Pneumonia is a major cause of death and disability, and Mycoplasma pneumoniae is one of the leading causes of pneumonia worldwide. We have shown that C57BL/6 mice are highly resistant and C3H/He mice are highly susceptible to Mycoplasma pulmonis infections. Also, we have extensively characterized these infections and shown them to be excellent models of human mycoplasmosis. More recently, we have carried out preliminary studies to identify the gene(s) responsible for resistance to mycoplasmal infection. We have screened 16 strains of inbred mice for susceptibility to a standard dose of M. pulmonis, and found C57BL/6 to be highly resistant and both C3H/He and DBA/2 to be highly susceptible. We also have screened all 9 BXH (C57BL X C3H/He) and all 26 BXD (C57BL/6J X DBA/2) recombinant inbred (RI) strains for susceptibility to the mycoplasma infection. Inasmuch as the much larger RI set of BXD strains provides far greater precision in gene mapping, we will in the present project focus on genetic analysis of the mycoplasma-resistant C57BL/6 mouse and the mycoplasma-susceptible DBA/2 mouse. The specific hypothesis to be tested is that the resistant C57BL/6 (""""""""wild type"""""""") and susceptible DBA/2 (""""""""mutant"""""""") antimycoplasmal phenotypes of our M. pulmonis-Mouse Model can be defined in terms of specific gene(s) that control the effector mechanisms in antimycoplasmal defenses. To test this hypothesis, our specific aims are to: (i) determine the number and chromosomal locations of those genes responsible for nonspecific antimycoplasmal defenses in the lungs of C57BL/6 and DBA/2 mice, (ii) use simple sequence length polymorphisms (SSLPs) to accomplish fine chromosomal mapping of each locus, (iii) identify candidate genes in the finely mapped chromosomal regions, (iv) determine the linkage of candidate genes with the resistance/susceptibility trait in RI and F2 generation mice, and (v) characterize candidate gene(s) by sequence and expression analyses. If time permits, we will also (i) validate the role of each protective gene by transgenic knockout of the resistant phenotype and rescue of the susceptible phenotype, and (ii) relate each of the gene(s) to their specific host defense effector functions, and (iii) eventually, compare the findings on genes and mechanisms of defense in C57BL/6 and DBA/2 mice to those in C3H/He mice.
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