Dissecting the role of sex hormones in human antiviral immunity

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.

During the period of SHIFT, we have performed extensive characterization of the immune system of 20 subjects undergoing Female-to-Male (FtM) sex reassignment therapy with testosterone treatment. During this period, the fellow developed her skills in computational analyses of multiomics datasets, including plasma proteome profiling, immune cell composition and function assessment via transcriptomics and mass cytometry. By the end of the project, we analyzed samples from 20 subjects before and after three and 12 months of testosterone treatment using systems immunology approaches. The major results obtained included extensive investigation and characterization of testosterone effects on the immune system. This enabled the identification of several sex-hormone regulated pathways in antiviral immunity in humans, including modulation of specific immune proteins in the plasma, the composition of immune subsets in the blood, as well as their function. Our overall observations highlighted a significant shift in immune function throughout FtM transition. Identifying such sex hormone-regulated pathways is valuable for vaccine design, antiviral therapies and immunomodulatory therapies at large. We are currently preparing a manuscript for comprehensive dissemination of our findings (expected submission for early 2023). Together with the submission, our manuscript will be made available online via BioRxiv, and data and code for computational analyses will be made available upon acceptance. Dissemination of our findings thus far have happened at scientific conferences (2021 CSHL Systems Immunology, 2021 SciLifeLab Seminar Series, 2021, 2022 ELLITT focus period, 2022 KI Immunology retreat, 2022 Keystone Symposia on Vaccine Development, 2022 ETHZ Workshop on Sex differences in Immunity) as well as internally to collaborators and lab members. Communication to the general public and the scientific community has also occured through social media, including Twitter and LinkedIn, and through seminars (2021 SciLifeLab Researchers Night). Finally, identifying sex-regulated pathways in immunity can have important consequences for therapy development; once the overall findings of SHIFT are put into context with other current projects in the host and collaborative lab pertaining to sex differences in immunity, we will pursue advice for the commercial exploitation of such sex-regulated pathways.

Utilizing state-of-the-art systems immunology approaches in SHIFT enabled us to address and go beyond the current challenges in the field regarding identifying sex chromosome vs sex hormone impacts in human immune function. For the first time in humans, we were able to characterize key immunological parameters impacted by testosterone, which lead to the identification of sex-regulated immune plasma proteins and immune cell composition and function. The wider impact of such findings is that such antiviral immune pathways modulated by sex hormones may be commercially exploited for the generation of new immunomodulatory therapies. Finally, identifying sexually dimorphic may further aid in the optimization of current treatment strategies according to biological sex.

Periodic Reporting for period 1 - SHIFT (Dissecting the role of sex hormones in human antiviral immunity)

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