RESUMEN
BACKGROUND: African trypanosomes are protozoan parasites that cause "sleeping sickness" in humans and a similar disease in livestock. Trypanosomes also infect laboratory mice and three major quantitative trait loci (QTL) that regulate survival time after infection with T. congolense have been identified in two independent crosses between susceptible A/J and BALB/c mice, and the resistant C57BL/6. These were designated Tir1, Tir2 and Tir3 for Trypanosoma infection response, and range in size from 0.9-12 cM. PRINCIPAL FINDINGS: Mapping loci regulating survival time after T. congolense infection in an additional cross revealed that susceptible C3H/HeJ mice have alleles that reduce survival time after infection at Tir1 and Tir3 QTL, but not at Tir2. Next-generation resequencing of a 6.2 Mbp region of mouse chromosome 17, which includes Tir1, identified 1,632 common single nucleotide polymorphisms (SNP) including a probably damaging non-synonymous SNP in Pram1 (PML-RAR alpha-regulated adaptor molecule 1), which was the most plausible candidate QTL gene in Tir1. Genome-wide comparative genomic hybridisation identified 12 loci with copy number variants (CNV) that correlate with differential gene expression, including Cd244 (natural killer cell receptor 2B4), which lies close to the peak of Tir3c and has gene expression that correlates with CNV and phenotype, making it a strong candidate QTL gene at this locus. CONCLUSIONS: By systematically combining next-generation DNA capture and sequencing, array-based comparative genomic hybridisation (aCGH), gene expression data and SNP annotation we have developed a strategy that can generate a short list of polymorphisms in candidate QTL genes that can be functionally tested.
Asunto(s)
Regulación de la Expresión Génica , Trypanosoma congolense/fisiología , Tripanosomiasis Africana/genética , Tripanosomiasis Africana/parasitología , Animales , Mapeo Cromosómico , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Polimorfismo de Nucleótido Simple , Proteínas/genética , Proteínas/metabolismo , Sitios de Carácter Cuantitativo , Tripanosomiasis Africana/metabolismoRESUMEN
Intensity of human schistosomiasis infection increases with age, a peak being attained at early puberty. Hormones could be involved in the age-related changes in susceptibility to schistosomiasis. Male BALB / c mice were infected with Schistosoma mansoni either before or after puberty and worm numbers, cellular immune responses, hormonal levels and pathology analysed. Pre-puberty infected mice had a significantly higher number of adult worms (p < 0.05), more severe granulomas, higher mortality rate and higher proliferative responses as compared to post-puberty infected mice. Levels of the hormones were lower in the pre-puberty infected mice as compared to the post-puberty group early in the infection. Plasma levels of testosterone and luteinizing hormones decreased significantly (p < 0.05) in infected mice when compared to controls. Susceptibility to S. mansoni in male BALB / c mice seems to be influenced by levels of testosterone and luteinizing hormone at infection. Albeit, an infection with S. mansoni seems to lower the hormonal levels.