Inhibition of T cells by Salmonella

描述(申请人提供)：细菌病原体必须避免被免疫系统清除以确定感染，然而许多细菌免疫颠覆的机制仍然不清楚。许多细菌病原体颠覆了天然免疫系统的途径，但细菌病原体如何克服适应性免疫系统的途径尚不清楚。T细胞是适应性免疫系统的关键组成部分，对许多细菌病原体的保护性免疫是必需的。鼠伤寒沙门氏菌是一种直接抑制T细胞反应的病原菌，但导致这种抑制的因素尚未确定。我们最近发现，鼠伤寒沙门氏菌通过产生L-天冬酰胺酶II来抑制T细胞反应，该酶能分解L-天冬酰胺。L-天门冬酰胺酶II是抑制T细胞母细胞生成、细胞因子的产生和增殖以及下调T细胞受体表达的必要条件和充分条件。此外，加入外源L-天冬酰胺可阻止鼠伤寒沙门氏菌在体外对T细胞的抑制作用。缺乏L天冬酰胺酶II基因的鼠伤寒沙门氏菌在体内不能抑制T细胞反应，也不能表现出减弱的毒力。L-天冬酰胺酶在临床上用于治疗急性淋巴细胞白血病，但病原菌产生L-天冬酰胺酶II尚未被认为是微生物免疫颠覆的机制。本申请中提出的研究将1)确定鼠伤寒沙门氏菌产生的L-天冬酰胺酶II抑制T细胞反应和介导毒力的机制，2)确定L-天冬酰胺酶II在鼠伤寒沙门氏菌感染的发病机制和宿主反应中的作用。这项拟议研究的完成将为重要的机制问题提供答案，并将为T细胞在鼠伤寒沙门氏菌保护性免疫中的作用提供一个极大的增强视角。鉴于L-天冬酰胺酶II基因在革兰氏阴性菌中高度保守，并已被证明与几种重要的人类病原体的毒力有关，我们的发现可能远远超出鼠伤寒沙门氏菌的范围。拟议研究的见解将对了解宿主与细菌病原体的相互作用具有基本意义，并可能导致开发新的广谱治疗方法和预防措施，以克服细菌感染性疾病。

DESCRIPTION (provided by applicant): Bacterial pathogens must avoid clearance by the immune system to establish infection, yet many mechanisms of bacterial immune subversion remain undefined. A number of bacterial pathogens subvert pathways of the innate immune system, but how bacterial pathogens overcome pathways of the adaptive immune system is not well understood. T cells are a key component of the adaptive immune system and are required for protective immunity against many bacterial pathogens. Salmonella enterica serovar Typhimurium (S. typhimurium) are pathogenic bacteria that inhibit the response of T cells directly, but the factor responsible for this inhibition has not been identified. We recently showe that S. typhimurium inhibit T cell responses by producing L- asparaginase II, which hydrolyzes L-asparagine. L-asparaginase II is necessary and sufficient to suppress T cell blastogenesis, cytokine production and proliferation, and to down-modulate expression of the T cell receptor. Furthermore, S. typhimurium-induced inhibition of T cells in vitro is prevented upon addition of exogenous L-asparagine. S. typhimurium lacking the L-asparaginase II gene are unable to inhibit T cell responses and exhibit attenuated virulence in vivo. L-asparaginases are used clinically to treat acute lymphoblastic leukemia, yet production of L-asparaginase II by pathogenic bacteria has been unrecognized as a mechanism of microbial immune subversion. The research proposed in this application will 1) determine the mechanism by which L-asparaginase II produced by S. typhimurium inhibits T cell responses and mediates virulence, and 2) determine the role of L-asparaginase II in the pathogenesis of, and host response to, infection with S. typhimurium. Completion of the proposed research will provide answers to important mechanistic questions and will provide a vastly enhanced perspective on the role of T cells in protective immunity against S. typhimurium. Given that the L-asparaginase II gene is highly conserved in Gram-negative bacteria and has been shown to contribute to virulence of several important human pathogens, our findings may extend well beyond S. typhimurium. Insights from the proposed research will have fundamental implications for understanding host interactions with bacterial pathogens and could lead to the development of new broad- spectrum therapeutic approaches and preventive measures to overcome bacterial infectious diseases.