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Updated: Oct 9, 2025
Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
RIG-I and MDA5 Protect Mice From Pichinde Virus Infection by Controlling Viral Replication and Regulating Immune
Morgan Brisse1,2, Qinfeng Huang2, Mizanur Rahman2
1Biochemistry, Molecular Biology and Biophysics Graduate Program, College of Veterinary Medicine, University of Minnesota, Twin Cities, MN, United States.
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.
Insights
RIG-I and MDA5 are crucial for controlling Pichinde virus (PICV) infection in mice. Their absence leads to increased susceptibility, highlighting their role in innate immunity against viral pathogens.
Area of Science:
- Immunology
- Virology
- Infectious Diseases
Background:
- RIG-I and MDA5 are key cytoplasmic sensors of viral double-stranded RNA.
- These sensors initiate type 1 interferon (IFN-I) and IFN-stimulated gene (ISG) expression to combat viral infections.
- The specific roles of RIG-I and MDA5 in Pichinde virus (PICV) infection remain unexamined.
Purpose of the Study:
- To investigate the roles of RIG-I and MDA5 in controlling Pichinde virus (PICV) replication in a mouse model.
- To elucidate the contribution of these innate immune sensors to antiviral responses against PICV.
Main Methods:
- Generation and infection of MDA5 single knockout (SKO) and RIG-I/MDA5 double knockout (DKO) mice with PICV.
- Analysis of viral titers, body weight changes, and IFN-I/ISG expression levels.
- Infection of mice with a recombinant rPICV mutant virus (rPICV-NPmut) lacking IFN-I suppression.
Main Results:
- SKO and DKO mice exhibited high susceptibility to PICV, with reduced body weight, increased viral titers, and lower early IFN-I expression.
- Despite initial susceptibility, SKO and DKO mice showed delayed but heightened adaptive immune responses for viral clearance.
- Infection with rPICV-NPmut revealed delayed and transient innate and adaptive immune responses in SKO and DKO mice compared to wild-type.
Conclusions:
- RIG-I and MDA5 play critical roles in controlling PICV infection and driving early innate immune responses.
- PICV infection activates immune sensors, including RIG-I and MDA5, to orchestrate effective innate and adaptive immunity.
- These findings underscore the importance of RIG-I and MDA5 in host defense against mammarenaviruses like PICV.
