I/St Mice Hypersusceptible toMycobacterium tuberculosisAre Resistant toM. avium

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.

RNA-Seq Analysis of Mycobacterium avium Non-Coding Transcriptome

“…Compared to I/St, B6 mice are considerably more susceptible to infection caused by M. avium in terms of bacterial multiplication and damage of the lung tissue: in B6, but not I/St mice prolonged infiltration with neutrophils leads to formation of necrotic lung granulomata and death [42]. The expression of igMAV_0468–0469 and igMAV_0469–0470 was very high in culture medium, only slightly lower in the lungs of susceptible, but dramatically reduced in the lungs of resistant mice (Figure 4).…”

“…Two groups of 5 female I/St and B6 mice were infected with 1–2×10 3 viable CFU of M. avium in the aerosol chamber as described [42]. 13 weeks following challenge, lungs were homogenized in Trizol reagent (Life Technologies, Carlsbad, CA) and RNA was isolated according to a standard protocol using BeadBeater cell disrupter with 0.1 mm zirconia/silica beads (BioSpec Products, Bartlesville, OK).…”

Host Genetics in Granuloma Formation: Human-Like Lung Pathology in Mice with Reciprocal Genetic Susceptibility to M. tuberculosis and M. avium

“…Recently we have shown that mice of the I/St strain, which are extremely susceptible to TB [14], are resistant to M. avium infection, whereas the opposite is true for the B6 strain [15]. In agreement with data obtained by Ehlers et al [12], [13], general appearance of M. avium -induced lung granuloma in B6 mice closely resembled that of human TB lesions, but in I/St mice lung pathology was much milder and was not regularly shaped.…”

Adaptive Changes in Mycobacterium avium Gene Expression Profile Following Infection of Genetically Susceptible and Resistant Mice

“…[10] and [16]. The airborne infected susceptible B6 mice died after 7 months, while the resistant I/St mice survived for longer than 11 months.…”