Human Monocytic Ehrlichiosis

Stone, John H.; Dierberg, Kerry; Aram, Ghazaleh; Dumler, J. Stephen

doi:10.1001/jama.292.18.2263

Cited by 57 publications

(49 citation statements)

References 50 publications

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“…Severe and fatal infection of immunocompetent mice with IOE, however, causes severe tissue damage to multiple organ systems in a setting of a low bacterial burden (26). This observation mirrors what occurs in immunocompetent patients who develop multisystem organ failure without an overwhelming infection (49). Our previous studies demonstrated that resistance to fatal disease is mediated by gamma interferon (IFN-␥) production and CD4…”

supporting

confidence: 69%

“…Human monocytotropic ehrlichiosis (HME) resembles toxic shock syndrome and is caused by Ehrlichia chaffeensis, a gram-negative, obligately intracellular bacterium that lacks lipopolysaccharide (LPS) and peptidoglycan (30,37,49,52). In mice, inoculation with a high dose of IOE (a monocytotropic Ehrlichia species isolated from Ixodes ovatus ticks in Japan) (46) results in a fatal syndrome that mimics severe HME (26,48).…”

mentioning

confidence: 99%

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Relative Importance of T-Cell Subsets in Monocytotropic Ehrlichiosis: a Novel Effector Mechanism Involved inEhrlichia-Induced Immunopathology in Murine Ehrlichiosis

Ismail

Crossley²,

Stevenson³

et al. 2007

Infect Immun

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Infection with gram-negative monocytotropic Ehrlichia strains results in a fatal toxic shock-like syndrome characterized by a decreased number of Ehrlichia-specific CD4 ؉ Th1 cells, the expansion of tumor necrosis factor alpha (TNF-␣)-producing CD8 ؉ T cells, and the systemic overproduction of interleukin-10 (IL-10) and TNF-␣. Here, we investigated the role of CD4 ؉ and CD8 ؉ T cells in immunity to Ehrlichia and the pathogenesis of fatal ehrlichiosis caused by infection with low-and high-dose (10 3 and 10 5 bacterial genomes/mouse, respectively) ehrlichial inocula. The CD4 ؉ T-cell-deficient mice showed exacerbated susceptibility to a lethal high-or low-dose infection and harbored higher bacterial numbers than did wild-type (WT) mice. Interestingly, the CD8؉ T-cell-deficient mice were resistant to a low dose but succumbed to a high dose of Ehrlichia. The absence of CD8 ؉ T cells abrogated TNF-␣ and IL-10 production, reduced tissue injury and bacterial burden, restored splenic CD4 ؉ T-cell numbers, and increased the frequency of Ehrlichia-specific CD4 ؉ Th1 cells in comparison to infected WT mice. Although fatal disease is perforin independent, our data suggested that perforin played a critical role in controlling bacterial burden and mediating liver injury. Similar to WT mice, mortality of infected perforin-deficient mice was associated with CD4 ؉ T-cell apoptosis and a high serum concentration of IL-10. Depletion of IL-10 restored the number of CD4 ؉ and CD8 ؉ T cells in infected WT mice. Our data demonstrate a novel mechanism of immunopathology in which CD8؉ T cells mediate Ehrlichiainduced toxic shock, which is associated with IL-10 overproduction and CD4 ؉ T-cell apoptosis.

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supporting

confidence: 69%

mentioning

confidence: 99%

Relative Importance of T-Cell Subsets in Monocytotropic Ehrlichiosis: a Novel Effector Mechanism Involved inEhrlichia-Induced Immunopathology in Murine Ehrlichiosis

Ismail

Crossley²,

Stevenson³

et al. 2007

Infect Immun

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“…Ehrlichia chaffeensis, the etiologic agent of HME, is an obligately intracellular bacterium that resides in mononuclear phagocytes. HME initially manifests as nonspecific flulike illness and can progress to severe toxic shock-like syndrome with thrombocytopenia, lymphopenia, liver dysfunction, and multi-organ failure (23,32). The presence of extensive inflammation in tissues in the absence of overwhelming bacterial burden in fatal cases of HME suggests that fatal disease is due to immune-mediated pathology (28).…”

mentioning

confidence: 99%

Protective Heterologous Immunity against Fatal Ehrlichiosis and Lack of Protection following Homologous Challenge

Thirumalapura¹,

Stevenson²,

Walker

et al. 2008

Infect Immun

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The roles of antibodies and memory T cells in protection against virulent Ehrlichia have not been completely investigated. In this study, we addressed these issues by using murine models of mild and fatal ehrlichiosis caused by related monocytotropic Ehrlichia strains. Mice were primed with either Ehrlichia muris or closely related virulent ehrlichiae transmitted by Ixodes ovatus (IOE) ticks given intraperitoneally or intradermally. All groups were reinfected intraperitoneally, 30 days later, with a lethal high dose of IOE. Priming with E. muris, but not IOE, induced strong CD4؉ and CD8 ؉ memory type 1 T-cell responses, Ehrlichia-specific immunoglobulin G (IgG) antibodies, and persistent infection. Compared to IOE-primed mice, subsequent lethal IOE challenge of E. muris-primed mice, resulted in (i) 100% protection against lethal infection, (ii) strong Ehrlichiaspecific secondary gamma interferon (IFN-␥)-producing effector/effector memory CD4 ؉ and CD8 ؉ T-cell responses, (iii) enhanced secondary anti-ehrlichial antibody response, (iv) accelerated bacterial clearance, and (v) the formation of granulomas in the liver and lung. E. muris-primed mice challenged with IOE had lower levels of serum interleukin-1␣ (IL-1␣), IL-6, and IL-10 compared to unprimed mice challenged with IOE. Interestingly, the fatal secondary response in IOE-primed mice correlated with (i) decline in the Ehrlichiaspecific CD4؉ and CD8 ؉ type 1 responses, (ii) marked hepatic apoptosis and necrosis, and (iii) substantial bacterial clearance, suggesting that fatal secondary response is due to immune-mediated tissue damage. In conclusion, protection against fatal ehrlichial infection correlates with strong expansion of IFN-␥-producing CD4 ؉ and CD8 ؉ effector memory type 1 T cells, which appear to be maintained in the presence of IgG antibodies and persistent infection.

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“…Infection is often self-limiting in immunocompetent individuals but can be fatal in immunocompromised, and in some cases apparently immunocompetent, individuals (13). Fatal disease is characterized by flu-like symptoms, thrombocytopenia, lymphopenia, and liver dysfunction (12,14). The ehrlichiae are primarily monocytotropic but can also infect other host cells, including endothelial cells and hepatocytes (15).…”

mentioning

confidence: 99%

Fatal Recall Responses Mediated by CD8 T cells during Intracellular Bacterial Challenge Infection

Bitsaktsis

Winslow

2006

The Journal of Immunology

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The roles(s) of CD8 T cells during infections by intracellular bacteria that reside in host cell endocytic compartments are not well understood. Our previous studies in a mouse model of human monocytotropic ehrlichiosis indicated that CD8 T cells are not essential for immunity. However, we have observed an unexpected role for these cells during challenge infection. Although immunocompetent mice cleared a primary low-dose (nonfatal) Ixodes ovatus ehrlichia infection, a secondary low-dose challenge infection resulted in fatal disease and loss of control of infection. The outcome was CD8-dependent, because CD8-deficient mice survived secondary low-dose challenge infection. Moreover, effector and/or memory phenotype CD8 T cells were responsible, because adoptive transfer of purified CD44high CD8 T cells to naive mice induced fatal responses following a primary low-dose infection. The fatal responses were perforin- and Fas ligand-independent, and were associated with high serum concentrations of TNF-α and CCL2, and low levels of IL-10. Accordingly, blockade of either TNF-α or CCL2 ameliorated fatal recall responses, and in vitro coculture of memory CD8 T cells and Ixodes ovatus ehrlichia-infected peritoneal exudate cells resulted in substantial increases in TNF-α and CCL2. Thus, during monocytotropic ehrlichiosis, inflammatory cytokine production, by CD8 T cells and/or other host cells, can trigger chemokine-dependent disease. These findings highlight a novel role for CD8 T cells, and reveal that live vaccines for intracellular bacteria can, under some conditions, induce undesirable consequences.

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Human Monocytic Ehrlichiosis

Cited by 57 publications

References 50 publications

Relative Importance of T-Cell Subsets in Monocytotropic Ehrlichiosis: a Novel Effector Mechanism Involved inEhrlichia-Induced Immunopathology in Murine Ehrlichiosis

Relative Importance of T-Cell Subsets in Monocytotropic Ehrlichiosis: a Novel Effector Mechanism Involved inEhrlichia-Induced Immunopathology in Murine Ehrlichiosis

Protective Heterologous Immunity against Fatal Ehrlichiosis and Lack of Protection following Homologous Challenge

Fatal Recall Responses Mediated by CD8 T cells during Intracellular Bacterial Challenge Infection

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