Mechanisms of MRSA intestinal colonization

摘要 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。在这里我们 重点关注社区获得性 (CA)-MRSA 如何在胃肠道 (GI) 定殖。一把钥匙，但是 观察发现，胃肠道定植建立了传播储存库，并且是最重要的 婴儿和幼儿 CA-MRSA 感染的常见来源，他们的感染风险比 成人。我们和其他人使用小鼠模型来识别支持胃肠道定植的金黄色葡萄球菌特征。然而， 对与 CA-MRSA 相关的胃肠道定植机制知之甚少，部分原因是使用 依赖抗生素消耗肠道微生物群来建立定植的动物模型。我们最近发布的 未发表的工作改编了婴儿小鼠模型，以提供与 CA-MRSA GI 相关的易处理系统 社区中的殖民化，特别是在婴儿和儿童中。我们使用此方法获得的初步数据 模型表明，断奶与 CA-MRSA 定植抗性相关。我们还表明，毛孔 形成白细胞毒素（“毒素”）促进断奶小鼠 CA-MRSA 定植，但对幼年小鼠没有影响 或无菌成年小鼠。鉴于我们发现断奶与 CA-定植抗性相关 MRSA 是一种被认为是由共生微生物群赋予的特性，我们假设 共生细菌通过毒素使 CA-MRSA 能够克服共生细菌的定植抗性 细菌。我们还发现小鼠体内对 CA-MRSA 的定植抵抗力反而增强 缺乏适应性免疫（B 细胞和 T 细胞）。鉴于先天免疫细胞在 在这些小鼠中，断奶和赋予对病原体的抵抗力上调，我们其次假设 先天免疫和微生物群结合起来抑制 CA-MRSA 定植。为了检验我们的假设，我们将 1) 识别介导肠道中 CA-MRSA 定植抗性的共生物种，2) 了解免疫 在没有适应性免疫的小鼠中抑制 CA-MRSA 定植的机制，以及 3) 确定 特定的 CA-MRSA 毒素以及影响细菌的金黄色葡萄球菌和肠道共生体之间的相互作用 竞争。这些研究的结果有望确定细菌分类群、先天免疫机制和 我们可以操纵 CA-MRSA 位点来扰乱 CA-MRSA 定植。结果将指导未来的努力 确定微生物群和细胞类型特异性靶标，以合理设计调节治疗策略 殖民化。在某种程度上，该工作确定了直接导致病原体的毒力因子 传播，我们的工作还将揭示可用作双重作用目标的细菌机制 疗法。

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 Our recent published and unpublished work adapted an infant mouse model to provide a tractable system relevant to CA-MRSA GI colonization in the community, especially among infants and children.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.