Inhibition of T cells by Salmonella

描述（由申请方提供）：细菌病原体必须避免被免疫系统清除以建立感染，但细菌免疫破坏的许多机制仍不明确。许多细菌病原体破坏先天免疫系统的途径，但细菌病原体如何克服适应性免疫系统的途径还不清楚。T细胞是适应性免疫系统的关键组成部分，并且是针对许多细菌病原体的保护性免疫所必需的。鼠伤寒沙门氏菌（S.鼠伤寒沙门氏菌（Typhimurium）是直接抑制T细胞应答的病原菌，但负责这种抑制的因子尚未被鉴定。我们最近证明S.鼠伤寒杆菌通过产生水解L-天冬酰胺的L-天冬酰胺酶II来抑制T细胞应答。L-天冬酰胺酶II对于抑制T细胞胚细胞生成、细胞因子产生和增殖以及下调T细胞受体的表达是必需的且足够的。此外，S.在加入外源性L-天冬酰胺后，在体外可防止鼠伤寒沙门氏菌诱导的T细胞抑制。S.缺乏L-天冬酰胺酶II基因的鼠伤寒沙门氏菌不能抑制T细胞应答并在体内表现出减弱的毒力。L-天冬酰胺酶在临床上用于治疗急性淋巴细胞白血病，但致病菌产生的L-天冬酰胺酶II尚未被认为是微生物免疫破坏的机制。本申请的研究将1）确定S.鼠伤寒沙门氏菌抑制T细胞应答并介导毒力，2）确定L-天冬酰胺酶II在沙门氏菌感染的发病机制和宿主应答中的作用。鼠伤寒。这项研究的完成将为重要的机制问题提供答案，并将为T细胞在保护性免疫中对S。鼠伤寒。鉴于L-天冬酰胺酶II基因在革兰氏阴性菌中高度保守，并已被证明有助于几种重要的人类病原体的毒力，我们的研究结果可能会远远超出S。鼠伤寒。从拟议的研究中获得的见解将对理解宿主与细菌病原体的相互作用产生根本性影响，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.