The SARS-CoV-2 pandemic has led to massive morbidity and mortality worldwide due to COVID-19, with the United States particularly affected. Risk factors for COVID-19 include male sex, older age, and obesity, amongst others, which are also key risk factors for Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). Thus, patients with BE will likely be infected with SARS-CoV-2 at markedly higher rates compared to the general population. Thus, patients with BE will likely be infected with SARS-CoV-2 at markedly higher rates compared to the general population. SARS-CoV-2 infects cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor and subsequent viral spike protein cleaving by transmembrane serine protease 2 (TMPRSS2). Infection induces key pathways and downstream effectors, resulting in pronounced inflammation. ACE2 is highly expressed in esophageal tissue, ACE inhibitors reduce NF-κB protein expression in BE, and ACE inhibitor use is associated with reduced risk of EAC. It is therefore plausible that SARS-CoV-2 infection in BE patients can result in direct effects on BE tissues that accelerate neoplasia. We published a retrospective cohort study of >1,600 hospitalized COVID-19 patients and found that use of the histamine-2 receptor antagonist famotidine was associated with a >2-fold reduction in the risk of death. While potential mechanisms underlying this observation remain poorly understood, famotidine may not only improve short-term clinical outcomes in these patients but also ameliorate the pro-neoplastic effects of SARS-CoV-2 in BE. Proton pump inhibitors (PPIs) were associated with worse outcomes in the cohort study, and we previously showed that PPI administration leads to increases in the renin-angiotensin pathway in the gut microbiome. Thus, we hypothesize the following: 1) BE patients with a history of COVID-19 are at increased risk for progression to EAC; and 2) famotidine may be indicated instead of PPIs for BE patients with a documented history of COVID19. In this proposal we will address the following specific aims: Aim 1) To define the functional role of ACE2 and TMPRSS2 in BE and EAC cells; Aim 2) To determine whether famotidine influences SARS-CoV-2 infection in BE and EAC cells; Aim 3) To assess the relationship between TMPRSS2 and ACE2 expression and immune cell populations in BE. A history of COVID-19 may represent a novel marker for risk for progression to EAC among BE patients, and this may need to be incorporated into clinical profiles aimed at identifying appropriate high-risk patients for screening and surveillance. Furthermore, treatment with famotidine and not PPIs may be more appropriate for BE patients with mild reflux symptoms and a history of documented COVID-19.