(890) Elevated type I interferon levels during Influenza virus infection profoundly suppress pulmonary innate and adaptive immunity and exacerbate disease.

Introduction/Rationale:

Introduction: Most mouse studies aimed at investigating the roles of specific cytokines in disease states use mice deficient for the cytokine or its receptor, or antibody treatment to block its signaling. While such analyses have found relatively minor impacts for type I interferon (IFN-I) signals during Influenza A (IAV) infection, elevated IFN-I expression has recently been correlated with worsened disease outcomes, though the underlying mechanisms are not clearly defined. Here, we investigated how increasing IFN-I availability during the first week of sublethal IAV infection impacts diverse aspects of the inflammatory landscape and disease severity.

Methods:

Methods: Mice were systemically treated with exogenous IFN-I or not from days 2-6 after IAV infection followed by analysis at day 7, which marks the peak of the cellular immune response in the lungs.

Results: .

Results: IFN-I treatment caused dramatic reductions of all innate and adaptive immune cell subsets assayed in the lungs, but not in the spleens, of both C57BL/6 and BALB/C mice. This impact was seen in unprimed mice responding to primary IAV infection, and in IAV-primed mice responding to heterosubtypic infection. Mechanistically, this broad suppressive impact requires expression of the IFN-I receptor on hematopoietic cells, but not the key downstream IFN-I signaling mediator, STAT1, or transcriptional regulators linked to antiviral Th1 immunity. Finally, we find that increasing IFN-I availability does not impact maximal weight loss or viral titers, but that it does promote altered expression of key inflammatory mediators, correlating with enhanced morbidity and mortality.

Conclusion:

Conclusion: Our findings provide novel insights into how dysregulated IFN-I levels can impact IAV infection. More broadly, they reveal that testing how elevated cytokine levels affect outcomes can provide potentially valuable translational insights that could go unnoticed when relying on loss-of-function studies alone.