Growing evidence indicates that biological sex impacts human immune responses, modulating susceptibility and severity to various immune-related diseases. The COVID-19 pandemic has highlighted sex differences during infection, with increased hospitalizations and deaths in SARS-CoV-2-infected men as compared to women. Generally, men mount less robust immune responses than women, resulting in higher frequency and severity of infections. Still, the precise mechanisms that underlie sex discrepancies in human antiviral immunity remain poorly understood. Moreover, while sex differences are attributed to the combined effects of sex hormones, genetics and societal factors, distinguishing the specific contribution of these factors in humans is challenging. The overarching goal of SHIFT was to dissect the precise contribution of sex hormones to antiviral immune function in humans. SHIFT had the unique ability to separate genetic from hormonal effects in humans by studying intra-individual immune changes over time in subjects undergoing sex-reassignment therapy with sex hormone treatment. SHIFT was based on three major research aims, which were 1) to evaluate the sex hormone contribution to viral infection susceptibility, 2) to characterize sex hormone effects on the immune-microbe interactions and balance, and 3) to assess sex hormone effects in antiviral immune responses during infection. The work from aim 1 led to an extensive characterization of immunity in subjects as they undergo Female-to-Male (FtM) transition, enhancing our understanding of how testosterone impacts different components of the baseline immune system (immune plasma proteins and blood immune cell composition and function) in humans. Results from Aim 3 further contributed to the findings from Aim 1, where we observed a shift in antiviral immune function throughout FtM transition. Unfortunately, Aim 2 is still at its early stages, where samples from the cohort are currently being analyzed by collaborative partners for microbiome changes during FtM. Overall, SHIFT allowed us to identify previously unknown sex-hormone regulated pathways in human antiviral immunity. Identification of such pathways are valuable for vaccine design, antiviral therapies, and immunomodulatory therapies at large. Finally, the MSCA fellowship provided the fellow with a strong training path in systems immunology that allowed her to reach academic independence in the EU and obtaining a highly competitive research position at Lund University, Sweden, where she is now a group leader investigating biological sex and immunological basis of disease susceptibility.
