Enhancement of Ebola virus infection by seminal amyloid fibrils

Abstract

The 2014 western Africa Ebola virus (EBOV) epidemic was unprecedented in magnitude, infecting over 28,000 and causing over 11,000 deaths. During this outbreak, multiple instances of EBOV sexual transmission were reported, including cases where the infectious individual had recovered from EBOV disease months before transmission. Potential human host factors in EBOV sexual transmission remain unstudied. Several basic seminal amyloids, most notably semen-derived enhancer of viral infection (SEVI), enhance in vitro infection by HIV and several other viruses. To test the ability of these peptides to enhance EBOV infection, viruses bearing the EBOV glycoprotein (EboGP) were preincubated with physiological concentrations of SEVI before infection of physiologically relevant cell lines and primary cells. Preincubation with SEVI significantly increased EboGP-mediated infectivity and replication in epithelium- and monocyte-derived cell lines. This enhancement was dependent upon amyloidogenesis and positive charge, and infection results were observed with both viruses carrying EboGP and authentic EBOV as well as with semen. SEVI enhanced binding of virus to cells and markedly increased its subsequent internalization. SEVI also stimulated uptake of a fluid phase marker by macropinocytosis, a critical mechanism by which cells internalize EBOV. We report a previously unrecognized ability of SEVI and semen to significantly alter viral physical properties critical for transmissibility by increasing the stability of EboGP-bearing recombinant viruses during incubation at elevated temperature and providing resistance to desiccation. Given the potential for EBOV sexual transmission to spark new transmission chains, these findings represent an important interrogation of factors potentially important for this EBOV transmission route.

When Dendritic Cells Go Viral: The Role of Siglec-1 in Host Defense and Dissemination of Enveloped Viruses

“…Moreover, a recent mathematical model is consistent with a significant contribution of sexual EBOV transmission during the 2014-2016 outbreak in West Africa [149]. Importantly, infectious viral particles are found in semen of EBOV convalescent individuals several months following symptoms onset [150][151][152][153], and seminal fluid amyloids may enhance EBOV infection [154]. As the cytokine TGF-β1 is abundant in semen, and it also upregulates Siglec-1 expression on DCs [155], the role of this receptor should be further assessed in the context of EBOV sexual transmission.…”

From Ancient to Emerging Infections: The Odyssey of Viruses in the Male Genital Tract

“…Seminal plasma, SEVI, and semenogelin amyloids enhanced in vitro infection of isolated cells by HIV-1 (355,488), HIV-2 (355) SIV (775), HSV (690), CMV (673) and EBOV (42) but not that of ZIKV, WNV and DENV, which were inhibited by seminal plasma (487). SEVI also increased the internalization of EBOV particles by macropinocytosis, the canonical EBOV entry pathway, and stabilized EBOV viability and infectivity (42). However, seminal plasma or SEVI A c c e p t e d M a n u s c r i p t enhancement of HIV infection in ano-genital explants was inconsistent (15,315,368) and in vivo experiments using humanized mice (120,148) or NHP models (489) failed to demonstrate any enhancing effect of semen on HIV/SIV transmission.…”

“…The positive charges of the peptides interact with the negatively charged surfaces of cells and virions to form an electrostatic bridge that promotes viral attachment and fusion (29,578). Seminal plasma, SEVI, and semenogelin amyloids enhanced in vitro infection of isolated cells by HIV-1 (355,488), HIV-2 (355) SIV (775), HSV (690), CMV (673) and EBOV (42) but not that of ZIKV, WNV and DENV, which were inhibited by seminal plasma (487). SEVI also increased the internalization of EBOV particles by macropinocytosis, the canonical EBOV entry pathway, and stabilized EBOV viability and infectivity (42).…”

Rapid formation of peptide/lipid co-aggregates by the amyloidogenic seminal peptide PAP248-286

“…Amyloid formed by the PAP 248-286 monomer, known as semen-derived enhancer of viral infection (SEVI), was discovered to be responsible for the large enhancement of HIV infectivity observed in seminal fluid (41). Since its discovery in 2008, SEVI has also been shown to enhance cytomegalovirus, herpes simplex virus type 1 and 2, and ebola virus infection as well as participate in sperm quality control (42–45). The exact mechanism for these activities is still unknown, but it has been hypothesized that the cationic SEVI amyloid can act like a bridge, trapping or bringing cells together (46).…”