ROLE OF GBS CAPSULE IN ASCENDING E. COLI UTI & UROSEPSIS IN AGED MULTIPAROUS MICE

描述（由申请人提供）：粘膜感染的发病机制通常在单微生物环境中研究，忽略了暴露时存在的其他潜在致病微生物菌群的可能影响。尿路感染（UTI）是一种常见且有时持续的疾病，可对易感人群造成危及生命的后果。女性感染尿路感染的风险比男性高得多，而且在生殖周期的特定阶段（怀孕期和绝经期）更容易出现感染并发症。尿道周围和粘膜附近存在丰富多样的微生物种群，因此尿路细菌暴露很可能是多微生物的。尿路致病性大肠杆菌（UPEC）是尿路感染最常见的原因，但在多微生物环境下，尿中经常与低水平的革兰氏阳性菌共同发生。尿中存在亚诊断水平的革兰氏阳性通常被认为是临床无关紧要的；然而，这一假设从未经过实验验证。B群链球菌（GBS）存在于下胃肠道和阴道的共生体中，通常从患有UPEC UTI或无症状细菌性尿路感染的妇女中分离出来。本提案描述了一种新的小鼠模型的发展，以研究小鼠尿路中多微生物与宿主的相互作用。拟议的实验使用该模型来研究GBS对upc UTI结果的影响。初步数据显示，GBS对UPEC感染有显著影响，改变尿路感染的过程、严重程度和结局。正在进行的细胞和分子研究正在确定参与多微生物对话的特定宿主和细菌因素。在本研究中，我们的目标是更全面地了解多微生物接种GBS后UPEC致病级联改变的机制。除了对泌尿系统发病机制的范式转换意义外，提出的研究可能会发现在特定临床环境中有价值的风险预测因子。

DESCRIPTION (provided by applicant): Pathogenesis of mucosal infections are often studied in monomicrobial settings that ignore the possible influence of other potentially pathogenic microbial flora present at the time of exposure. Urinary tract infection (UTI) is a common and sometimes persistent disease that can have life-threatening outcomes in susceptible populations. Women are at much higher risk of UTI than men, and are more likely to experience complications of infection during particular stages of the reproductive lifespan -- in pregnancy and after menopause. Abundant and diverse microbial populations exist in periurethral and nearby mucosal sites, therefore there is a high likelihood that bacterial exposures of the urinary tract are often polymicrobial. Uropathogenic E. coli (UPEC) is the most common cause of UTI, but often co-occurs with low levels of Gram positive bacteria in urine in a polymicrobial context. The presence of sub-diagnostic levels of Gram positives in urine is usually considered clinically insignificant; however, this assumption has never been tested experimentally. Group B Streptococcus (GBS) in a common commensal of the lower gastrointestinal and vaginal tracts and is commonly isolated from women with UPEC UTI or asymptomatic bacteriuria. This proposal describes the development of a novel murine model to study polymicrobial-host interactions in the urinary tract in mice. Proposed experiments use this model to investigste the impact of GBS on UPEC UTI outcomes. Preliminary data show that GBS has a striking impact on UPEC infection, altering the course, severity, and outcome of UTI. Ongoing cellular and molecular studies are defining specific host and bacterial factors involved in the polymicrobial dialogue. In this proposal, we aim to more fully understand the mechanisms driving alterations to the UPEC pathogenic cascade upon polymicrobial inoculation with GBS. In addition to paradigm-shifting implications for urinary pathogenesis, the proposed studies may uncover valuable predictors of risk in particular clinical settings. PUBLIC HEALTH RELEVANCE: Urinary tract infection (UTI) caused by uropathogenic E. coli (UPEC) is a major public health problem. We have developed an aged multiparous mouse model to study the impact of polymicrobial urinary tract exposure on the development of ascending and systemic infection caused by UPEC. Mechanistic insights about the role of Group B Streptococcus (GBS) in the exacerbation of UPEC infection will lay the foundation for a better clinical understanding of microbial risk factors for the development complicated UTI in susceptible groups.