RIG-I and MDA5 Protect Mice From Pichinde Virus Infection by Controlling Viral Replication and Regulating Immune Responses to the Infection

Abstract

RIG-I and MDA5 are major cytoplasmic innate-immune sensor proteins that recognize aberrant double-stranded RNAs generated during virus infection to activate type 1 interferon (IFN-I) and IFN-stimulated gene (ISG) expressions to control virus infection. The roles of RIG-I and MDA5 in controlling replication of Pichinde virus (PICV), a mammarenavirus, in mice have not been examined. Here, we showed that MDA5 single knockout (SKO) and RIG-I/MDA5 double knockout (DKO) mice are highly susceptible to PICV infection as evidenced by their significant reduction in body weights during the course of the infection, validating the important roles of these innate-immune sensor proteins in controlling PICV infection. Compared to the wildtype mice, SKO and DKO mice infected with PICV had significantly higher virus titers and lower IFN-I expressions early in the infection but appeared to exhibit a late and heightened level of adaptive immune responses to clear the infection. When a recombinant rPICV mutant virus (rPICV-NPmut) that lacks the ability to suppress IFN-I was used to infect mice, as expected, there were heightened levels of IFN-I and ISG expressions in the wild-type mice, whereas infected SKO and DKO mice showed delayed mouse growth kinetics and relatively low, delayed, and transient levels of innate and adaptive immune responses to this viral infection. Taken together, our data suggest that PICV infection triggers activation of immune sensors that include but might not be necessarily limited to RIG-I and MDA5 to stimulate effective innate and adaptive immune responses to control virus infection in mice.

Immunogenicity and Protective Efficacy of a Recombinant Pichinde Viral-Vectored Vaccine Expressing Influenza Virus Hemagglutinin Antigen in Pigs

“…PICV is considered non-pathogenic as there are no known PICV-associated diseases in humans or other animals [34]. The virus can infect a wide range of cell types from diverse host animal species that may include but are not necessarily limited to human, mouse, monkey, and avian species [34][35][36][37]. The wide host ranges and avirulent nature of PICV makes it a promising viral vector for flexible delivery of vaccine immunogens in humans and various animal species.…”

IRF1 Is Required for MDA5 (IFIH1) Induction by IFN-α, LPS, and poly(I:C) in Murine Macrophages

“…Mda5-deficient mice exhibited a selectively impaired response to several viruses including encephalomyocarditis picornavirus [9,10], norovirus-1 [11], paramyxoviri-dae [12,13], Theiler's encephalomyelitis virus [14], acute lymphocytic choriomeningitis virus [15], or Pichinde virus [16]. Interestingly, the absence of Mda5 protects mice from malaria plasmodium yoelii [17].…”

Understanding Immune Responses to Lassa Virus Infection and to Its Candidate Vaccines

“…This cross-reactivity of T-cell mediated immunity to different lineages of LASV thus implies a significant functional level of adaptive cellular immunity in spite of the immunosuppressive effect during the early phase of the virus infection and suggests that high diversity among the different viral lineages does not necessarily abolish the putative conserved immune dominant T cell epitopes. It is noteworthy that we have recently shown that mice that lack the expression of one or both major cytosolic innate immune receptors (RIG-I and/or MDA5 knock out) can also exhibit a late but heightened level of adaptive (T-cell) immune responses to clear the infection by a prototypic arenavirus, called Pichinde virus (PICV), despite a defective level of innate immunity [ 55 ].…”