Role of Immunity and the Microbiota in Enteropathogenic E. coli Eradication

摘要 由病原体引起的肠道和消化道疾病是世界范围内儿童死亡的重要原因。 据估计，这些疾病每年在全世界造成近100万5岁以下儿童死亡， 在这个年龄组中排在第二位。这主要是由于他们的敏感性增加， 新生儿和幼儿肠道感染。在健康成人的肠道中，微生物群提供了 “定殖抗性”，形成抵抗入侵病原体的屏障。增加的易感性 感染通常归因于免疫系统的不成熟;然而，其他因素可能 发挥着重要作用，因为新生儿对不同刺激的免疫反应差异很大。 我们实验室最近的研究表明，新生小鼠的微生物群在介导 对沙门氏菌和啮齿类柠檬酸杆菌的定植抗性，这是一种模拟感染的细菌， 肠致病性E.大肠杆菌（EPEC），世界范围内细菌导致的腹泻死亡的最常见原因。缺乏 定植抗性的增加是由新生儿微生物群中梭菌目的缺乏引起的。我们也 发现感染后诱导的IgG而不是伊加识别表面C。啮齿动物毒力因子， 在肠腔内结合有毒细菌，导致它们被中性粒细胞调理和吞噬， 而表型无毒的病原体保留在肠腔中， 微生物群因此，免疫系统和微生物群在C. rodentium 根除在该提案中，我们提出了三个具体目标：（i）确定梭菌 物种介导肠道病原体的抑制;（ii）了解促进肠道病原体的机制。 保护性梭菌在新生儿肠道中的定殖，以及（iii）确定 肠IgG抗C.啮齿动物毒力因子保护新生儿免受感染。拟议的研究 有可能对人类健康，特别是婴儿和儿童的健康产生重大影响。

ABSTRACT Enteric and diarrheal diseases caused by pathogens are important causes of childhood death worldwide. These diseases are estimated to cause near 1 million deaths per year in children under 5 years old worldwide, ranking second as the cause of death in this age group. This is largely due to their increased susceptibility of neonates and young children to enteric infections. In the healthy adult gut, the microbiota provides “colonization resistance”, forming a barrier against invading pathogens. The increased susceptibility to infections has been generally ascribed to immaturity of the immune system; however, additional factors may play an important role because immune responses to different stimuli are highly variable among neonates. Recent studies in our laboratory showed that the microbiota of neonatal mice is impaired in mediating colonization resistance against Salmonella and Citrobacter rodentium, a bacterium that models infection by enteropathogenic E. coli (EPEC), the most common cause of diarrheal deaths by bacteria worldwide. The lack of colonization resistance was caused by the absence of Clostridiales in the neonatal microbiota. We also found that IgG, but not IgA, induced after infection recognized surface C. rodentium virulence factors and bound virulent bacteria within the intestinal lumen leading to their opsonization and engulfment by neutrophils, while phenotypically avirulent pathogens remained in the intestinal lumen and are out-competed by the microbiota. Thus, the immune system and the microbiota play cooperative and essential roles in C. rodentium eradication. In this proposal, we proposed three specific Aims (i) to identify mechanisms by which Clostridia species mediate inhibition of enteric pathogen in the gut; (ii) understand the mechanisms that promote the colonization of protective Clostridiales in the neonatal intestine and (iii) determine the mechanism by which intestinal IgG against C. rodentium virulence factors protects neonates from infection. The proposed studies have the potential for a major impact on human health and in particular on that of infants and children.