Metabolite sensing in an oral polymicrobial community

描述（由申请人提供）：病原体在人体内的生存已经被严格研究了一个多世纪。由于一系列的能力，细菌能够在体内定植，持续存在和茁壮成长。大多数细菌致病机制的研究都集中在单一培养感染上；然而，很明显，许多细菌感染不仅仅是单一物种定植的结果，而是几个物种定植的结果。多微生物感染中的微生物经常表现出协同相互作用，导致感染部位的定植和持久性增强，而控制这些协同相互作用的分子过程尚未得到很好的定义。我们的实验室利用两种模型系统来研究多微生物的协同作用。该系统由机会性革兰氏阴性病原菌放线菌聚集菌（Aa）和革兰氏阳性病原菌戈登氏链球菌（Sg）组成。使用这个模型系统，我们正在测试一个重要的假设，即多微生物感染中的细菌对微生物群落其他成员产生的初级代谢物表现出明确的反应，这些反应对于建立多微生物感染至关重要。我们主要集中于阐明Aa对Sg产生的两种主要代谢物，l -乳酸和H2O2的分子反应。这些研究揭示了新的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)从机制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展、对宿主先天免疫的抗性和体内持久性；(2)开发探索多微生物相互作用的新技术。为此，我们提出了以下实验：(i)阐明Aa l -乳酸偏好的分子机制并评估其在体内的重要性；（ii）阐明Aa在共培养过程中对先天免疫的保护机制并评估其在体内的重要性；（iii）表征H2O2和共培养对生物膜分散的影响。

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.