions on the palms and soles (Organization 2022). Di Giulio and Eckburg 2004). The natural host of MPXV Diagnosis of human MPX is done depending on the is not certainly identified, though it infects a wide-spec - clinical features and history for contacts with animals. trum of animal and mammalian species. MPX is mostly Polymerase chain reaction (PCR) of samples from skin endemic in Democratic Republic of Congo (DRC) and lesions is definitive for the final diagnosis. Blood PCR some area of Ivory Coast (Alkhalil et  al. 2010; Di Giulio is not a definitive since MPXV is no longer persisting in and Eckburg 2004). Particularly, there are two clades of the blood (Organization 2022). Human MPX in severe MPXV that vary clinically and epidemiologically. Central conditions may lead to various complications including African clade (Congo Basin clade) characterized by ele- bronchopneumonia, acute respiratory distress, sepsis, vated case fatality rate (CFR) about 11% with confirmed gastrointestinal complications, dehydration, encephali- person-to-person transmission. Though, West African tis, and visual loss due to involvement of cornea. Human clade is characterized by low CFR about 1% without per- MPX may be misdiagnosed with chickenpox, small- son- to- person transmission (Likos et al. 2005). pox, anthrax and HIV-induced skin lesion (Adalja and MPX was initially documented in 1958 as smallpox-like Inglesby 2022). disease in the laboratory monkeys in Denmark by Preben von Magnus (Xiang and White 2022). The first reported Pathogenesis and immunological response case of human MPX was in 1970, and on 1972 a case of of MPXV human MPX was recognized a 9-month neonate in DRC Human MPX is caused by an enveloped dsDNA MPXV (Xiang and White 2022). A sum number of 50 reported which has 250 nm width and 170–250 kb in size of DNA cases of human MPX were established from 1970 to genome. MPXV consist of surface tubules, outer enve- 1979, two thirds of these cases being from DRC (Breman lope of extracellular virion, lateral bodies, plasid layer, et  al. 1980). Meyer et  al., reported that by end of 1986 core fibrils, and outer membrane of intracellular and more than 400 cases of human MPX characterized by extracellular virions (Fig. 5). 10% CFR were identified in West and Central Africa that MPXV enters the mucous membrane of mouth, eye was design as a first outbreak (Meyer et  al. 2002). The and respiratory tracts (Guarner et al. 2004). Similar to the second outbreak of human MPX was identified in DRC other Orthopoxviruses, entry of MPXV into host cells is in a period between 1996 and 1997 (Qiao et al. 2020). In a achieved by binding to the glycosaminoglycan (GAGs) period from 1991 to 1999 a 511 reported cases of human on the cell membrane, which mediate viral endocyto- MPX were celebrated in DRC (Meyer et al. 2002). sis (Guarner et  al. 2004). In the cytoplasm the viral core The clinical picture of human MPX is highly identical and genomes are released with succeeding replication to that of smallpox, nevertheless early lymphadenopa- of viral proteins by viral DNA polymerase. Indeed, viral thy in human MPX is the distinguishing sign not present structural proteins are produced within 48  h post-infec- in smallpox. The incubation period is 1–3  weeks, fever, tion with subsequent assembly into mature virions in the headache, joint pain, myalgia and nausea for about 3 days Golgi apparatus. From Golgi apparatus, the mature viri- (Minhaj et al. 2022). Skin lesions which appear 1–3 days ons are transported by microtubules to the plasma mem- subsequent fever and lymphadenopathy are typically brane and released outside the infected cells to infect appearing at the same time on the face and periphery other cells in the same manner (Likos et al. 2005). (Weinstein et al. 2005) (Adler et al. 2022). Lymphadenop- There are four types of GAGs including HS, chondrio - athy characterized by lymph node enlargement mainly in tin/dermatan sulfate, keratin sulfate and hayluronic acid the neck, groin, and submandibular area. The skin lesions (Bartlett and Park 2010; Gandhi and Mancera 2008; Sodhi cover all the body in severe cases. The skin lesions started and Panitch 2020). GAGs are complex carbohydrate as a small flat spot which become small bumps (papules) ubiquitously expressed on cell surface and extracellular which later filled with clear fluid and then with yellow matrix. The interactions between GAGs and microbial fluid, sometimes merge to form large lesions. The lesions pathogens represent a defense line against invasion (Lin progress in the same time similar to that of smallpox, fol- et  al. 2020). Several pathogens including MPXV induce lowing healing the lesions leaves pale marks which finally release of GAGs with formation of soluble GAGs which become darks (Adalja and Inglesby 2022). coat the pathogen to escape immune detection (Akhtar A l‑Kuraishy et al. AMB Express (2023) 13:13 Page 9 of 13 Fig. 5 Structure of monkeypox virus: Human MPX is an enveloped dsDNA MPXV which has 250 nm width and 170–250 kb in size of DNA genome. MPXV consist of surface tubules, outer envelope of extracellular virion, lateral bodies, plasid layer, core fibrils, and outer membrane of intracellular and extracellular virions and Shukla 2009; Hughes et  al. 2014). HS together with immunosuppressive effect of MPXV as evident by reduc - sialic acid are highly expressed in dermal and epidermal tion of T lymphocytes in MPX (Townsend et  al. 2013; cells that enhance binding and entry of MPXV to the skin Hammarlund et al. 2008). (Hughes et al. 2014). Different studies showed that binding of MPXV to the In MPXV like other Orthopoxviruses there is activa- HS may induce activation of HPSE and release of pro- tion of genes concerned in activation expression of pro- inflammatory cytokines (Khanna et  al. 2017; Bhatt et  al. inflammatory cytokines and chemokines like IL-6 and 2021; Kindrachuk et  al. 2012). In severe MPXV infec- CCL-2 respectively (Bourquain et  al. 2013). As well, tion, activation of inflammatory signaling pathways with MAPK and ERK are activated by MPXV which encour- release of pro-inflammatory cytokines may lead to the age viral entry, viral replication and augment expression development of CS. It has been shown that MPX may of viral proteins needed for viral replication (DuShane causes fatal complications like sepsis, bronchopneumo- and Maginnis 2019). Furthermore, heat shock protein 1 nia and ALI (Stittelaar et  al. 2005) which might develop (HSP-1) is necessary for replication of MPXV so it highly due to propagation of CS. Stanford et  al. observed that induced during infection with MPXV (Filone et al. 2014). severity of MPX and smallpox was related to the direct Notably, MPXV induces activation of NF-κB through cytopathic effect and immunopathological changes due suppression of signal transducer and activator of tran- to release of immunomodulatory molecules. Invasion of scription (STAT) which has antiviral effects (Filone injured tissues by immune and inflammatory cells due to et  al. 2014). Besides, MPXV activates NK cells to release exaggerated immune response may cause extensive tissue interferon gamma (INF-γ) and TNF-α which stimulate damage due to propagation of CS (Stanford et al. 2007). Th1 immune response (Filone et  al. 2014). Overall, due to selective tropism of lymphoid tissues, MPXV can The potential link between MPX and Covid‑19 induce lymphopenia and lymphadenopathy (Townsend In both Covid-19 and MPX, lymphopenia is developed et  al. 2013). Inhibition of CD4 and CD8 as well as main- by different mechanisms. Direct injury of lymphocyte taining of major histocompatibility complex 1 (MHC1) by SARS-CoV-2, lymphocyte exhaustion and sequestra- could be the probable mechanism for immune evasion tion of lymphocytes in the lymphoid tissues could be the of MPXV (Hammarlund et  al. 2008). MPXV can evade possible cause of lymphopenia in Covid-19 (Fathi and the immune response through release of viroceptors Rezaei 2020). Similarly, exaggeration immune response and virokines which are like to the host cytokines. These and development of CS may induce lymphocyte apopto- annotations may clarify the immunosuppressive effect of sis inhibit bone marrow proliferation and production of MPXV as evident by reduction of T lymphocytes in MPX lymphocytes (Fathi and Rezaei 2020). Of note, lympho- (Hammarlund et  al. 2008). Consequently, the immune penia is associated with Covid-19 severity due to loss of response unlike other viral infections is complex and anti-inflammatory function of lymphocytes (Fathi and need further attention. These verdicts may explain the Rezaei 2020). A systematic review and meta-analysis Al‑Kuraishy et al. AMB Express (2023) 13:13 Page 10 of 13 from 24 studies included 3099 Covid-19 patients showed that lymphopenia at time of admission is linked with poor clinical outcomes and high mortality (Huang and Pranata 2020). In MPX, lymphopenia is a characteristic pathognomic feature due to lymphotropism of MPXV with inhibition release of lymphocytes (Mucker et  al. 2015). As well, abnormal immune response and hypercy- tokinemia in MPX exhausts circulating lymphocytes with development of lymphopenia (Stanford et al. 2007). Furthermore, over-expression of HPSE in both Covid- 19 and MPX with higher immune response may induce propagation of lymphopenia (Digre et al. 2017). Of note, inflammatory signaling pathways and pro-inflammatory cytokines are exaggerated in both Covid-19 and MPX leading to hyperinflammation and development of CS (Buijsers et al. 2020; DuShane and Maginnis 2019). Inter- estingly, degradation and release of pro-inflammatory HS is triggered by HPSE. SARS-CoV-2 and MPXV are impli- cated to induce HPSE expression and dissociation of HS Fig. 6 The possible link between SARS‑ CoV‑2 and MPXV infections: SARS‑ CoV‑2 and MPXV infections activate heparanase (HPSE) leading from cell membrane GAGs (Buijsers et al. 2020; Lin et al. to lymphpenia which cause complications 2020). Pro-inflammatory HS and activated HPSE pro - mote release of pro-inflammatory cytokines which also trigger stimulation of HPSE in a positive loop manner pandemic. Further studies are required to find the magic in SARS-CoV-2 and MPXV infections (Kindrachuk et al. link between MPX and Covid-19. 2012; Yang et al. 2021; Kim et al. 2021). The present review had many limitations like rareness Up-regulation of HPSE in SARS-CoV-2 infection might of clinical studies concerning role MPX in propagation be the potential cause for progression of coagulopa- of thrombotic events and CS which are the hallmark of thy (Buijsers et  al.2020). Though, HPSE expression and Covid-19. As well, HS level and HPSE activity in relation development of coagulopathy was not precisely reported to pro-inflammatory cytokines and inflammatory sign - in MPX (Hutson and Damon 2010). The underlying aling pathways were not listed from previous studies in mechanism of coagulopathy and thrombotic events in both MPX and Covid-19. Though the present review sug - Covid-19 and MPX could in part relate to HPSE expres- gests that HPSE could be the latent link between MPX sion. u Th s, administration of LMWH in severely affected and Covid-19. Covid-19 or MPX patients may reduce risk of thrombotic complications by inhibiting HPSE expression and activa- tion of TF/TFIP axis (Hutson and Damon 2010) (Gran- Conclusions done et  al. 2021). What’s more, HS mimetic compounds HPSE is an endoglycosidase cleaves heparin sulfate (HS) like pixatimod which is a potent inhibitor of HPSE could and this contributes to the degradation and remodeling be of value in the management of Covid-19 and MPX by of the  extracellular matrix. HS cleaved by HPSE induces inhibiting HPSE-induced inflammation and coagulopa - activation of autophagy and formation of autophago- thy (Hutson and Damon 2010; Guimond et al. 2022). somes which facilitate binding of HPSE to the HS and These findings and observations proposed that HPSE consequent release of growth factors and pro-inflam - expression which involved in the progression hyperin- matory cytokines. The interface between HPSE and HS flammation, CS, and coagulopathy could be the poten - triggers releases of chemokines and cytokines which tial link between Covid-19 and MPX (Fig.  6). Targeting influence inflammatory response and cell signaling of HPSE by treatment with LMWH in severely affected pathways with propagation of hyperinflammation, CS, Covid-19 or MPX patients may reduce risk of thrombotic and thrombotic events. HPSE expression is induced and inflammatory complications. In addition, MPX- by both SARS-CoV-2 and MPXV in severely affected induced immunosuppressant effects (Hammarlund et  al. patients leading to induction release of pro-inflammatory 2008) may increase risk of SARS-CoV-2 infection. Co- cytokines, endothelial dysfunction, and coagulopathy. infection of MPX with SARS-CoV-2 may occur as we Co-infection of MPX with SARS-CoV-2 may occur as we facing many outbreaks of MPX cases during Covid-19 facing many outbreaks of MPX cases during Covid-19 A l‑Kuraishy et al. AMB Express (2023) 13:13 Page 11 of 13 Al‑Kuraishy HM, Al‑ Gareeb AI, Alblihed M, Cruz‑Martins N, Batiha GE (2021) pandemic. Therefore, targeting of HPSE by specific inhib - COVID‑19 and risk of acute ischemic stroke and acute lung injury in itors like LMWH may reduce risk of complications in patients with type ii diabetes mellitus: the anti‑inflammatory role of both SARS-CoV-2 and MPXV infections. Taken together, metformin. Front Med. 1:110 Al‑Kuraishy HM, Al‑ Gareeb AI, Alblihed M, Guerreiro SG, Cruz‑Martins N, Batiha HPSE could be a potential link between MPX with SARS- GE (2021) COVID‑19 in relation to hyperglycemia and diabetes mellitus. CoV-2 in Covid-19 era. In this regards, various experi- Front Cardiovasc Med. 8:644095 mental, preclinical, and clinical studies are warranted to Al‑Kuraishy HM, Al‑ Gareeb AI, Alzahrani KJ, Alexiou A, Batiha GE (2021) Niclosa‑ mide for Covid‑19: bridging the gap. Mol Biol Rep. 48(12):8195–202 explore and confirm the possible role in the pathogenesis Al‑Kuraishy HM, Al‑ Gareeb AI, Alzahrani KJ, Cruz‑Martins N, Batiha GE (2021) of SARS-CoV-2 and MPXV infections. The potential role of neopterin in Covid‑19: a new perspective. Mol Cell Biochem. 476(11):4161–6 Acknowledgements Al‑Kuraishy HM, Al‑ Gareeb AI, Faidah H, Al‑Maiahy TJ, Cruz‑Martins N, Batiha Not applicable. GE (2021) The looming effects of estrogen in Covid‑19: a rocky rollout. Front Nutr. 8:649128 Author contributions Al‑Kuraishy HM, Al‑ Gareeb AI, Qusty N, Cruz‑Martins N, Batiha GE (2021) Conceptualization, HMA, AIA, HFH, GEB; methodology, HMA, AIA, HFH, GEB; Sequential doxycycline and colchicine combination therapy in Covid‑ formal analysis, HMA, AIA, HFH, GEB.; writing original draft, HMA, AIA, HFH, GEB; 19: The salutary effects. Pulm Pharmacol Ther. 67:102008 AA, MP, writing the revised manuscript and critical revision. All authors have Al‑Kuraishy HM, Al‑ Gareeb AI, Al‑Hussaniy HA, Al‑Harcan NA, Alexiou A, Batiha read and approved the final manuscript. GE (2022) Neutrophil Extracellular Traps (NETs) and Covid‑19: A new frontiers for therapeutic modality. Int Immunopharmacol 6:108516 Funding Al‑Kuraishy HM, Al‑ Gareeb AI, Onohuean H, El‑Saber Batiha G (2022) COVID ‑19 Open Access funding enabled and organized by Projekt DEAL. and erythrocrine function: the roller coaster and danger. Int J Immuno‑ pathol Pharmacol. 4:36 Availability of data and materials Al‑Kuraishy HM, Batiha GE, Faidah H, Al‑ Gareeb AI, Saad HM, Simal‑ Gandara All generated data are included in this manuscript. J (2022) Pirfenidone and post‑ Covid‑19 pulmonary fibrosis: invoked again for realistic goals. Inflammopharmacology. 31:1 Al‑Kuraishy HM, Al‑ Gareeb AI, Kaushik A, Kujawska M, Batiha GE (2022) Hemo‑ Declarations lytic anemia in COVID‑19. Ann Hematol. 8:1–9 Al‑Kuraishy HM, Al‑ Gareeb AI, Al‑Niemi MS, Alexiou A, Batiha GE (2022) Calpro ‑ Ethics approval and consent to participate tectin: the link between acute lung injury and gastrointestinal injury in Not applicable. Covid‑19: Ban or boon. Curr Prot Pept Sci. 23(5):310–20 Al‑Kuraishy HM, Al‑ Gareeb AI, Alexiou A, Batiha GE (2022) Central effects of Consent for publication ivermectin in alleviation of Covid‑19‑induced dysautonomia. Curr Drug Not applicable. Targets. 23(13):1277–87 Al‑Kuraishy HM, Al‑Fakhrany OM, Elekhnawy E, Al‑ Gareeb AI, Alorabi M, De Competing interests Waard M, Albogami SM, Batiha GE (2022) Traditional herbs against The authors declare no conflict of interest. COVID‑19: back to old weapons to combat the new pandemic. Eur J Med Res. 27(1):1–1 Al‑kuraishy HM, Al‑ Gareeb AI, Elekhnawy E, Batiha GE (2022) Dipyridamole and Received: 17 August 2022 Accepted: 18 January 2023 adenosinergic pathway in Covid‑19: a juice or holy grail. Egypt J Med Hum Genet. 23(1):1–6 Al‑Kuraishy HM, Al‑Niemi MS, Hussain NR, Al‑ Gareeb AI, Al‑Harchan NA, Al‑ Kurashi AH. The potential role of renin angiotensin system (RAS) and dipeptidyl peptidase‑4 (DPP ‑4) in COVID ‑19: navigating the uncharted. References Selected chapters from the reninangiotensin system, Kibel A (Ed). Adalja A, Inglesby T (2022) A novel international monkeypox outbreak. In.: IntechOpen, London. 2020a;1:151–65. 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Journal

AMB ExpressSpringer Journals

Published: Jan 27, 2023

Keywords: Heparanase; SARS-CoV-2; Monkeypox

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