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

III型分泌（T3S）系统被细菌病原体用于将效应子易位到受感染的宿主中 细胞，以提高毒力。T3S还可以触发代偿性先天免疫应答， 被感染的宿主例如，T3S可以在感染的宿主细胞中触发炎性小体组装，导致细胞凋亡。 死亡和分泌细胞因子。因此，致病病原体必须抑制保护性补偿宿主 T3S引发的免疫反应该项目的长期目标是了解T3 S如何 系统中的细菌病原体耶尔森氏菌最初触发并随后抑制宿主炎性小体。一 人类遗传性自身炎性疾病和对耶尔森氏菌感染的抵抗力之间可能存在联系， 探讨了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： 灭活RhoA以抑制吞噬作用。YopE RhoA GAP活性最近被证明可以触发Pyrin 巨噬细胞中的炎性小体。已知与RhoA共价结合的细菌毒素会触发窥探， 炎症小体，通过使用激酶α的调节机制。具体而言，活性RhoA阳性 通过别构相互作用调节pyrin，而pyrin通过磷酸化负性控制pyrin。触发 由YopE GAP引起的炎症反应是出乎意料的，因为已发表的数据表明， 需要RhoA的共价失活。目前尚不清楚YopE是否通过相同的方式触发pyrin炎性小体， 这是一种与RhoA共价结合的毒素机制，目前还不清楚其他细菌RhoA GAP是否诱导这种机制。 反应目的1将检验YopE、其他细菌GAP和共价修饰的毒素的假设。 RhoA通过一种保守的变构失活机制触发炎症小体。T3S 效应子YopM通过抑制炎性小体促进耶尔森氏菌毒力。最近发现， YopM抑制pyrin，使耶尔森氏菌绕过YopE触发的炎性小体。机械地，YopM 劫持pyrin以维持pyrin处于磷酸化和非活性状态。使用敲除获得的已发表数据 耶尔森氏菌感染试验中的小鼠系表明，YopM靶向炎症单核细胞， 耶尔森氏菌毒力。目的2将检验耶尔森氏菌毒力需要YopM来抑制 炎性单核细胞中的pyrin。编码pyrin的基因Mefv中的密码子变化负责 人类自身炎症性疾病家族性地中海热（FMF）。有人建议 地中海和中东人群中FMF的高携带频率是由选择性的 在抵抗未知感染方面的优势。目的3将检验FMF pyrin变体的假设， 触发组成性炎性体活化，提供宿主对鼠疫耶尔森氏菌感染的抗性。

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.