Mechanisms of MRSA intestinal colonization

MRSA肠道定植机制

• 批准号: 10548125
• 负责人: BO SHOPSIN
• 金额: $ 69.97万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-17 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548125
• 关键词: Achievement; Address; Adoptive Cell Transfers; Adult; Affect; Animal Model; Antibiotics; Anus; B-Lymphocytes; Cell Shape; Cells; Child; Communities; Data; Development; Feasibility Studies; Future; Gastrointestinal tract structure; Genus staphylococcus; Germ-Free; Goals; Growth; Human; Immune; Immune response; Immune system; Immunity; Infant; Infection; Infectious Skin Diseases; Innate Immune Response; Intestines; Knowledge; Link; Lymphocyte; Lymphoid Cell; Measures; Mediating; Modeling; Mus; Natural Immunity; Outcome Study; Pathway interactions; Patients; Phenotype; Population; Probiotics; Process; Property; Public Health; Publishing; Rag1 Mouse; Rectum; Resistance; Resolution; Risk; Role; Shapes; Site; Skin; Sorting; Staphylococcus aureus; Staphylococcus aureus infection; System; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxin; Virulence; Virulence Factors; Weaning; Work; adaptive immunity; cell type; chemokine; clinically relevant; colonization resistance; commensal bacteria; commensal microbes; community transmission; cytokine; empowerment; gastrointestinal; gut colonization; gut microbiota; infection risk; innate immune mechanisms; insight; leukotoxin; member; methicillin resistant Staphylococcus aureus; microbiota; mouse model; mutant; normal microbiota; novel therapeutics; novel vaccines; pathogen; permissiveness; prevent; rational design; rectal; response; theories; trait; transmission process; unpublished works

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.

概括 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。我们在这里 专注于表征社区获得的（CA）-MRSA如何定居胃肠道（GI）。一个钥匙，但是 被低估的观察结果是，胃肠道殖建立了传播的储层，是最多的 婴儿和幼儿感染CA-MRSA感染的常见起源，感染的风险大于 成年人。我们和其他人使用鼠模型来识别支持GI定植的金黄色葡萄球菌特征。然而， 与CA-MRSA相关的GI殖民化的机制知之甚少，部分原因是 依靠肠道菌群抗生素部署来建立定殖的动物模型。我们最近出版的 未发表的工作改编了婴儿小鼠模型，以提供与CA-MRSA GI相关的可拖动系统 社区的殖民化，尤其是在婴儿和儿童中。我们的初步数据，使用此数据获得 模型表明断奶与对CA-MRSA的定殖抗性有关。我们还表明毛孔 - 形成白细胞毒素（“毒素”）促进断奶小鼠的CA-MRSA定植，但对婴儿小鼠没有影响 或无菌成年小鼠。鉴于我们发现断奶与对ca-的定殖抗性有关 MRSA，被认为是由Comensal Microbiota授予的财产，我们假设这种扰动 毒素的共生细菌使CA-MRSA能够克服共生的定殖抗性 细菌。我们还确定，小鼠对CA-MRSA的定殖耐药性在矛盾上增加。 缺乏适应性免疫（B和T细胞）。鉴于先天性免疫史细胞在塑造肠道菌群 在这样的小鼠中，对病原体的断奶和会议抵抗有所更新，我们次要假设 先天免疫和微生物群合抑制CA-MRSA定殖。为了检验我们的假设，我们将1） 确定介导肠道中CA-MRSA定殖抗性的共生物种，2）了解免疫 抑制没有适应性免疫的小鼠中CA-MRSA定殖的机制，3）确定 特定的CA-MRSA毒素以及金黄色葡萄球菌和影响细菌的肠道分子之间的相互作用 竞赛。这些研究的结果有望识别细菌分类群，先天免疫力学和 CA-MRSA基因座我们可能会操纵CA-MRSA定植。结果将指导未来的努力 确定用于调节合理设计的治疗策​​略的微生物群和细胞类型的靶标 殖民化。在某种程度上，工作鉴定了直接促成病原体的病毒因子 传播，我们的工作还将发现可作为双重动作目标探索的细菌机制 疗法。