Genes from Chagas Susceptibility Loci That Are Differentially Expressed in T. cruzi-Resistant Mice Are Candidates Accounting for Impaired Immunity

Sebastian E B Graefe,Christiane Steeg,Thomas Streichert,Bernhard Fleischer,Birgit S Budde,Bertram Müller-Myhsok,Peter Nürnberg,Derya Unutmaz

doi:10.1371/journal.pone.0000057

Abstract

Variation between inbred mice of susceptibility to experimental Trypanosoma cruzi infection has frequently been described, but the immunogenetic background is poorly understood. The outcross of the susceptible parental mouse strains C57BL/6 (B6) and DBA/2 (D2), B6D2F1 (F1) mice, is highly resistant to this parasite. In the present study we show by quantitative PCR that the increase of tissue parasitism during the early phase of infection is comparable up to day 11 between susceptible B6 and resistant F1 mice. A reduction of splenic parasite burdens occurs thereafter in both strains but is comparatively retarded in susceptible mice. Splenic microarchitecture is progressively disrupted with loss of follicles and B lymphocytes in B6 mice, but not in F1 mice. By genotyping of additional backcross offspring we corroborate our earlier findings that susceptibility maps to three loci on Chromosomes 5, 13 and 17. Analysis of gene expression of spleen cells from infected B6 and F1 mice with microarrays identifies about 0.3% of transcripts that are differentially expressed. Assuming that differential susceptibility is mediated by altered gene expression, we propose that the following differentially expressed transcripts from these loci are strong candidates for the observed phenotypic variation: H2-Eα, H2-D1, Ng23, Msh5 and Tubb5 from Chromosome 17; and Cxcl11, Bmp2k and Spp1 from Chromosome 5. Our results indicate that innate mechanisms are not of primary relevance to resistance of F1 mice to T. cruzi infection, and that differential susceptibility to experimental infection with this protozoan pathogen is not paralleled by extensive variation of the transcriptome.

Highlights

Chagas’ disease severely affects a considerable number of persons on the American continent, but in the majority of infected, it takes an ‘indeterminate’ course over a long period of time [1]
Some controversy has prevailed over the question whether the severity of the acute phase of the infection and the degree of parasitaemia and/or tissue parasitism correlated with the severity of the chronic complications of Chagas’ disease
The rate of parasite clearance in the spleen was lower than in F1 mice. These results indicate that innate resistance is not compromised, if not more effective, in B6 mice. They indicate that acquired immune responses develop in B6 mice with a delay and appear to be less efficient in containing tissue parasitism, especially in the spleen and liver

Summary

Introduction

Chagas’ disease severely affects a considerable number of persons on the American continent, but in the majority of infected, it takes an ‘indeterminate’ course over a long period of time [1]. Some controversy has prevailed over the question whether the severity of the acute phase of the infection and the degree of parasitaemia and/or tissue parasitism correlated with the severity of the chronic complications of Chagas’ disease. It has increasingly been appreciated that the persistence of parasites, rather than the occurence of autoreactive antibodies or cells, determines the degree of tissue destruction [7,8,9,10,11]. It was shown that an early phase with high parasitic loads resulted in a late phase with more prominent repercussions on the integrity of affected tissue, with more intense inflammatory infiltrates, more tissue destruction and greater loss of physiological function [12,13]

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Conclusion