Effects of estrus cycle stages on murine CDI severity

摘要 艰难梭菌感染(CDI)是抗生素相关性腹泻的主要可识别原因。这个 在美国，CDI的发病率约为677/10万患者，导致每年近50万例 独自一人。CDI每年造成约25,000人死亡，医疗保健系统的成本估计为6.3美元 十亿/年。 CDI的主要风险因素是积极使用广谱抗生素。同样，老年人口也是 与年轻人群相比，他们更容易受到CDI的影响。降低免疫力的情况(例如器官移植、 化疗、艾滋病)也与CDI的严重程度密切相关。重要的是，研究表明 女性罹患CDI的风险高于男性。 CDI的症状从无症状的定植、轻度腹泻到致死性结肠炎。所有研究表明 已经在感染人群中描述了与CDI相关的危险因素。因此， 对感染CDI的个人易感性的决定因素还没有很好地理解。同样，也不清楚 为什么CDI症状的严重程度在不同的患者之间存在差异。 小鼠已经被成功地用作测试治疗艰难梭菌感染的新方法的模型。 小鼠CDI模型表现出与人类CDI相似的症状进展，并对相同的症状做出反应 治疗。在我们对CDI预防药物进行筛选的过程中，我们观察到雌性小鼠出现了更严重的 与男性相比，CDI的符号。 在本应用程序中，我们将检验性激素水平与CDI症状相关的假设 发病和严重程度。我们还将确定与性别相关的变量是否会影响CDI的预防和治疗。 在这个项目中获得的数据将有助于确定类固醇性激素的贡献。 和/或性状况对小鼠CDI易感性的影响。该信息随后将用于后续的R01 应用于确定男性和女性CDI差异的机制 敏感度。

Abstract Clostridium difficile infection (CDI) is the main identifiable cause of antibiotic assoicated diarreah. The incidence of CDI is approximately 677/100,000 patients resulting in close to 500,000 cases annually in the US alone. CDI causes approximately 25,000 deaths a year and costs the health care system an estimated $6.3 billion/year. The main CDI risk factor is aggressive broad-spectrum antibiotic use. Similarly, older populations are more susceptible to CDI than younger cohorts. Conditions that reduce immunity (e.g. organ transplant, chemotherapy, AIDS) are also strongly correlated with CDI severity. Importantly, studies have shown that women have higher risk of CDI than men. CDI symptoms range from asymptomatic colonization to mild diarrhea to deathly colitis. All studies that delineate risk factors associated with CDI have been conducted with infected populations. Hence, the determinants of individual predisposition to contracting CDI are not well understood. Similarly, it is not clear why CDI symptoms severity vary among individual patients. Mice have been used successfully as a model to test novel approaches to treat for C. difficile infections. The murine CDI model present symptoms progression reminiscent of human CDI and respond to the same treatments. During our screening for CDI prophylactics, we observed that female mice developed more severe CDI signs compared to their male counterpart. In this application, we will test the hypothesis that sex hormone levels correlate with CDI symptom onset and severity. We will also determine whether sex-related variables affect CDI prevention and treatment. The data obtained in this project will allow determining the contribution of steroidal sex hormones and/or sexual status to murine CDI susceptibility. This information will then be used in a follow-up R01 application to determine the mechanisms underlying the differences between male and female CDI susceptibility.