Mechanisms of MRSA intestinal colonization

总结 我们的长期目标是找到控制耐甲氧西林金黄色葡萄球菌（MRSA）的方法。这里我们 重点是表征社区获得性（CA）-MRSA如何定植于胃肠道（GI）。一把钥匙，但是 然而，据观察，胃肠道定植建立了一个传播库， CA-MRSA感染在婴儿和幼儿中的常见起源，他们的感染风险高于 成年人了我们和其他人已经使用小鼠模型来鉴定S。支持GI定植的金黄色葡萄球菌性状。然而，在这方面， 与CA-MRSA相关的胃肠道定植机制知之甚少，部分原因是使用 依赖于肠道微生物群的抗生素消耗来建立定植的动物模型。我们最近出版的 和未发表的工作改编了一个婴儿小鼠模型，以提供一个与CA-MRSA GI相关的易处理系统 在社区中，特别是在婴儿和儿童中的殖民化。我们使用此方法获得的初步数据 模型，表明断奶与CA-MRSA的定植抗性有关。我们还表明，孔- 形成白细胞毒素（“毒素”）促进CA-MRSA在断奶小鼠中的定殖，但对幼鼠没有影响 或无菌成年小鼠。鉴于我们发现断奶与对CA的定植抗性有关- MRSA，一种被认为是由肠道微生物群赋予的特性，我们假设， 通过毒素使CA-MRSA能够克服细菌的定殖抗性 细菌我们还确定了小鼠对CA-MRSA的定植抗性矛盾地增加， 缺乏适应性免疫（B和T细胞）。考虑到先天免疫细胞在肠道微生物群中的作用， 断奶和赋予对病原体的抗性在这些小鼠中上调，我们其次假设， 先天免疫和微生物群联合收割机抑制CA-MRSA定殖。为了验证我们的假设，我们将1） 鉴定在肠道中介导CA-MRSA定殖抗性的细菌种类，2）了解免疫系统中的 在没有获得性免疫的小鼠中抑制CA-MRSA定殖的机制，和3）确定CA-MRSA的 特异性CA-MRSA毒素和S.金黄色葡萄球菌和肠道细菌， 竞争这些研究的结果有望确定细菌分类群，先天免疫机制， 我们可以操纵CA-MRSA基因座以干扰CA-MRSA定植。研究结果将指导今后的努力， 鉴定微生物群和细胞类型特异性靶标，用于合理设计的治疗策略， 殖民化在某种程度上，这项工作确定了直接导致病原体的毒力因子， 传播，我们的工作也将揭示细菌的机制，可以利用作为目标的双重作用 治疗学

SUMMARY Our long-term objective is to find ways to control methicillin-resistant Staphylococcus aureus (MRSA). Here we focus on characterizing how community-acquired (CA)-MRSA colonizes the gastrointestinal (GI) tract. A key, but underappreciated, observation is that GI colonization establishes a reservoir for transmission and is the most common origin for CA-MRSA infection in infants and young children, who are at greater risk of infection than adults. We and others have used murine models to identify S. aureus traits that support GI colonization. However, the mechanisms governing GI colonization relevant to CA-MRSA are poorly understood, in part due to the use of animal models that rely on antibiotic depletion of gut microbiota to establish colonization. Our recent published and unpublished work adapted an infant mouse model to provide a tractable system relevant to CA-MRSA GI colonization in the community, especially among infants and children. Our preliminary data, obtained using this model, show that weaning is associated with colonization resistance to CA-MRSA. We also show that pore- forming leukotoxins (“toxins”) promote CA-MRSA colonization in weaned mice, but had no effect in infant mice or germ-free adult mice. Given our finding that weaning was associated with colonization resistance to CA- MRSA, a property thought to be conferred by commensal microbiota, we hypothesize that perturbation of commensal bacteria by toxins empowers CA-MRSA to overcome colonization resistance by commensal bacteria. We also established that colonization resistance against CA-MRSA is paradoxically increased in mice that lack adaptive immunity (B and T cells). Given that innate immune cells that shape the gut microbiota during weaning and confer resistance to pathogens are upregulated in such mice, we secondarily hypothesize that innate immunity and the microbiota combine to inhibit CA-MRSA colonization. To test our hypotheses, we will 1) identify commensal species that mediate CA-MRSA colonization resistance in the gut, 2) understand the immune mechanisms that inhibit the CA-MRSA colonization in mice without adaptive immunity, and 3) determine the specific CA-MRSA toxins and interactions between S. aureus and gut commensals that affect bacterial competition. The outcomes of these studies promise to identify bacterial taxa, innate immune mechanisms, and CA-MRSA loci we might manipulate to perturb CA-MRSA colonization. The results will guide future efforts to identify microbiota and cell-type-specific targets for rationally designed therapeutic strategies that modulate colonization. To the extent that the work identifies virulence factors that contribute directly to pathogen transmission, our work will also uncover bacterial mechanisms that could be exploited as targets for dual-action therapeutics.