Trim7 does not have a role in the restriction of murine norovirus infection in vivo
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Abstract
Trim7 is an E3 ubiquitin ligase that was recently identified as a central regulator of host- viral interactions with both pro-viral and anti-viral activity in cell culture. As an inhibitor, Trim7 overexpression ubiquitinates viral proteins by recognizing C-terminal glutamines that are hallmarks of 3C-like protease cleavage events. Here we sought to determine the physiological impact of Trim7 in resolving murine norovirus (MNV) infection of mice as MNV is potently inhibited by Trim7 in vitro. Utilizing two independently derived Trim7 deficient mouse lines we found no changes in the viral burden or tissue distribution of MNV in both an acute and persistent model of infection. Additionally, no changes in cytokine responses were observed after acute MNV infection of Trim7-deficient mice. Furthermore, removal of potentially confounding innate immune responses such as STING and STAT1 did not reveal any role for Trim7 in regulating MNV replication. Taken together, our data fails to find a physiological role for Trim7 in regulating MNV infection outcomes in mice and serves as a caution for defining Trim7 as a broad acting antiviral.
Importance
Intrinsic antiviral molecules that restrict viral replication are important drivers of viral evolution and viral tropism. Recently, Trim7 was shown to provide cell intrinsic protection against RNA viruses, including murine norovirus. Biochemically, Trim7 recognizes the cleavage product of viral proteases, suggesting a novel and broad mechanism to restrict viral replication. Here, we tested whether Trim7 had a physiological role in restricting murine norovirus replication in mice. Unexpectedly, we found no impact of viral replication or innate immune responses during murine norovirus infection. Our findings urge caution in defining Trim7 as a broad antiviral factor in the absence of in vivo evidence.
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overexpression
Thank you for sharing this work! Negative data is published much less frequently, it's great that you put this out here.
Regarding your results, you mention several times that the Trim7 antiviral phenotype comes from an in vitro overexpression system. It seems like you may be attributing the lack of activity in vivo to due to lower expression levels in the mouse. I would be curious to know if in vitro you also see a strong dose dependence, where Trim7 can only restrict viral replication at high expression levels.
If the differences are driven by expression levels, one interesting explanation might be that MNV has a natural inhibitor of Trim7, and only when you overexpress Trim7 do you see antiviral effects. I used to study anti-CRISPRs (phage encoded inhibitors of bacterial immunity), and we would see a very similar …
overexpression
Thank you for sharing this work! Negative data is published much less frequently, it's great that you put this out here.
Regarding your results, you mention several times that the Trim7 antiviral phenotype comes from an in vitro overexpression system. It seems like you may be attributing the lack of activity in vivo to due to lower expression levels in the mouse. I would be curious to know if in vitro you also see a strong dose dependence, where Trim7 can only restrict viral replication at high expression levels.
If the differences are driven by expression levels, one interesting explanation might be that MNV has a natural inhibitor of Trim7, and only when you overexpress Trim7 do you see antiviral effects. I used to study anti-CRISPRs (phage encoded inhibitors of bacterial immunity), and we would see a very similar dynamic. In our experiments, if a phage had an anti-CRISPR, it would appear to be unimpacted by the CRISPR-Cas immune system, but if we overexpressed CRISPR, we could "overwhelm" the anti-CRISPR and the phage would fail to replicate.
If you have any genomic libraries of MNV it could be interesting to see if any MNV ORFs are able to rescue MNV growth in the the Trim7 cell line.
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