Calming the Cytokine Storm: Elucidating Mechanisms Contributing to Toxic Inflammatory Responses to Viruses

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Viruses induce type I interferons (IFNs) after cells sense viral pathogen-associated molecular patterns. These IFNs are detected by the IFN a/ß receptor (IFNAR), with downstream signaling inducing IFN-stimulated genes that facilitate clearance of viruses through mechanisms that include secretion of pro-inflammatory cytokines. Although this would suggest that a lack of type I IFN signaling might reduce pro-inflammatory cytokines, our results demonstrated the opposite. We developed a murine model of viremia in which hematopoietic cells lacked IFNARs. After these mice received intravenous injections of a highly attenuated, non-pathogenic vesicular stomatitis virus, they succumbed to massive cytokine storms in 18 hours. Out of 26 cytokines that were assessed, 25 reached abnormally high levels. Unexpectedly, and a focus of this application, was that cytokine dysregulation was more exaggerated in females compared to males. This is notable because there is a sex bias towards females in the incidence of many inflammation-mediated diseases. Preliminary results suggested neutrophils may have a predominantly regulatory role in this model, since pro-inflammatory cytokines became more dysregulated when these cells were depleted. Neutrophils can be sub-divided into two major phenotypes after separation in a density gradient. Hypothetically, one of these subsets may have a suppressive role during cytokine responses. Quantitative or qualitative differences in a suppressive subset of male neutrophils may confer resistance to dysregulated cytokine responses to viruses. We also propose a model of cell signaling cascades as a blueprint for testing a second hypothesis: interferon-stimulated response elements in sex-dependent promoters contribute to differential regulation of type I IFN-modulated cytokine responses to viruses. Objectives: 1. Assess quantitative versus qualitative differences in the immunoregulatory potential of subsets of neutrophils from males and females. 2. Identify other leukocytes, beyond neutrophils, that contribute to the virus-induced cytokine storm. 3. Identify mechanisms underlying sex-biased dysregulation of cytokine responses, including intracellular changes in cytokine signaling pathways during viral infection with and without IFNAR-blockade, and the role of host factors that may explain sex differences. Training the next generation of Canadian biomedical scientists in the interdisciplinary field of viral immunology is integral to this research. A need for this expertise has been highlighted by the protracted struggle for scientists to develop solutions for the coronavirus disease (COVID)-19 pandemic. This research should provide a mechanistic understanding of how sex can influence the link between impaired IFNAR-mediated signaling, cytokine overproduction, and the leukocyte subsets that are involved. This has relevance for a spectrum of sex-biased cytokine disorders ranging from life-threatening cytokine storms to excessive inflammation.