Regulation of host innate and adaptive immunity by bacterial type III effectors

细菌病原体使用III型分泌系统(T3s)将效应物转移到受感染的宿主体内。 促进毒力的细胞。T3还可以触发补偿性先天免疫反应，从而保护 受感染的主机。例如，T3s可以在受感染的宿主细胞中触发炎症体组装，导致细胞 死亡和细胞因子的分泌。因此，毒力强的病原体必须抑制保护性代偿宿主 由T3s引发的免疫反应。该项目的长期目标是了解T3S如何 细菌病原体耶尔森氏菌中的系统最初触发并随后抑制宿主炎症体。一个 人类遗传性自体炎症性疾病和对耶尔森氏菌感染的抵抗力之间的可能联系也是 探索过了。T3S效应子YopE是一种GTP酶激活蛋白(GAP)，通过以下方式促进耶尔森氏菌的毒力 使RhoA失活以抑制吞噬作用。YopE RhoA GAP活性最近被证明可以触发吡喃 巨噬细胞中的炎性小体。已知的是，共价灭活RhoA的细菌毒素会触发这种印迹 炎症体，通过一种使用激酶PrK的调节机制。具体地说，活跃的RhoA积极 PrK通过变构相互作用调节，PrK通过磷酸化负性调控吡喃。触发 YopE缺口打印炎症体是意想不到的，因为已发表的数据表明，这种反应 所需的共价灭活RhoA。目前尚不清楚YopE是否会通过同样的方式触发吡咯炎症体 机制是毒素共价灭活RhoA，目前尚不清楚其他细菌RhoA间隙是否会导致这一过程 回应。目标1将检验YopE、其他细菌间隙和毒素共价修饰的假设 RhoA，通过PRK失活的保守变构机制触发印迹炎症体。T3S 效应剂YopM通过抑制炎性小体提高耶尔森氏菌的毒力。最近发现， YopM抑制比林，使耶尔森氏菌绕过YopE引发的炎性小体。从机械上讲，YopM 劫持PRK以维持吡喃的磷酸化和非活性状态。使用挖掘机获取的已发布数据 耶尔森氏菌感染小鼠实验表明，YopM靶向炎性单核细胞促进 耶尔西尼亚毒力。目标2将检验耶尔森氏菌毒力需要YopM抑制激活的假设 炎性单核细胞中的吡喃。编码吡喃的基因MEFV的密码子变化是导致 人类自身炎症性疾病家族性地中海热(FMF)。有人建议说， 地中海和中东人群中FMF的高携带者频率是由于选择性 在抵抗未知感染方面的优势。目标3将测试FMF吡喃变体的假设，这是 触发结构性炎症小体激活，提供宿主对鼠疫耶尔森氏菌感染的抵抗力。

Type III secretion (T3S) systems are used by bacterial pathogens to translocate effectors into infected host cells to promote virulence. T3S can also trigger compensatory innate immune responses that can protect the infected host. For example, T3S can trigger inflammasome assembly in infected host cells, resulting in cell death and secretion of cytokines. Virulent pathogens must therefore inhibit protective compensatory host immune responses triggered by T3S. The long-term objective of this project is to understand how a T3S system in the bacterial pathogen Yersinia initially triggers and subsequently inhibits host inflammasomes. A possible link between a human genetic autoinflammatory disease and resistance to Yersinia infection is also explored. The T3S effector YopE is a GTPase-activation protein (GAP) that promotes Yersinia virulence by deactivating RhoA to inhibit phagocytosis. YopE RhoA GAP activity was recently shown to trigger the pyrin inflammasome in macrophages. Bacterial toxins that covalently inactivate RhoA are known to trigger the pryin inflammasome, via a regulatory mechanism that uses the kinase PRK. Specifically, active RhoA positively regulates PRK by allosteric interaction and PRK negatively controls pyrin by phosphorylation. Triggering of the pryin inflammasome by the YopE GAP is unexpected because published data indicated that this response required covalent inactivation of RhoA. It is unknown if YopE triggers the pyrin inflammasome by the same mechanism as toxins that covalently inactivate RhoA, and it is unclear if other bacterial RhoA GAPs induce this response. Aim 1 will test the hypothesis that YopE, other bacterial GAPs, and toxins that covalently modify RhoA, trigger the pryin inflammasome by a conserved allosteric mechanism of PRK inactivation. The T3S effector YopM promotes Yersinia virulence by inhibiting inflammasomes. It has recently been discovered that YopM inhibits pyrin, allowing Yersinia to bypass YopE-triggered inflammasomes. Mechanistically, YopM hijacks PRK to maintain pyrin in a phosphorylated and inactive state. Published data obtained using knock out mouse lines in Yersinia infection assays suggest that YopM targets inflammatory monocytes to promote Yersinia virulence. Aim 2 will test the hypothesis that Yersinia virulence requires YopM to inhibit activation of pyrin in inflammatory monocytes. Codon changes in the gene Mefv, which encodes pyrin, are responsible for the human autoinflammatory disease Familial Mediterranean Fever (FMF). It has been suggested that the high carrier frequency of FMF in Mediterranean and Middle Eastern populations has resulted from a selective advantage in resistance to an unknown infection. Aim 3 will test the hypothesis that FMF pyrin variants, which trigger constitutive inflammasome activation, provide host resistance to Yersinia pestis infection.