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February 2000, Volume 1, Number 3, Pages 200-206
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Full Paper
Susceptibility to Leishmania major infection in mice: multiple loci and heterogeneity of immunopathological phenotypes
M Lipoldová1, M Svobodová2, M Krulová1, H Havelková1, J Badalová1, E Nohyacutenková3, V Holán caron1, A A M Hart4, P Volf2 and P Demant4

1Institute of Molecular Genetics, Academy of Sciences of the Czech Republic,

2Department of Parasitology, Faculty of Science, Charles University, Prague, Czech Republic

3Department of Tropical Medicine, Ist Medical Faculty, Charles University, Prague, Czech Republic

4The Netherlands Cancer Institute, Amsterdam, The Netherlands

Correspondence to: Marie Lipoldová, Institute of Molecular Genetics, Fleming. nám. 2, 16637 Praha 6, Czech Republic. E-mail: lipoldova@img.cas.cz

This investigation received financial support from UNDP / World Bank / WHO Special program for research and Training in Tropical Diseases (TDR I.D. 970772). This work was also supported by grants NM/28-3 and 4122-3 from the Ministry of Health of the Czech Republic and by the contracts CIPA-CT 940040 and 930262 from the European Commission.

Abstract

Susceptibility as opposed to resistance of mouse strains (eg, BALB/c vs C57BL/6) to Leishmania major has been attributed to a defective Th1 and a predominant Th2-response, resulting in increased IL-4 and IgE production, and decreased interferon gamma (IFNbold gamma) production, macrophage activation and elimination of parasites. Here we report dissection of genetic and functional aspects of susceptibility to leishmaniasis using two contrasting inbred strains BALB/cHeA (susceptible) and STS/A (resistant) and a resistant Recombinant Congenic (RC) Strain, CcS-5/Dem, which carries a random set of 12.5% of genes from the strain STS and 87.5% genes from the susceptible strain BALB/c. Linkage analysis of F2 hybrids between the resistant RC strain CcS-5 and the susceptible strain BALB/c revealed five loci affecting the response to the infection, each apparently associated with a different combination of pathological symptoms and immunological reactions. The correlation between Th2-type immune reactions and the disease in the F2 mice was either absent, or it was limited to mice with specific genotypes at loci on chromosomes 10 and 17. This suggests that the resistance vs susceptibility is influenced by mechanisms additional to the postulated antagonistic effects of Th1 and Th2 responses, and that the host's genotype affects the development of leishmaniasis in a complex way. Genes and Immunity (2000) 1, 200-206.

Keywords

Leishmania major; immune response; pathology; genetic control; Th1/Th2 paradigm

Received 26 August 1999; revised 11 October 1999; accepted 12 October 1999
February 2000, Volume 1, Number 3, Pages 200-206
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