The UNC Chapel Hill Superfund Research Program (UNC-SRP) (2)

Abstract: This proposal is being submitted as an Emergency Competitive Revision for the University of North Carolina(UNC) Superfund Research Program (SRP) in the context of the Coronavirus Disease 2019 (COVID-19)pandemic. We focus on inorganic arsenic (iAs), the #1 contaminant of the Agency for Toxic Substances Registry(ATSDR) contaminating drinking water around the globe. iAs is toxic to many organs in the body, acting as acarcinogen, diabetogen, neurotoxicant, and immunosuppressant. Notably, in several of the North Carolinacounties where iAs levels in drinking water are high, the prevalence of severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) infection is also high, indicating that a co-exposure to iAs and SARS-CoV-2 likelyoccurs. This co-exposure to iAs on the susceptibility to SARS-CoV-2 infection and COVID-19 severity has neverbeen studied. The goal of this proposal is to characterize the interaction between iAs exposure and SARS-CoV-2 infection using differentiated primary human nasal epithelial cells, an established in vitro model for respiratoryinfections, and a novel humanized hAS3MT mouse strain, in which the metabolism of iAs and disposition of itsmetabolites resemble those in humans. In a strong, transdisciplinary approach, we will use differentiatedprimary human nasal epithelial cells and a humanized hAS3MT mice to test the hypothesis that chronicexposure to iAs enhances susceptibility to SARS-CoV2 infection and severity of COVID-19. Whileintegrating human and mouse models, we will also examine the role of sex and genetic background on thedisease outcome. The two new additional Aims include: (Aim 1) Identify the effects of iAs and its metabolites onSARS-CoV-2 infection in differentiated primary human nasal epithelial cells; and (Aim 2) Characterize the effectsof iAs exposure on SARS-CoV-2 MA infection and COVID-19 outcomes in hAS3MT mice. In Aim 1, we test thehypothesis is that exposure to iAs or its metabolites enhances susceptibility to and severity of SARS-CoV-2infection in the human nasal epithelial cells. In Aim 2, we will compare immune response, viral titer, lungpathology and mortality in hAS3MT mice exposed to iAs in drinking water (0, 40, or 400 ppb) and infected witha mouse-adapted SARS-CoV-2 that has been recently created at UNC Chapel Hill. To assess the role of sexand genetics, we will use male and female hAS3MT mice with C57BL/6NCrl and 129S6/SvEvTac backgrounds.The proposed research utilizes novel laboratory models that are available only at UNC and are uniquely suitedfor studies of the interaction between environmental iAs exposure and SARS-CoV2 infection. The proposedresearch addresses a critical need for understanding of the interaction between a widespread environmentalexposure and a pandemic infection that affects hundreds of millions of people worldwide.