SARS-CoV-2, ACE2 and Esophageal Neoplasia

SARS-CoV-2大流行导致全球因COVID-19而大量发病和死亡，美国受到的影响尤其严重。2019冠状病毒病的危险因素包括男性、年龄较大和肥胖等，这些也是巴雷特食管（BE）和食管腺癌（EAC）的关键危险因素。因此，与普通人群相比，BE患者感染SARS-CoV-2的几率可能要高得多。因此，与普通人群相比，BE患者感染SARS-CoV-2的几率可能要高得多。SARS-CoV-2通过与血管紧张素转换酶2 （ACE2）受体结合并随后通过跨膜丝氨酸蛋白酶2 （TMPRSS2）切割病毒刺突蛋白而感染细胞。感染诱导关键通路和下游效应物，导致明显的炎症。ACE2在食管组织中高表达，ACE抑制剂可降低BE中NF-κB蛋白的表达，使用ACE抑制剂可降低EAC的风险。因此，BE患者的SARS-CoV-2感染可能对BE组织产生直接影响，从而加速肿瘤形成，这是合理的。我们发表了一项回顾性队列研究，研究对象为1,600名住院的COVID-19患者，发现使用组胺-2受体拮抗剂法莫替丁可将死亡风险降低2倍。虽然这一观察结果的潜在机制尚不清楚，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在BE中的促肿瘤作用。在队列研究中，质子泵抑制剂（PPIs）与较差的结果相关，我们之前的研究表明，PPI的使用会导致肠道微生物群中肾素-血管紧张素途径的增加。因此，我们假设如下：1)有COVID-19病史的BE患者进展为EAC的风险增加；2)对于有covid - 19病史的be患者，可能需要使用法莫替丁代替PPIs。在本文中，我们将解决以下具体目标：目标1)明确ACE2和TMPRSS2在BE和EAC细胞中的功能作用；目的2)确定法莫替丁是否影响BE和EAC细胞的SARS-CoV-2感染；目的3)探讨脑出血患者TMPRSS2和ACE2表达与免疫细胞群的关系。COVID-19病史可能是BE患者进展为EAC风险的新标志物，可能需要将其纳入临床资料，以确定适当的高风险患者进行筛查和监测。此外，对于有轻度反流症状和有COVID-19病史的be患者，使用法莫替丁而不是PPIs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.