Assessing the mechanisms underlying female sex-predominance in Long COVID

PROJECT SUMMARY Long COVID, or post-acute sequelae of COVID-19 (PASC), is estimated to occur after ~10% of COVID-19 cases and affects tens of millions of people worldwide. The mechanisms underlying Long COVID remain poorly understood, which hinders the ability to establish effective evidence-based treatments for the condition. One of the most striking observations in the epidemiology of Long COVID is its female sex predominance: women, particularly pre-menopausal women, are much more likely than men to have the condition. In this proposal, we leverage the Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort (NCT04362150) - which since April 2020 has recruited >1,000 participants with and without Long COVID - to interrogate the mechanistic basis underlying the increased prevalence of Long COVID in women. Our central hypothesis is that in women with Long COVID, there is an elevated and sustained immune type I IFN (T1IFN) response to SARS-CoV-2 (SCV2) gene products, which in turn diminishes the quality of adaptive immune responses against chronic herpesviruses (EBV, CMV) and SCV2 itself, increases the risk of pathogenic autoantibody responses, and results in overall systemic inflammation and immune dysregulation that is characteristic of Long COVID. We further postulate that both incomplete X chromosome inactivation and sex hormones drive the elevated T1IFN responses in women with Long COVID. In Aim 1, we will subject banked longitudinal blood specimens from women and men from LIINC (including both those with and without Long COVID) to assays that will measure the extent of persistent SCV2, T1IFN responses, the features of adaptive immune responses to persistent viruses associated with Long COVID (SCV2, EBV, CMV), autoantibody responses, and the overall state of inflammation. In Aim 2, we will leverage the LIINC Tissue Biopsy program to obtain paired endometrial and gut biopsies from women with Long COVID, to test the hypothesis that the endometrium is a key site of SCV2 persistence and immune dysregulation during Long COVID. This analysis will be compared to a parallel set of studies using gut specimens from matched men with Long COVID. Finally, Aim 3 will analyze specimens from two clinical trials designed to eliminate SCV2 gene products as treatment for Long COVID. The first of these, performed by Resolve Therapeutics, found that administration of RSLV-132, a catalytically active RNase1 intended to degrade SCV2 RNA, improved Long COVID symptoms in women but not men (NCT04944121). The second, occurring within LIINC, is ongoing (enrollment is complete) and testing the effects of AER002, a monoclonal antibody that directly targets and clears SCV2 protein (NCT05877508). Using specimens from both trials, we will test the notion that SCV2 gene products drive sustained T1IFN responses in women that contribute to Long COVID symptoms. Collectively, our aims will improve our understanding of the mechanisms underlying the female-predominance of Long COVID and improve our overall understanding of the disease. This will be a key step in the identification of evidence-based treatments for both women and men who continue to develop and live with this disabling condition.