The critical role of copper homeostasis during the immune response

Abstract Copper homeostasis is tightly regulated in living organisms, as copper is essential to numerous cellular processes but toxic in excess. Dysregulated copper homeostasis is associated with numerous human diseases, including genetic diseases of copper transport, cancer, autoimmune disease, and infection. Although patients with mutations in copper transporters have an increased susceptibility to infection, little is known about the changes in immune function in these diseases. Further, altering copper availability has shown promise in treating either autoimmunity or infection, but the mechanisms underlying this effect are unresolved. We examined serum copper levels in human samples during acute influenza or SARS-CoV-2 virus infections, revealing unique virus-dependent copper dynamics. As copper is required for important immune cell processes such as metabolism, signaling and maintenance of reactive oxygen species, we next investigated the effect of modulating copper levels on T cell activation. We found that copper chelation impaired T cell proliferation, reduced expression of T cell activation markers, and altered gene expression following stimulation. To determine the impact of copper levels during the immune response in vivo, we then treated mice with copper chelation prior to and during an influenza A virus infection. Notably, mice treated with copper chelation prior to infection had altered serum copper dynamics, greater weight loss, and more flu-specific T cells compared to untreated mice. Overall, our results demonstrate the importance of copper homeostasis during the immune response. Ongoing experiments will investigate the mechanisms underlying this role in immune function during disease. Supported by ALSAC and NIH (5T32AI106700).