The Glycoproteins of All Filovirus Species Use the Same Host Factors for Entry into Bat and Human Cells but Entry Efficiency Is Species Dependent

Hoffmann, Markus; González Hernández, Mariana; Berger, Elisabeth; Marzi, Andrea; Pöhlmann, Stefan

Filovirus entry into human cells starts with the attachment of GP to molecules on the cell surface, such as lectins or the human T cell immunoglobulin mucin 1 (TIM-1) surface molecule [25] [26] [27] [28] . In addition, signaling factors like members of the TAM (Tyro3/Axl/Mer) family of tyrosine kinase receptors and α5β1-Integrin have been shown to promote filovirus entry [29] [30] [31] . Upon uptake of EBOV particles into endosomes, the activity of two-pore channels (TPCs, endosomal calcium channels) [32] and GP processing by endosomal pH-dependent cysteine proteases cathepsin B/L are believed to be required for the entry cascade to progress [33] [34] [35] , at least in several cell culture systems. Cleavage removes the MLD and allows binding of the RBD to NPC1 [36, 37] . Subsequently, an incompletely understood trigger is required to start the GP2-driven fusion of the viral and the endosomal membrane, which allows for the DAAD (Deutscher Akademischer Austauschdienst) and CONACYT (Consejo Nacional de Ciencia y Tecnología) by the National Council for Science and Technology in Mexico. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Filovirus glycoproteins and distribution of fruit bats believed to serve as natural reservoir. (A) Phylogenetic tree based on the amino acid (aa) sequences of the glycoproteins (GP) of different filoviruses was generated using MEGA 6 (version 6.06). Viruses from which GPs were examined in the present study are written in bold. Viruses were named as follows: Filovirus species (abbreviation)/Country where the sample specimen originates from (abbreviation)/year of sampling/isolate-specific name (if available). In addition to GPs from viruses that have caused infection in humans and non-human primates, GP sequences of one Reston virus from a pig (diamond), as well as four Marburg virus-related and two Ravn virus-related GP sequences from bats (circles) were included. Construction of the tree was performed by the neighbor joining method with 1,000 bootstrap replications, using the MEGA 6 software (version 6.06). Small numbers at the nodes and the scale bar indicate bootstrap values and the number of aa substitutions per site, respectively. GenBank accession numbers for all GPs are given in brackets after the virus name. release of the viral genetic information in the host cell cytoplasm. Whether the same molecular mechanisms underlie filovirus entry into bat cells is largely unknown, although LLOV entry into human and NHP cells has been reported to depend on NPC1 and cathepsins [38] .