Mechanisms of MRSA intestinal colonization

MRSA肠道定植机制

基本信息

批准号：
10321574
负责人：
Ken Hashigiwa Cadwell
金额：
$ 69.97万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10321574
关键词：
Achievement Address Adoptive Cell Transfers Adult Affect Animal Model Antibiotics B-Lymphocytes Cell Shape Cells Child Communities Data Development Feasibility Studies Future Gastrointestinal tract structure Genus staphylococcus Germ-Free Goals Growth Immune Immune response Immune system Immunity Infant Infection Infectious Skin Diseases Innate Immune Response Intestines Knowledge Lead 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 Staphylococcus aureus Staphylococcus aureus infection System T-Lymphocyte Testing Therapeutic Tissues Toxin Virulence Virulence Factors Weaning Work adaptive immunity base cell type chemokine clinically relevant colonization resistance commensal bacteria commensal microbes community transmission cytokine gastrointestinal gut colonization gut microbiota human microbiota infection risk innate immune mechanisms insight leukotoxin member methicillin resistant Staphylococcus aureus microbiota mouse model mutant normal microbiota novel therapeutics novel vaccines pathogen prevent rational design response theories trait transmission process unpublished works

项目摘要

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 Our recent published and unpublished work adapted an infant mouse model to provide a tractable system relevant to CA-MRSA GI colonization in the community, especially among infants and children.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。重点关注社区获得性 (CA)-MRSA 如何在胃肠道 (GI) 定殖，但这是一个关键。未被充分认识到，观察结果表明，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，他们的感染风险高于我们和其他人已经使用小鼠模型来鉴定支持胃肠道定植的金黄色葡萄球菌特征。对与 CA-MRSA 相关的胃肠道定植机制知之甚少，部分原因是使用我们最近发表的依赖抗生素消耗肠道微生物群来建立定植的动物模型。未发表的工作改编了婴儿小鼠模型，以提供与 CA-MRSA GI 相关的易处理系统我们的初步数据是通过此方法获得的。模型表明，断奶与 CA-MRSA 的定植抗性相关。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，我们捕捉到了这种扰动共生细菌通过毒素使 CA-MRSA 能够克服共生细菌的定植抗性我们还发现小鼠体内对 CA-MRSA 的定植耐药性反而增加。缺乏适应性免疫（B 细胞和 T 细胞）的先天免疫细胞在过程中塑造肠道微生物群。在这些小鼠中，断奶和赋予对病原体的抵抗力上调，我们其次发现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。