Metabolite sensing in an oral polymicrobial community

描述（由申请人提供）：世纪以来，对病原体在人体内的存活进行了严格的研究。由于一系列的能力，细菌能够在体内定殖、存活和繁殖。大多数细菌发病机制研究都集中在单一培养物感染;然而，很明显，许多细菌感染不仅仅是单一物种定植的结果，而是多个物种定植的结果。多微生物感染中的微生物通常显示协同相互作用，导致感染部位的定殖和持久性增强，并且控制这些协同相互作用的分子过程没有很好地定义。我们的实验室利用两种模型系统来研究多微生物协同作用。该系统由条件致病的革兰氏阴性病原菌伴放线菌聚集杆菌（Aa）和革兰氏阳性细菌戈登链球菌（Sg）组成。使用这个模型系统，我们正在测试压倒一切的假设，即多微生物感染内的细菌显示由微生物群落的其他成员产生的初级代谢产物的确定的反应，这些反应是建立多微生物感染的关键。我们主要集中在阐明Aa的分子反应，以两个主要的代谢产物产生的Sg，L-乳酸和H2 O2。这些研究发现了新的Aa反应，不仅影响这种细菌如何与Sg相互作用，而且影响它如何与宿主相互作用。本研究计划的总体目标是：1）从机理的角度研究口腔细菌之间的多微生物相互作用如何影响群落发育，对宿主先天免疫的抵抗力和体内持久性，以及2）开发用于探测多微生物相互作用的新技术。为此，我们提出了实验，（i）阐明的分子机制的Aa L-乳酸盐的偏好，并评估其在体内的重要性，（ii）阐明的机制，Aa的保护先天免疫在共培养过程中，并评估其在体内的重要性，（iii）表征的影响H2 O2和共培养生物膜分散。 公共卫生相关性：大多数细菌在自然界中并不以单一培养物的形式存在，而是以复杂的群落形式存在，其中细菌物种之间的相互作用会影响个体和群落的命运。该项目的目标是研究人类口腔中两种机会致病菌之间的相互作用，并确定这些相互作用如何增强这些细菌对免疫系统杀死的抵抗力。这项研究对疾病有直接的影响，因为多微生物相互作用对人体内病原体存活的重要性尚未深入研究。

DESCRIPTION (provided by applicant): The survival of pathogens in the human body has been rigorously studied for well over a century. Bacteria are able to colonize, persist and thrive in vivo due to an array of capabilities. Most bacterial pathogenesis studies have focused on mono-culture infections; however, it is clear that many bacterial infections are not simply the result of colonization with a single species, but are instead a result of colonization with several. Microbes within polymicrobial infections often display synergistic interactions that result in enhanced colonization and persistence in the infection site, and the molecular processes controlling these synergistic interactions are not well defined. Our lab utilizes a two-species model system to study polymicrobial synergy. The system is composed of the opportunistic Gram-negative pathogen Aggregatibacter actinomycetemcomitans (Aa) and the Gram-positive bacterium Streptococcus gordonii (Sg). Using this model system, we are testing the overriding hypothesis that bacteria within polymicrobial infections display defined responses to the primary metabolites produced by other members of the microbial community, and these responses are critical for establishing polymicrobial infections. We have primarily focused on elucidating the molecular responses of Aa to two primary metabolites produced by Sg, L-lactate and H2O2. These studies have uncovered novel Aa responses that not only affect how this bacterium interacts with Sg but also how it interacts with the host. The overall goals of this research plan are to 1) examine from a mechanistic standpoint, how polymicrobial interactions between oral bacteria impact community development, resistance to host innate immunity, and in vivo persistence, and 2) develop novel technologies for probing polymicrobial interactions. To this end, we have proposed experiments to (i) elucidate the molecular mechanism of Aa L-lactate preference and assess its importance in vivo, (ii) elucidate the mechanism of Aa protection from innate immunity during co-culture and assess its importance in vivo, (iii) characterize the impact of H2O2 and co-culture on biofilm dispersion. PUBLIC HEALTH RELEVANCE: Most bacteria do not exist in nature as monocultures, but instead as complex communities in which interactions between bacterial species affect the fate of the individual as well as the community. The goal of this project is to examine interactions between two opportunistic pathogens of the human mouth and define how these interactions enhance resistance of these bacteria to killing by the immune system. This research has direct consequences for disease as the importance of polymicrobial interactions for pathogen survival in the human body has not been investigated in depth.