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Infection and Immunity, December 2002, p. 6919-6925, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6919-6925.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Association between the Tumor Necrosis Factor Locus and the Clinical Outcome of Leishmania chagasi Infection

Theresa M. Karplus,^1, Selma M. B. Jeronimo,² Haeok Chang,¹ Bethany K. Helms,¹ Trudy L. Burns,³ Jeffrey C. Murray,⁴ Adele A. Mitchell,^5, Elizabeth W. Pugh,⁵ Regina F. S. Braz,⁶ Fabiana L. Bezerra,⁶ and Mary E. Wilson^1,7,8*

Departments of Internal Medicine,¹ Departments of Biochemistry,² Biostatistics,³ Pediatrics, University of Iowa,⁴ Center for Inherited Diseases Research, Johns Hopkins University, Baltimore, Maryland,⁵ Microbiology, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil,⁶ Microbiology,⁷ Veterans Affairs Medical Center, Iowa City, Iowa⁸

Received 18 June 2002/ Returned for modification 30 July 2002/ Accepted 15 September 2002

A periurban outbreak of visceral leishmaniasis (VL) caused by the protozoan Leishmania chagasi is ongoing outside Natal, northeast Brazil. Manifestations range from asymptomatic infection to disseminated visceral disease. Literature reports suggest that both genetic and environmental factors influence the outcome of infection. Due to the association of the tumor necrosis factor (TNF) locus with other infectious diseases, we examined whether polymorphic alleles at this locus are associated with the outcome of L. chagasi infection. Neighborhoods with ongoing transmission were identified through patients admitted to local hospitals. Altogether, 1,024 individuals from 183 families were classified with the following disease phenotypes: (i) symptomatic VL, (ii) asymptomatic infection (positive delayed-type hypersensitivity [DTH+]), or (iii) no evidence of infection (DTH-). Genotypes were determined at a microsatellite marker (MSM) upstream of the TNFB gene encoding TNF-ß and at a restriction fragment length polymorphism (RFLP) at position -307 in the promoter of the TNFA gene encoding TNF-. Analyses showed that the distribution of TNFA RFLP alleles (TNF1 and TNF2) and the TNF MSM alleles (TNFa1 to TNFa15) differed between individuals with VL and those with DTH+ phenotypes. TNF1 was transmitted more frequently than expected from heterozygous parents to DTH+ offspring (P = 0.0006), and haplotypes containing TNF2 were associated with symptomatic VL (P = 0.0265, transmission disequilibrium test). Resting serum TNF- levels were higher in TNF1/2 heterozygotes than in TNF1/1 homozygotes (P < 0.05). These data led us to hypothesize that an individual's genotype at the TNF locus may be associated with whether he or she develops asymptomatic or symptomatic disease after L. chagasi infection. The results preliminarily suggest that this may be the case, and follow-up with larger populations is needed for verification.

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* Corresponding author. Mailing address: Department of Internal Medicine, University of Iowa, SW34-GH, Iowa City, IA 52242. Phone: (319) 356-3169. Fax: (319) 356-4600. E-mail: mary-wilson{at}uiowa.edu.

Editor: W. A. Petri, Jr.

Present address: Vancouver Clinic, Vancouver, Wash.

Present address: School of Medicine, Johns Hopkins University, Baltimore, Md.

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Infection and Immunity, December 2002, p. 6919-6925, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6919-6925.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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