Synergistic effects of silica exposure, virus infection and genetic predisposition in systemic autoimmunity

Project Summary COVID-19 caused by the novel coronavirus SARS-Cov-2 first emerged in December 2019 and was officially declared a pandemic by WHO in March 2020. During this time, COVID-19 has caused millions of cases and deaths across the world. While most cases are asymptomatic or present with mild respiratory and flu-like symptoms, a significant fraction of COVID-19 patients develop severe pulmonary complications, overproduction of inflammatory factors and other manifestations, leading in critical cases to multiorgan dysfunction, respiratory failure and death. Strikingly, recent evidence indicates that, besides the typical severe lung pathology, SARS-Cov-2 infection also promotes autoantibody production and other autoimmune manifestations in some patients. However, why other patients seem protected and the mechanisms for COVID-19-associated autoimmunity remain unknown. We hypothesize that autoimmunity development in SARS-Cov-2-infected patients depends on genetic predisposition but also on the history of the individual's exposure to environmental triggers, including crystalline silica, an abundant mineral often associated with autoimmunity. To test this possibility, in this supplemental application we propose experiments with mice expressing human ACE2, the receptor for SARS-Cov-2. These mice will be infected with SARS-Cov-2 at doses that induce low-level COVID-related pathology but no mortality, allowing long-term monitoring for autoimmunity. We will test the effect of the time of SARS-Cov-2 infection and airway exposure to crystalline silica on autoimmune manifestations in hACE2-expressing non-autoimmune and lupus-prone mouse models. In addition, we will examine how the dose of silica affects induction of autoimmunity in SARS-Cov-2-infected mice. The results will provide proof of concept that exposure to environmental agents may exacerbate COVID-19-associated inflammatory and autoimmune responses, creating the foundation for future studies to assess the effect of other environmental triggers, mechanisms of disease pathogenesis, and potential therapeutic interventions.