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Infection and Immunity, September 2007, p. 4608-4620, Vol. 75, No. 9
0019-9567/07/$08.00+0     doi:10.1128/IAI.00198-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Relative Importance of T-Cell Subsets in Monocytotropic Ehrlichiosis: a Novel Effector Mechanism Involved in Ehrlichia-Induced Immunopathology in Murine Ehrlichiosis{triangledown}

Nahed Ismail,1,2,3* Emily C. Crossley,1,4 Heather L. Stevenson,1 and David H. Walker1,2,3

Department of Pathology,1 Department of Microbiology and Immunology,4 Sealy Center for Vaccine Development,2 Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas 77555-06093

Received 6 February 2007/ Returned for modification 22 May 2007/ Accepted 3 June 2007

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-{alpha})-producing CD8+ T cells, and the systemic overproduction of interleukin-10 (IL-10) and TNF-{alpha}. 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 (103 and 105 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-{alpha} 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 Ehrlichia-induced toxic shock, which is associated with IL-10 overproduction and CD4+ T-cell apoptosis.

* Corresponding author. Mailing address: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, 301 University Blvd., Galveston, TX 77555-0609. Phone: (409) 772-3111. Fax: (409) 772-5683. E-mail: naismail{at}utmb.edu

{triangledown} Published ahead of print on 11 June 2007.

Editor: W. A. Petri, Jr.

Infection and Immunity, September 2007, p. 4608-4620, Vol. 75, No. 9
0019-9567/07/$08.00+0     doi:10.1128/IAI.00198-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Thirumalapura, N. R., Stevenson, H. L., Walker, D. H., Ismail, N. (2008). Protective Heterologous Immunity against Fatal Ehrlichiosis and Lack of Protection following Homologous Challenge. Infect. Immun. 76: 1920-1930 [Abstract] [Full Text]  
  • Stevenson, H. L., Crossley, E. C., Thirumalapura, N., Walker, D. H., Ismail, N. (2008). Regulatory Roles of CD1d-Restricted NKT Cells in the Induction of Toxic Shock-Like Syndrome in an Animal Model of Fatal Ehrlichiosis. Infect. Immun. 76: 1434-1444 [Abstract] [Full Text]  


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