Does Disruption of Integrins Play a Role on Ebola Virus Hemorrhagic Fever Syndrome?

Abstract

Heterodimeric receptors of the beta1 and beta3 integrin families are shown to play an important role in platelet adhesion and aggregation, which is critical for homeostasis and thrombosis [11]. In particular, GPIIb/IIIa integrant complex on platelets binds to collagen, fibrinogen and Von Willebrand Factor, resulting in platelet activation. This activation triggers the coagulation cascade resulting in blood clot formation and hemorrhage control. Ebola virus glycoprotein’s (GP) are shown to interact with Integrins (beta1) and may be involved in the virus entry. Ebola GP expression also led to the down regulation of integrins [12]. Integrand αV was required for efficient GP-mediated transduction and EBOV infection of macrophages [13]. Binding of Ebola virus GP to aVbIII integrins is also shown to prime the endosomal cathepsins, a necessary step in the Ebola virus entry [14]. VP35 protein (required for viral transcription) of Ebola virus contains RGD (Arg-Gly-Asp) and several RGD like motifs in the Table 1. Interestingly, RGD/KGD peptide motif is a conserved feature of low molecular weight non-enzymatic proteins called as “disinterring” present in snake venoms [15]. These molecules bind to the platelet surface integrins (such as alphaII-beta3), blocking the interaction of the platelets with the natural substrates such as fibrinogen and von Willebrand factor. This blockage results in potential inhibition of platelet aggregation [16] (and thus preventing fibrin clots), a crucial step in homeostasis. Due to the presence of conserved RGD and RGD like motifs in VP35, it is possible that VP35 protein might potentially block/delay platelet aggregation. Delayed platelet aggregation might inhibit blood clotting in response to vascular injury/altered vascular barrier observed in the Ebola virus infected patients, thus exacerbating hemorrhages. Significantly decreased platelet aggregation observed in experimentally infected rhesus macaques supports this theory [17]. Table 1: Arg-Gly-Asp (RGD) and similar motifs present in the VP35 protein of Ebola virus (Accession number AAM76032) with the amino acid residue numbers are shown in the figure. Amino acids are represented by single alphabets according to the standard nomenclature.