Ismail Nahed, Sharma Aditya, Soong Lynn, Walker David H
Clinical Microbiology, Laboratory Medicine, University of Illinois at Chicago-College of Medicine, University of Illinois Hospitals & Health Science System, Chicago, IL.
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX.
Zoonoses. 2022 Jan 6;2(1). doi: 10.15212/zoonoses-2022-0009. Epub 2022 Jul 5.
Human monocytic ehrlichiosis, a tick transmitted infection, ranges in severity from apparently subclinical to a fatal toxic shock-like fatal disease. Models in immunocompetent mice range from an abortive infection to uniformly lethal depending on the infecting Ehrlichia species, dose of inoculum, and route of inoculation. Effective immunity is mediated by CD4+ T lymphocytes and gamma interferon. Lethal infection occurs with early overproduction of proinflammatory cytokines and overproduction of TNF alpha and IL-10 by CD8+ T lymphocytes. Furthermore, fatal ehrlichiosis is associated with signaling via TLR 9/MyD88 with upregulation of several inflammasome complexes and secretion of IL-1 beta, IL-1 alpha, and IL-18 by hepatic mononuclear cells, suggesting activation of canonical and noncanonical inflammasome pathways, a deleterious role for IL-18, and the protective role for caspase 1. Autophagy promotes ehrlichial infection, and MyD88 signaling hinders ehrlichial infection by inhibiting autophagy induction and flux. Activation of caspase 11 during infection of hepatocytes by the lethal ehrlichial species after interferon alpha receptor signaling results in the production of inflammasome-dependent IL-1 beta, extracellular secretion of HMGB1, and pyroptosis. The high level of HMGB1 in lethal ehrlichiosis suggests a role in toxic shock. Studies of primary bone marrow-derived macrophages infected by highly avirulent or mildly avirulent ehrlichiae reveal divergent M1 and M2 macrophage polarization that links with generation of pathogenic CD8 T cells, neutrophils, and excessive inflammation or with strong expansion of protective Th1 and NKT cells, resolution of inflammation and clearance of infection, respectively.
人单核细胞埃立克体病是一种由蜱传播的感染性疾病，其严重程度从明显的亚临床状态到致命的中毒性休克样致命疾病不等。在免疫功能正常的小鼠中，根据感染的埃立克体种类、接种剂量和接种途径，模型表现从流产感染到一致致死。有效的免疫由CD4 + T淋巴细胞和γ干扰素介导。致死性感染发生时，促炎细胞因子早期过度产生，CD8 + T淋巴细胞过度产生肿瘤坏死因子α和白细胞介素-10。此外，致命的埃立克体病与通过Toll样受体9/髓样分化因子88（TLR 9/MyD88）信号传导相关，伴有几种炎性小体复合物上调以及肝单核细胞分泌白细胞介素-1β、白细胞介素-1α和白细胞介素-18，提示经典和非经典炎性小体途径激活、白细胞介素-18的有害作用以及半胱天冬酶1的保护作用。自噬促进埃立克体感染，而MyD88信号传导通过抑制自噬诱导和通量来阻碍埃立克体感染。在α干扰素受体信号传导后，致死性埃立克体种类感染肝细胞期间半胱天冬酶11激活导致炎性小体依赖性白细胞介素-1β产生、高迁移率族蛋白B1（HMGB1）细胞外分泌和细胞焦亡。致死性埃立克体病中高水平的HMGB1提示其在中毒性休克中的作用。对由高毒力或低毒力埃立克体感染的原代骨髓来源巨噬细胞的研究揭示了不同的M1和M2巨噬细胞极化，分别与致病性CD8 T细胞、中性粒细胞的产生和过度炎症相关，或与保护性Th1和自然杀伤T（NKT）细胞的强烈扩增、炎症消退和感染清除相关。
