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Mechanisms of Corynebacterium-Dolosigranulum Interactions that Shape Human Nasal Microbiota

棒状杆菌与多洛西颗粒相互作用塑造人类鼻腔微生物群的机制

基本信息

批准号：
10205817
负责人：
Katherine Paige Lemon
金额：
$ 43.6万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10205817
关键词：
Address Affect Age Air Area Bacteria Benign Biochemical Pathway Biological Models Biomimetics Cell Line Coculture Techniques Collaborations Collection Communities Corynebacterium Data Disease Environment Epithelial Etiology Food Webs Funding Genes Genetic Engineering Genomics Goals Growth Health Health Benefit Health Promotion Human In Vitro Infection Infection prevention Liquid substance Metabolic Microbe Modeling Molecular Nasal Epithelium National Institute of General Medical Sciences Nose Nutrient Organoids Otitis Media Phenotype Physiology Play Pneumonia Proteins Research Risk Role Shapes Staphylococcus aureus Streptococcus pneumoniae Structure Surface System auxotrophy host-microbe interactions in vivo innovation metabolomics microbial microbial community nasal microbiome nasal microbiota novel strategies pathobiont transcriptomics volunteer

项目摘要

The objective unifying our two areas of NIGMS-funded research is to identify molecular mechanisms underlying microbe-microbe and microbe-host interactions involving D. pigrum and nasal Corynebacterium species that shape the human nasal microbiota. Evidence indicates that Corynebacterium species and Dolosigranulum pigrum play key roles in structuring a nasal microbiota beneficial to human health. For example, people with high levels of Corynebacterium and/or D. pigrum in their nasal microbiota are less likely to be colonized by pathobionts and, therefore, are at lower risk of invasive infections in other parts of their bodies. Similarly, nasal microbiota dominated by Corynebacterium/D. pigrum are often associated with health rather than with diseases such as otitis media and pneumonia. Our overarching hypothesis is that interactions between D. pigrum and Corynebacterium species drive a beneficial health-promoting human nasal microbiota. A central goal of this research is to shift from correlations in compositional data to causation by identifying molecular mechanisms that underlie both in vivo associations and in vitro phenotypes. Our NIGMS-supported preliminary data show that there are four common species of nasal Corynebacterium. Three of these are positively correlated with D. pigrum and enhance D. pigrum growth in vitro. Furthermore, cocultivation of D. pigrum with Corynebacterium pseudodiphtheriticum together robustly inhibits S. pneumoniae in vitro, compared to either alone. D. pigrum also inhibits S. aureus growth in vitro. These in vitro results support a role for in vivo interactions with potential health benefits. To understand microbe-microbe and microbe-epithelium interactions in the human nasal passages, we will use human nasal epithelial organoids at an air-liquid interface (aka nasanoids) as an innovative biomimetic model system in collaboration with our Organoid Core. Microbial communities are characterized by a network of metabolic interactions among microbes and with the environment. Genomic analysis uncovered D. pigrum auxotrophies indicating it depends on the host or microbial neighbors for key nutrients. Our research will address gaps in understanding the food web that supports human nasal microbiota; the effects on the epithelium of hosting microbes; and the physiology and function of potentially beneficial nasal bacteria. A key advantage of using human nasal microbiota to identify metabolic interactions is that it is a self-contained bacterial-epithelial system with regard to nutrients. We will use complementary approaches including pan-genomics, metabolic modeling, dual bacteria-epithelium transcriptomics, metabolomics and genetic engineering. We will also tackle key technical challenges in the nasal microbiome field to facilitate identification of metabolites, proteins and genes involved in interactions. To advance research on D. pigrum and nasal Corynebacterium, we have established a large culture collection of nasal bacteria from > 400 volunteers of all ages. By identifying metabolic interactions between nasal Corynebacterium species, D. pigrum, and the nasal epithelium that sculpt a health- promoting human nasal microbiota, we hope to catalyze new approaches for preventing infection.

统一nigms资助的两个研究领域的目标是确定潜在的分子机制