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Chapter 9 : Innate Immune Response and Inflammation: Roles in Pathogenesis and Protection ()

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Abstract:

The family includes several species of obligate intracellular gram-negative bacteria. The early immune responses to and infections are likely to be important factors in determining the outcome of infection and clinical course of disease. This chapter discusses recent studies on the kinetics and quality of early immune responses to and briefly to , and the implications for development of successful preventative immune-based therapeutic approaches. Five members can infect humans, but only two of them—, the causative agent of human monocytic ehrlichiosis (HME); and , the causative agent of human granulocytic anaplasmosis (HGA)—have been thoroughly investigated. There is only limited information on the mechanisms of pathogenesis of and and the role of host innate immune responses in contributing to disease virulence in humans; therefore, animal models are necessary to identify bacterial and host characteristics of disease. Murine models have been developed to study differences in host immunity and disease susceptibility. -infected DCs from MyD88 mice are able to stimulate gamma interferon (IFN-ү); production by innate invariant natural killer T (iNKT) lymphocytes. Such responses were dependent on direct recognition of unidentified ehrlichial ligands by CD1d, but were not dependent on TLR signals. The author has investigated the contribution of NK cells to protective immunity against . Studies of the pathogenesis of severe and fatal ehrlichiosis and anaplasmosis, or protective immunity against and infection, have largely focused on the analysis of effector CD4+ T cells and their control by CD8+ T cells.

Citation: Ismail N, Stevenson H. 2012. Innate Immune Response and Inflammation: Roles in Pathogenesis and Protection (), p 270-303. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch9

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Rocky Mountain Spotted Fever
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Tumor Necrosis Factor alpha
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Innate Immune System
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FIGURE 1

Early interactions between ehrlichiae and target cells: a model of -induced toxic shock.The induction phase of immune responses against or infections occurs in the skin, followed by systemic dissemination through the reticuloendothelial system, where conventional DCs and macrophages (the main target cells for ) capture and process ehrlicial antigens. Infected macrophages can undergo apoptosis following intracellular bacterial replication. Apoptotic cells containing ehrlichial antigen can be phagocytosed by immature DCs and presented to naïve CD8 T cells via direct or cross-presentation pathways in the context of MHC class I molecule (i.e., cross-priming). Activated DCs prime pathogenic CD8 T cells as well as protective CD4 Th1 cells (not shown) after migration to the draining lymphoid organs (lymph nodes and spleen), and macrophages also promote this activation, possibly via IL-12p40 secretion. iNKT cells and CD4 Th1 cells control bacterial replication via IFN-γ production, preventing subsequent inflammation and severe HME (not shown). The expansion of -specific CD4 T cells can be inhibited by NK cells through various mechanisms, including IL-10 production, but other surface molecules can be involved in this process (not shown). NK cells can promote the recruitment of pathogenic CD8 T cells to peripheral sites of infection such as the liver, and also recruit different subsets of DCs that further enhance the expansion of pathogenic CD8 T cells in this organ. In the liver, hepatocytes as well as infected target cells can be killed by pathogenic NK and CD8 T cells, possibly through the release of IFN-γ TNF-α, granzymes, and perforin. IL-18 produced by DCs and macrophages sustains the effector functions of activated pathogenic CD8 T cells and NK cells in the liver (not shown). NK cells producing IL-10 may further suppress expansion of CD4 Th1 cells in the liver, while pathogenic CD8 T cells induce apoptosis of these cells. This complex cross talk between innate and adaptive immune cells results in the development or the prevention of severe and potentially fatal HME and HGA. doi:10.1128/9781555817336.ch9.f1

Citation: Ismail N, Stevenson H. 2012. Innate Immune Response and Inflammation: Roles in Pathogenesis and Protection (), p 270-303. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch9
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Tables

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Table 1

Symptoms, clinical characteristics, laboratory abnormalities, and diagnostic tests for HME

Citation: Ismail N, Stevenson H. 2012. Innate Immune Response and Inflammation: Roles in Pathogenesis and Protection (), p 270-303. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch9
Generic image for table
Table 2

Cytokines identified in monocytotropic ehrlichiosis

Citation: Ismail N, Stevenson H. 2012. Innate Immune Response and Inflammation: Roles in Pathogenesis and Protection (), p 270-303. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch9