Hepatovirus 3ABC proteases and evolution of mitochondrial antiviral signaling protein (MAVS)

Abstract

Background & Aims: Unlike other hepatitis viruses that have infected primates for millions of years, hepatitis A virus (HAV) likely entered human populations only 10-12 thousand years ago after jumping from a rodent host. The phylogeny of modern hepatoviruses infecting rodents and bats suggest multiple similar host shifts have occurred in the past. The factors determining such shifts are unknown, but the capacity to overcome innate antiviral responses in a foreign species is likely key. Methods: We assessed the capacity of diverse hepatovirus 3ABC proteases to cleave MAVS and disrupt antiviral signaling in HEK293 and human hepatocyte-derived cell lines, and applied maximum-likelihood and Bayesian algorithms to identify sites of diversifying selection in MAVS orthologs from 75 chiropteran, rodent and primate species.

Novel Insights Into Immune Systems of Bats

“…Functional conservation in MAVS signaling has been demonstrated in the Chinese rufous horseshoe bat (Rhinolophus sinicus) and the straw-colored fruit bat (Eidolon helvum). Interestingly, expression of bat MAVS in MAVS knockout human cells resulted in induction of the IFNβ promoter and expression of an ISG, namely IFN-induced protein with tetratricopeptide repeats 1 (IFIT1) (62). Expression of bat and rodent MAVS in human MAVS knockout cells also resulted in the activation of IRF3 post Sendai virus infection (62).…”

“…Interestingly, expression of bat MAVS in MAVS knockout human cells resulted in induction of the IFNβ promoter and expression of an ISG, namely IFN-induced protein with tetratricopeptide repeats 1 (IFIT1) (62). Expression of bat and rodent MAVS in human MAVS knockout cells also resulted in the activation of IRF3 post Sendai virus infection (62). These studies suggest that rodent, human and bat MAVS have conserved functional properties, however, downstream signaling pathways and molecules involved in MAVS-mediated signaling are yet to be characterized in bats.…”

“…The 3ABC proteases of human hepatitis viruses cleave MAVS to evade the innate immune response (137). A recent study demonstrated that bat MAVS orthologs are relatively resistant to cleavage by their cognate 3ABC proteases, whereas proteases from bat-borne viruses retain the ability to cleave human MAVS (62).…”

“…There are limited studies that have studied the functional conservation and ability of bat cellular molecules to stimulate antiviral signaling pathways in human cells. The above study by Feng et al showed that in addition to being resistant to cleavage by 3ABC proteases, bat MAVS can actively signal in human cells to activate the IFN promoter (62). The idea of using bat molecules that are resistant to viral protein-mediated modulation as therapeutics is still far-fetched.…”

Sloths host Anhanga virus‐related phleboviruses across large distances in time and space

“…Recombination was assessed using the Recombination Detection Package V4 (Martin et al, ) and GARD (Kosakovsky Pond, Posada, Gravenor, Woelk, & Frost, ). Analyses of selection pressure were done using fixed‐effects likelihood (FEL) and single‐likelihood ancestor counting (SLAC), both using the GTRxMG94 substitution model as done in Lam et al (), and random‐effects likelihood (REL; substitution model HKY85 as done in Feng et al () within Datamonkey from the HYPHY package (Pond & Frost, ) and comparing the M1 versus M2 and M7 versus M8 models implemented in the CodeML program in the PAML package using the codon frequency model F61 (Xu & Yang, ). Since formal selection pressure analyses within ANHV‐related viruses are limited by the small data set, we selected the 10 genetically most closely related phleboviruses based on amino acid pairwise sequence distances within the complete L gene for these analyses (details on those viruses are provided in the figure legend).…”