Marburg and Ebola virus infections elicit a complex, muted inflammatory state in bats

Abstract

The filoviruses Ebola (EBOV) and Marburg (MARV) cause severe disease in humans. In contrast, the Egyptian rousette bat (Rousettus aegyptiacus), a natural reservoir of MARV, exhibits a subclinical phenotype with limited MARV replication and nearly undetectable EBOV replication. Rousettus cell lines support replication of filoviruses, however. To understand the bat-filovirus interaction, transcriptomes of tissues from EBOV-and MARV-infected R. aegyptiacus bats were analyzed. While viral transcripts were only detected in liver, a systemic response was observed involving other tissues as well. By focusing on evolutionarily divergent (from human homologues) protein-coding genes, we identified novel transcriptional pathways that suggest infected bats exhibit impaired coagulation, vasodilation, aberrant iron regulation, and impaired complement system leading to muted antibody responses. Furthermore, a robust T-cell response and an antiinflammatory state driven by M2 macrophages were identified. These processes likely control infection and limit pathology. All data can be freely explored and downloaded through our tools (http://katahdin.girihlet.com/shiny/bat/). bat-filovirus-jayaprakashWe experimentally infected Egyptian rousettes with EBOV and MARV and analyzed mRNA transcripts from multiple tissue types: liver, kidney, spleen, peripheral blood mononuclear cells (PBMCs), and testes. For that purpose, we compiled a comprehensive list of bat transcripts, based on our sequence data together with existing genome annotations 28 , and, where possible, identified genes with human or mouse homologues.The majority of the differentially-expressed genes upon filoviral infection were common to bats and humans 29 . These genes include components of a number of pathways involved in the innate, inflammatory, acute phase, and adaptive immune responses, as well as in the activation of the complement/coagulation pathway. Despite this broad similarity of the responses, filoviral infections in vivo result in very different outcomes in bats compared to humans. bat-filovirus-jayaprakash 2 bat-filovirus-jayaprakash 4

Traits, phylogeny and host cell receptors predict Ebolavirus host status among African mammals

“…Conversely, an important reservoir for Marburgvirus, Rousettus aegyptiacus [63,64], does not carry the residues thought to confer resistance, carrying instead residues that increase affinity to the virus [26] (S5 Table ). Furthermore, when inoculated with Marburgvirus, R. aegyptiacus tolerates infection and sheds virus [65,66] suggesting the operation of other mechanisms beyond its NPC1 receptors that allow it to fight infection [57]. This discrepancy of R. aegyptiacus not carrying the sequences needed to confer resistance to Ebolavirus was noted by Takadate et al [26] in their study also leading to the conclusion that unique host factors such as interferons likely influence susceptibility to infection.…”

“…Volant species and fast paced species, such as mice ( Mus musculus ), were more likely to survive ( Fig 1A and Table 2 ), supporting one theory that these species regulate inflammatory immune defenses to fight viral infections [ 53 ]. Several studies also suggest that bats have specific immune strategies to fight infections which could allow these species to serve as reservoirs for viruses [ 56 ]; including one study providing evidence of bat responses to Ebolavirus [ 57 ].…”

“…Furthermore, when inoculated with Marburgvirus , R . aegyptiacus tolerates infection and sheds virus [ 65 , 66 ] suggesting the operation of other mechanisms beyond its NPC1 receptors that allow it to fight infection [ 57 ]. This discrepancy of R .…”

“…Kurosaki et al [ 67 ] also showed that small mutations, affecting only two amino acid residues in Zaire ebolavirus compared to wild type strains, can greatly increase infectivity across cell lines expressing NPC1 sequences found in both bats and primates, including humans. More work is clearly needed to identify how binding affinity to NPC1 and host immune responses relates to viral replication within an infected individual (e.g., [ 26 , 57 ]). Sequencing NPC1 gene regions for additional species could also be useful.…”