Refinement of the genetics of the host response to Salmonella infection in MOLF/Ei: regulation of type 1 IFN and TRP3 pathways by Ity2.

Typhoid fever, which is caused by Salmonella typhi and paratyphi, is a severe systemic disease that remains a major public health issue in several areas of the world. We can model the human disease using mice infected with a related bacterium, Salmonella typhimurium. This model recapitulates several clinical aspects of the human disease and allows for the study of the host response to Salmonella typhimurium infection in vivo. Previous work in our laboratory has identified three Immunity to typhimurium loci (Ity, Ity2 and Ity3) in the wild-derived MOLF/Ei mice, influencing survival after infection with Salmonella typhimurium. The MOLF/Ei alleles at Ity and Ity2 are protective, while the MOLF/Ei allele at Ity3 confers susceptibility. In this paper, we have generated a novel cross combination between the highly susceptible strain, MOLF/Ei, and the resistant strain, 129S6, to better define the genetic architecture of susceptibility to infection in MOLF/Ei. Using this cross, we have replicated the locus on chr 11 (Ity2) and identified a novel locus on chr 13 (Ity13). Using microarrays and transcriptional profiling, we examined the response of uninfected and infected Ity2 congenic mice. These analyses demonstrate a role for both type-1-interferon (IFN) and TRP53 signaling in the pathogenesis of Salmonella infection.

Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell-mediated innate resistance to cytomegalovirus infection.

Experimental infection with mouse cytomegalovirus (MCMV) has been used to elucidate the intricate host-pathogen mechanisms that determine innate resistance to infection. Linkage analyses in F(2) progeny from MCMV-resistant MA/My (H2 (k)) and MCMV-susceptible BALB/c (H2 (d)) and BALB.K (H2 (k)) mouse strains indicated that only the combination of alleles encoded by a gene in the Klra (also called Ly49) cluster on chromosome 6, and one in the major histocompatibility complex (H2) on chromosome 17, is associated with virus resistance. We found that natural killer cell-activating receptor Ly49P specifically recognized MCMV-infected cells, dependent on the presence of the H2 (k) haplotype. This binding was blocked using antibodies to H-2D(k) but not antibodies to H-2K(k). These results are suggestive of a new natural killer cell mechanism implicated in MCMV resistance, which depends on the functional interaction of the Ly49P receptor and the major histocompatibility complex class I molecule H-2D(k) on MCMV-infected cells.

A locus for Bowen-Conradi syndrome maps to chromosome region 12p13.3.

Bowen-Conradi syndrome (BCS) is a lethal autosomal recessive disorder with an estimated incidence of 1 in 355 live births in the Hutterite population. A few cases have been reported in other populations. Here, we report the results of a genome-wide scan and fine mapping of the BCS locus in Hutterite families. By linkage and haplotype analysis the BCS locus was mapped to a 3.5 cM segment (1.9 Mbp) in chromosome region 12p13.3 bounded by F8VWF and D12S397. When genealogical relationships among the families were taken into account in the linkage analysis, the evidence for linkage was stronger and the number of potentially linked regions was reduced to one. Under the assumption that all the Hutterite patients were identical by descent for a disease-causing mutation, haplotype analysis was used to infer likely historical recombinants and thereby narrow the candidate region to a chromosomal segment shared in common by all the affected children. This study also demonstrates that BCS and cerebro-oculo-facial-skeletal syndrome (COFS) are genetically distinct.