Enhancement of Ebola Virus Infection via Ficolin-1 Interaction with the Mucin Domain of GP Glycoprotein

Abstract

Ebola virus infection requires the surface viral glycoprotein to initiate entry into the target cells. The trimeric glycoprotein is a highly glycosylated viral protein which has been shown to interact with host C-type lectin receptors and the soluble complement recognition protein mannose-binding lectin, thereby enhancing viral infection. Similarly to mannose-binding lectin, ficolins are soluble effectors of the innate immune system that recognize particular glycans at the pathogen surface. In this study, we demonstrate that ficolin-1 interacts with the Zaire Ebola virus (EBOV) glycoprotein, and we characterized this interaction by surface plasmon resonance spectroscopy. Ficolin-1 was shown to bind to the viral glycoprotein with a high affinity. This interaction was mediated by the fibrinogen-like recognition domain of ficolin-1 and the mucin-like domain of the viral glycoprotein. Using a ficolin-1 control mutant devoid of sialic acid-binding capacity, we identified sialylated moieties of the mucin domain to be potential ligands on the glycoprotein. In cell culture, using both pseudotyped viruses and EBOV, ficolin-1 was shown to enhance EBOV infection independently of the serum complement. We also observed that ficolin-1 enhanced EBOV infection on human monocyte-derived macrophages, described to be major viral target cells,. Competition experiments suggested that although ficolin-1 and mannose-binding lectin recognized different carbohydrate moieties on the EBOV glycoprotein, the observed enhancement of the infection likely depended on a common cellular receptor/partner. In conclusion, ficolin-1 could provide an alternative receptor-mediated mechanism for enhancing EBOV infection, thereby contributing to viral subversion of the host innate immune system. E bola virus (EBOV), a member of the Filoviridae family, can cause a severe, often fatal, hemorrhagic fever (HF) in humans and nonhuman primates (1). The first Ebolavirus species was discovered in 1976 in the Democratic Republic of Congo (previously called Zaire), near the Ebola River (2). Subsequently, 28 outbreaks appeared sporadically until March 2014, when the most devastating outbreak occurred in western Africa, including the countries of Guinea, Liberia, and Sierra Leone (3-6). Most outbreaks are caused by the Zaire Ebola virus subspecies (7), which is the most pathogenic (case fatality rate, up to 90%). EBOV is classified in the category A agents of the Centers for Disease Control and Prevention (CDC) because it represents a substantial threat to public health, and consequently, its handling requires a biosafety level 4 (BSL-4) laboratory. The development of effective therapies against EBOV became an urgent priority during the spread of the most recent epidemics throughout Africa, which, in addition to causing the loss of thousands of human lives, caused economic and social instability (8).The trimeric transmembrane glycoprotein (GP) of EBOV plays a crucial role in EBOV infection by mediating its cellular attachment and entry into host cells (9, 1...

A journey through the lectin pathway of complement—MBL and beyond

“…Ficolin‐1 binds to acetylated carbohydrates such as GlcNAc and GalNAc as well as to sialic acid, a hallmark of ‘self’ . In addition, ficolin‐1 binds to certain strains of bacteria and to a viral glycoprotein from Ebola virus . Interestingly, the ligand‐binding activity of ficolin‐1 is pH‐dependent .…”

“…11,115 In addition, ficolin-1 binds to certain strains of bacteria 11,116 and to a viral glycoprotein from Ebola virus. 117 Interestingly, the ligand-binding activity of ficolin-1 is pH-dependent. 14 Also ficolin-2 binds to GlcNAc and GalNAc 96,118 and additionally to the bacterial compounds lipoteichoic acid 119 and 1,3-β-D-glucan.…”

Achieving cross-reactivity with pan-ebolavirus antibodies

“…Initial attachment of filoviruses to target cells is thought to be initiated via interactions between virions and cell surface lectins [19], membrane phosphatidylserine, or TIM-1 proteins [20]. Following internalization by macropinocytosis [21][22][23], the virion enters the endosome.…”

Select membrane proteins modulate MNV-1 infection of macrophages and dendritic cells in a cell type-specific manner

“…Recently, Ebola virus was shown to have enhanced infectivity in vitro when incubated with ficolin-1 prior to infection. Ficolin-1 is thought to function as a bridge molecule in receptor-mediated Ebola virus entry into target cells (Favier et al, 2016). However, whether the enhancement of MNV-1 attachment occurs in a physiological context, remains to be determined in the future.…”