Impact of Měnglà virus proteins on human and bat innate immune pathways

Abstract

<jats:title>Abstract</jats:title><jats:p>Měnglà virus (MLAV), identified in <jats:italic>Rousettus</jats:italic> bats, is a phylogenetically distinct member of the family <jats:italic>Filoviridae</jats:italic>. Because filoviruses Ebola virus (EBOV) and Marburg virus (MARV) modulate host innate immune pathways, MLAV VP35, VP40 and VP24 proteins were compared with their EBOV and MARV homologs for innate immune pathway modulation. In human and <jats:italic>Rousettus</jats:italic> cells, MLAV VP35 behaved like EBOV and MARV VP35s, inhibiting virus-induced activation of the interferon (IFN)-β promoter. MLAV VP35 inhibited IRF3 phosphorylation and interacted with PACT, a host protein engaged by EBOV VP35 to inhibit RIG-I signaling. MLAV VP35 also inhibited PKR activation. MLAV VP40 was demonstrated to inhibit type I IFN induced gene expression in human and bat cells. It blocked STAT1 tyrosine phosphorylation induced either by type I IFN or over-expressed Jak1, paralleling MARV VP40. MLAV VP40 also inhibited virus-induced IFNβ promoter activation, a property shared by MARV VP40 and EBOV VP24. The inhibition of IFN induction was preserved in the presence of a Jak kinase inhibitor, demonstrating that inhibition of Jak-STAT signaling is not sufficient to explain inhibition of IFNβ promoter activation. MLAV VP24 did not inhibit IFN-induced gene expression or bind karyopherin α5, properties of EBOV VP24. MLAV VP24 also differed from MARV VP24 in that it failed to interact with Keap1 or activate an antioxidant response element reporter gene, due to the absence of a Keap1-binding motif. These studies demonstrate similarities between MLAV and MARV in how they suppress IFN responses and differences in how MLAV VP24 interacts with host pathways.</jats:p><jats:sec><jats:title>Importance</jats:title><jats:p>EBOV and MARV, members of the family <jats:italic>Filoviridae</jats:italic>, are highly pathogenic zoonotic viruses that cause severe disease in humans. Both viruses use several mechanisms to modulate the host innate immune response, and these likely contribute to severity of disease. Here, we demonstrate that MLAV, a filovirus newly discovered in a bat, suppresses antiviral type I interferon responses in both human and bat cells. Inhibitory activities are possessed by MLAV VP35 and VP40, which parallels how MARV blocks IFN responses. However, whereas MARV activates cellular antioxidant responses through an interaction between its VP24 protein and host protein Keap1, MLAV VP24 lacks a Keap1 binding motif and fails to activate this cytoprotective response. These data indicate that MLAV possesses immune suppressing functions that could facilitate human infection. They also demonstrate key differences in MLAV versus either EBOV or MARV engagement of host signaling pathways.</jats:p></jats:sec>

Characterization of SARS-CoV-2 N protein reveals multiple functional consequences of the C-terminal domain

“…Using an IFN-β promoter assay, we showed that N has a role in suppressing IFN signaling pathway when stimulated by Sendai virus (SeV) infection ( Figure 5G ). N WT can inhibit IFN-β promoter activity, although not as well as Měnglà virus (MLAV) VP35, a potent inhibitor of IFN signaling (Williams et al, 2020). Both N Narm-NTD-LKR and N NTD show modest inhibition at the highest concentration tested.…”

Characterization of SARS-CoV-2 nucleocapsid protein reveals multiple functional consequences of the C-terminal domain

“…Using an IFNb promoter reporter assay, we showed that N has a role in suppressing IFN signaling pathway when stimulated by Sendai virus (SeV) infection (Figure 5G). N WT can inhibit IFNb promoter activity, although not as well as M englà virus (MLAV) VP35, a potent inhibitor of IFN signaling (Williams et al, 2020). Both N Narm-NTD-LKR and N NTD show modest inhibition at the highest concentration tested.…”