I/St Mice Hypersusceptible to Mycobacterium tuberculosis Are Resistant to M. avium

Abstract

ABSTRACT We previously demonstrated that mice of the I/St strain are extremely susceptible to Mycobacterium tuberculosis , as well as to the taxonomically distant intracellular bacteria Chlamydia pneumoniae and Salmonella enterica . To broaden our knowledge about the control of susceptibility to intracellular pathogens, we studied the infection caused by Mycobacterium avium virulent strain 724 in a panel of inbred mouse strains and found that I/St mice are resistant to M. avium . By comparing I/St mice with B6 mice, we demonstrated that (i) B6 mice are much more susceptible to infection caused by M. avium in terms of bacterial multiplication in the lung tissue and severity of lung pathology; (ii) in B6 mice but not in I/St mice infection leads to prolonged leukocyte infiltration of the lung tissue, development of necrotic lung granulomata, and lethality; and (iii) the unfavorable infectious course in B6 mice is accompanied by elevated production of gamma interferon, tumor necrosis factor alpha, and especially interleukin-12 in the lungs. Importantly, M. avium -resistant I/St mice carry a functional r allele of the Slc11a1 (formerly Nramp1 ) gene, while B6 mice have the Slc11a1 s genotype. Segregation genetic analysis of (I/St × B6) F2 hybrids demonstrated that susceptibility or resistance to infection caused by M. avium largely depended upon the Slc11a1 genotype and that other genetic traits had a relatively weak influence. This close-to-monogenic pattern differs sharply from the host control of many other intracellular bacterial infections, for which the involvement of numerous quantitative trait loci has been ubiquitously observed.