The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of Coronavirus Disease 2019 (COVID-19) and its rapid global spread has led to an unprecedented global public health crisis. Currently, treatment options are very limited and vaccines against SARS-CoV-2 are still pending widespread use. Host immune responses to SARS-CoV-2 play a crucial role in the containment of the infection. Although SARS-CoV-2 is generally thought of as a respiratory disease, an unexpected consequence is severe complications of the gastrointestinal tract (GIT). Indeed, up to two-thirds of COVID-19 patients have some GIT symptoms and several lines of evidence suggest a breakdown of the epithelial barrier resulting in widespread inflammation. While recent studies in COVID-19 patients and nonhuman primate (NHP) models described T lymphocytes and antibody responses, less is known about natural killer (NK) cell responses in SARS-CoV-2 infection. Classically, NK cells are viewed as nonspecific effector cells of the innate immune system that play critical roles in defense against viral infections. However, besides their ability to rapidly eliminate virus-infected cells without the need for prior antigen sensitization, NK cells also exhibit adaptive immune functions. Different forms of adaptive capabilities have been identified among human NK cell subpopulations, including reports of true antigen-specific memory NK cells as well as adaptive NK cells with enhanced antibody-dependent functions. NK cells may be crucial for early containment of SARS-CoV-2 and formation of adaptive responses elicited by infection, yet uncontrolled NK response may also contribute to the hyperinflammatory responses observed in COVID-19 patients, including in the GIT. In this proposal we will use NHP models, which recapitulate viral replication, immune responses and disease pathology observed in human COVID-19 infection, to test the following hypotheses: (i) pathogenic inflammation in the gastrointestinal tract in COVID-19 is a consequence, in part, of dysregulated or exacerbated NK cell responses, and (ii) specific subsets of NK cells mediate potent anti-viral responses against SARS-CoV-2, associated with enhanced viral clearance and reduced disease severity. We will address these hypotheses through two specific aims: 1. Determine the contribution of systemic and GIT NK cell mobilization to SARS-CoV-2 pathogenesis and clearance in macaque models; 2. Evaluate the mechanisms by which specific innate and adaptive NK cell subpopulations modulate SARS-CoV-2 infection in the GIT. If successful, the results of these innovative studies will contribute new knowledge of human immune responses against SARS-CoV-2 and provide the rationale to develop novel immunotherapeutic approaches to target specific NK cell subsets that could substantially contribute to prevent and treat COVID-19.