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Infection and Immunity, March 2006, p. 1846-1856, Vol. 74, No. 3
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.3.1846-1856.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Role of Tumor Necrosis Factor Alpha (TNF-) and Interleukin-10 in the Pathogenesis of Severe Murine Monocytotropic Ehrlichiosis: Increased Resistance of TNF Receptor p55- and p75-Deficient Mice to Fatal Ehrlichial Infection

Department of Pathology,¹ Department of Microbiology and Immunology,² Sealy Center for Vaccine Development,³ Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas 77555-0609⁴

Received 9 September 2005/ Returned for modification 14 October 2005/ Accepted 20 December 2005

Intraperitoneal (i.p.) infection with a high dose of a highly virulent Ehrlichia strain (IOE) results in a toxic shock-like syndrome characterized by severe liver injury and systemic overproduction of tumor necrosis factor alpha (TNF-) by CD8⁺ T cells. We examined the role of TNF- and TNF receptors in high-dose-IOE-induced shock/liver injury. TNF receptor (TNFR) I/II^–/– mice lacking both the p55 and p75 receptors for this cytokine were more resistant to IOE-induced liver injury than their wild-type background controls. TNFR I/II^–/– mice survived longer, dying between 15 and 18 days, with evidence of mild liver necrosis/apoptosis. In contrast, wild-type mice were not rescued from the lethal effect of IOE by TNF- neutralization. TNF--depleted mice developed severe liver injury and succumbed to disease between days 9 and 11 postinfection, similar to sham-treated, infected wild-type mice. Although IFN- production in the spleens of IOE-infected TNFR I/II^–/– and TNF--depleted mice was higher than that detected in wild-type controls, these mice had higher bacterial burdens than infected controls. Following high-dose IOE challenge, TNFR I/II^–/– and TNF--depleted mice have an early increase in IL-10 levels in sera and spleens, which was produced mainly by adherent spleen cells. In contrast, a late burst of interleukin-10 (IL-10) was observed in control mice. Nonadherent spleen cells were the major source of IL-10 in IOE-infected wild-type mice. We conclude that TNFR I/II and TNF- participate in Ehrlichia-induced shock and host defense by regulating liver injury and controlling ehrlichial burden. Our data suggest that fatal ehrlichiosis could be a multistep process, where TNF- is not solely responsible for mortality.

Editor: F. C. Fang

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