Interpersonal variation in microbiome structure modulates inter-individual immune responses to Vibrio cholerae

项目摘要 霍乱弧菌是一种革兰氏阴性细菌，是霍乱的病原体， 一种以大量水样腹泻和呕吐为特征的疾病，如果不治疗， 脱水低血容量性休克和死亡已经开发了几种口服霍乱疫苗（OCV）， 在不同的地理区域表现出不同的功效。因此，定义调节这种 变化和发展战略，以尽量减少变异的预防效果仍然是一个重大的全球性问题， 健康优先。一种宿主相关因子已证明在组成和功能上存在差异， 高OCV功效和低OCV功效的群体之间的输出是 胃肠道肠道菌群我们的中心假设是， 胃肠道的微生物群落有助于显著的人际差异， 肠道免疫系统的微生物特异性调节引起的OCV反应。我们 初步数据表明，肠道微生物群可能是口服霍乱疫苗的个性化贡献者， 结果，其中（i）特定的微生物类群与对口服霍乱的不同免疫反应相关 疫苗接种;（ii）微生物群结构的个体间差异和（iii）代表 在霍乱流行地区发现的肠道微生物群落直接影响感染和疫苗接种 结果为霍乱弧菌;和（iv）宿主肠道CD 4 + T细胞的调节调节宿主免疫应答 到霍乱弧菌挑战对肠道微生物群的精确编辑可能是一种有效的策略， 口服疫苗的反应性，但这种方法将需要详细了解的具体 涉及的微生物及其增强或抑制人类免疫功能的特定机制 免疫表型，特别是在口服疫苗应答的情况下。我们的最终目标是 鉴定驱动对霍乱弧菌的不同免疫应答的特定微生物分类群，因为这些候选物可以 更好地为针对肠道微生物的益生元和益生菌策略的发展提供信息 预防。我们将通过以下研究目标来解决这个问题：目标1 -确定跨- OCV响应性的个体微生物群变化;目的2 -定义介导免疫细胞群体 微生物群驱动对OCV响应的影响。

PROJECT SUMMARY Vibrio cholerae is a Gram-negative bacterium and the etiologic agent of cholera, a severe human diarrheal disease characterized by voluminous watery diarrhea and vomiting and when left untreated, severe dehydration, hypovolemic shock, and death. Several oral cholera vaccines (OCV) have been developed but demonstrate variable efficacy in distinct geographical regions. Thus, defining the factors that modulate such variation and developing strategies to minimize variability in prophylactic efficacy remains a significant global health priority. One host-associated factor that has demonstrated differences in composition and functional output between populations of high and low OCV efficacy is the commensal microbial community of the gastrointestinal tract, the gut microbiota. Our central hypothesis is that interpersonal variation in the microbial community of the gastrointestinal tract contributes to significant interpersonal variation in OCV responses caused by microbe-specific modulation of the intestinal immune system. Our preliminary data suggest that the gut microbiota may acts a personalized contributor to oral cholera vaccination outcome, whereby (i) specific microbial taxa correlate with distinct immune responses to oral cholera vaccination; (ii), inter-individual variation in microbiota structure and (iii) dysbiotic microbiotas, representative of gut microbial communities found in cholera endemic areas, directly influence infection and vaccination outcomes to V. cholerae; and (iv) modulation of host intestinal CD4+ T-cells regulate host immune responses to V. cholerae challenge. Precision editing of the gut microbiota may represent an effective strategy to enhance oral vaccine responsiveness, but such approaches will require a detailed understanding of the specific microbe(s) involved and the particular mechanisms by which they enhance or inhibit human immunophenotypes of interest, particularly in the context of oral vaccine responses. Our ultimate goal is to identify specific microbial taxa that drive differential immune responses to V. cholerae, as such candidates may better inform the development of gut microbiota-targeted prebiotic and probiotic strategies for cholerae prophylaxis. We will address this problem with the following study aims: Aim 1 - Determine the effect of inter- individual microbiota variation on OCV responsiveness; Aim 2 - Define immune cell populations that mediate microbiota-driven effects on OCV responses.