# Gasdermin E is dispensable for H1N1 influenza virus pathogenesis in mice

## TL;DR

This study shows that gasdermin E does not significantly impact H1N1 influenza virus infection in mice, unlike its role in other flu strains.

## Contribution

The study clarifies the context-specific role of gasdermin E in influenza pathogenesis, specifically for H1N1.

## Key findings

- Gsdme-/- mice showed similar weight loss, survival, and lung damage as wild-type mice during H1N1 infection.
- Transcriptomic analysis revealed no significant differences in inflammatory or antiviral gene expression between Gsdme-/- and wild-type mice.
- Similar results were observed with both adapted and minimally adapted H1N1 virus strains.

## Abstract

Targeting cell death pathways, including pyroptosis and necroptosis, has been shown to mitigate influenza virus infection severity. Here, we examined whether pyroptosis specifically driven by the pore-forming protein gasdermin E (GSDME) is involved in regulating influenza virus infection outcomes. We found that Gsdme-/- mice showed similar weight loss and survival in severe A/PR/8/34 (H1N1) virus infections compared to WT counterparts. Likewise, lung dysfunction, histopathological damage, viral titers, and inflammatory cytokine levels were similar in the two groups. Global transcriptomic analysis also revealed similar inflammatory and antiviral gene expression programs in WT versus Gsdme-/- mouse lungs at baseline and in response to infection. To confirm the generality of these findings, we infected mice with minimally mouse-adapted 2009 pandemic H1N1 virus and again observed similar weight loss, lung dysfunction, and mortality in WT and Gsdme-/- mice. Our results overall demonstrate that GSDME contributes negligibly to the host response against H1N1 influenza virus, refining our understanding of cell death pathways in influenza pathogenesis.

Influenza virus infection activates multiple cell death pathways that shape disease outcomes. Here, we demonstrate that gasdermin E (GSDME)-mediated pyroptotic cell death does not significantly affect lung pathology or survival during severe H1N1 influenza virus infection. This finding contrasts with prior reports showing that GSDME worsens disease caused by H3N2 or H7N9 strains, as well as studies implicating gasdermin D in exacerbating H1N1 pathology. Thus, our data clarify that gasdermin family members contribute to influenza pathogenesis in a context-specific manner, underscoring the importance of considering viral diversity when evaluating the therapeutic potential of targeting cell death pathways.