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* Department of Neurology and Neuroscience and Center for Emerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103;
Clinical Studies Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
Clinical Services Program, Science Applications International Corporation-Frederick, National Cancer Institute, Frederick, MD 21702
During relapsing fever borreliosis, a high pathogen load in the blood occurs at times of peak bacteremia. Specific IgM Abs are responsible for spirochetal clearance so in absence of B cells there is persistent high-level bacteremia. Previously, we showed that B cell-deficient mice persistently infected with Borrelia turicatae produce high levels of IL-10 and that exogenous IL-10 reduces bacteremia. This suggested that IL-10 helps reduce bacteremia at times of high pathogen load by a B cell-independent mechanism, most likely involving innate immunity. To investigate this possibility, we compared B. turicatae infection in RAG2/IL-10–/– and RAG2–/– mice. The results showed that IL-10 deficiency resulted in significantly higher bacteremia, higher TNF levels, and early mortality. Examination of the spleen and peripheral blood showed markedly increased apoptosis of immune cells in infected RAG2/IL-10–/– mice. Neutralization of TNF reduced apoptosis of leukocytes and splenocytes, increased production of IFN-
by NK cells, increased phagocytosis in the spleen, decreased spirochetemia, and rescued mice from early death. Our results indicate that at times of high pathogen load, as during peak bacteremia in relapsing fever borreliosis, IL-10 protects innate immune cells from apoptosis via inhibition of TNF resulting in improved pathogen control.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Institutes of Health (R21NS053997-01) and the University of Medicine and Dentistry of New Jersey Foundation (to D.C.). This project has been funded in part with federal funds from the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, and from the National Cancer Institute, National Institutes of Health, under Contract N01-CO-12400.
The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
2 Address correspondence and reprint requests to Dr. Diego Cadavid at the current address: Experimental Neurology Group, Biogen Idec, 14 Cambridge Center, Building 6A, 6th floor, Cambridge, MA 02142. E-mail address: diego.cadavid{at}biogenidec.com
3 Abbreviations used in this paper: RF, relapsing fever; Bt2, B. turicatae serotype 2; Vsp2, variable small protein 2; TRITC, tetramethylrhodamine isothiocyanate.
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