SARS-CoV-2, ACE2 and Esophageal Neoplasia

由于新冠肺炎，SARS-CoV-2的大流行在全球范围内导致了大规模的发病率和死亡率，其中美国受到的影响尤为严重。新冠肺炎的风险因素包括男性、年龄较大和肥胖等，这些因素也是巴雷特食道(BE)和食管腺癌(EAC)的关键风险因素。因此，与普通人群相比，BE患者感染SARS-CoV-2的比率可能会明显更高。因此，与普通人群相比，BE患者感染SARS-CoV-2的比率可能会明显更高。SARS-CoV-2通过与血管紧张素转换酶2(ACE2)受体结合，然后通过跨膜丝氨酸蛋白酶2(TMPRSS2)裂解病毒尖峰蛋白来感染细胞。感染诱导关键途径和下游效应器，导致明显的炎症。血管紧张素转换酶2在食道组织中高表达，血管紧张素转换酶抑制剂可降低BE中NF-κB蛋白的表达，血管紧张素转换酶抑制剂的使用与降低食道癌变的风险有关。因此，在BE患者中感染SARS-CoV-2可以直接影响BE组织，从而加速肿瘤的发生。我们发表了一项针对1,600名新冠肺炎住院患者的回顾性队列研究，发现组胺-2受体拮抗剂法莫替丁的使用与死亡风险降低2倍相关。虽然这一观察结果背后的潜在机制仍不清楚，但法莫替丁不仅可以改善这些患者的短期临床结果，还可以改善SARS-CoV-2对BE的促肿瘤作用。在队列研究中，质子泵抑制剂(PPI)与较差的结果相关，我们之前表明，PPI的应用会导致肠道微生物组中肾素-血管紧张素途径的增加。因此，我们假设：1)有新冠肺炎病史的患者进展为EAC的风险增加；2)对于有COVID19病史的BE患者，可以用法莫替丁代替PPI。目的1)确定ACE2和TMPRSS2在BE和EAC细胞中的功能作用；2)确定法莫替丁是否影响BE和EAC细胞中SARS-CoV-2的感染；目的3)评估TMPRSS2和ACE2表达与BE中免疫细胞群的关系。新冠肺炎病史可能代表着BE患者发展为EAC的一个新的风险标志，这可能需要被纳入旨在识别适当的高危患者进行筛查和监测的临床资料中。此外，对于有轻度反流症状和有记录的新冠肺炎病史的BE患者，用法莫替丁而不是PPI治疗可能更合适。

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.