RovA regulon and virulence of Yersinia enterocolitica

描述（由申请人提供）：小肠结肠炎耶尔森菌是一种细菌性病原体，可导致多种临床综合征，但主要与胃肠道疾病相关。肠致病性耶尔森菌在分子水平上已经成为研究细菌发病机制的重要模型，这在很大程度上是因为它们易于在实验室中操作，基因组测序的存在，以及存在良好的小鼠感染模型。近年来，小肠结肠炎耶氏菌及其伴生致病菌假结核耶氏菌的研究出现了许多重要的发病机制范式。在这些细菌中首次描述了ii型分泌系统（TTSS），而耶尔森菌的ysc TTSS仍然是最具特征的一种。此外，小肠结肠炎耶氏菌和假结核耶氏菌是细菌入侵的重要模型，这一过程主要由inv基因编码。在进一步了解inv及其在毒力中的作用的研究中，我们最近发现了一种基因rovA，它在实验室和感染期间都能调节inv的表达。用rovA突变体进行的毒力研究表明，rovA突变体的毒力明显低于野生型菌株或inv突变体。有证据表明，RovA调节先前未描述的毒力决定因素。对rovA突变体与宿主的更详细检查表明，它在诱导il -1 α产生的能力和向更深组织传播的能力方面存在缺陷。尽管存在其他几种促炎细胞因子，但无法诱导IL-1a似乎导致宿主无法在Peyer's补丁中触发炎症反应。初步证据还表明，未能诱导IL-1a至少是rovA突变体无毒的部分原因。基于这些结果和其他信息，我们假设感染期间局部Peyer's补丁中IL-1a的产生是完全炎症反应所必需的，而炎症反应反过来又影响细菌的全身传播和毒力。因此，通过分析体内rovA突变体揭示的宿主-病原体相互作用的各个方面，并结合对rovA调控子的研究，我们可以更好地了解早期宿主-病原体相互作用影响毒力的分子细节。具体而言，我们建议：(1)表征IL-1a在小肠结肠炎菌的毒力和传播中的反应；(2) RovA调控基因在毒力、IL-1a应答和传播中的作用；(3) RovA调控基因表达的机制。

DESCRIPTION (provided by applicant): Yersinia enterocolitica is a bacterial pathogen responsible for a wide range of clinical syndromes but is primarily associated with gastrointestinal disorders. The enteropathogenic yersiniae have served as important models for the study of bacterial pathogenesis at the molecular level due in large part to their ease of manipulation in the laboratory, the existence of a sequenced genome, and the existence of an excellent murine model of infection. In recent years a number of important paradigms of pathogenesis have emerged from the studies of Y. enterocolitica and its companion enteropathogen, Y. pseudotuberculosis. Type Ill secretion systems (TTSS) were first described in these bacteria and the ysc TTSS of yersiniae remains one of the best characterized. In addition Y. enterocolitica and Y. pseudotuberculosis have served as important models of bacterial invasion, a process primarily encoded by the inv gene. In studies to further our knowledge of inv and its role in virulence we recently identified a gene, rovA, that regulates expression of inv both in the lab and during an infection. Virulence studies with a rovA mutant indicated that the rovA mutant was significantly less virulent than the wildtype strain or the inv mutant. Evidence suggests that RovA regulates previously undescribed virulence determinants. A more detailed examination of the rovA mutant with the host indicated it is defective in its ability to induce production of IL-1alpha and its ability to disseminate to deeper tissues. The inability to induce IL-1a appears to result in the inability of the host to trigger an inflammatory response in the Peyer's patches despite the presence of several other proinflammatory cytokines. Preliminary evidence also suggests that the failure to induce IL-1a is at least partly responsible for the avirulence of the rovA mutant. Based on these results and other information, we hypothesize that production of IL-1a locally in the Peyer's patches during infection is necessary for the full inflammatory response that in turn affects systemic dissemination and virulence of the bacteria. Therefore by studying aspects of the host-pathogen interaction revealed by analyzing the rovA mutant in vivo, and together with studying the RovA regulon, we can gain a better understanding of the molecular details of the early host-pathogen interactions that affect virulence. Specifically we propose: (1) Characterization of the IL-1a response in virulence and dissemination of Y. enterocolitica; (2) The role of RovA regulated genes in virulence, the IL-1a response and dissemination; (3) The mechanism of RovA regulation of gene expression.