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

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 interaction 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-inflammatory 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 inhibitors 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; Monkeypox; SARS-CoV-2.

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

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

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

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

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

Fig. 6

The possible link between SARS-CoV-2 and MPXV infections: SARS-CoV-2 and MPXV infections activate heparanase (HPSE) leading to lymphpenia which cause complications