The Host Resistance Locussst1Controls Innate Immunity toListeria monocytogenesInfection in Immunodeficient Mice

Abstract

Epidemiological, clinical, and experimental approaches have convincingly demonstrated that host resistance to infection with intracellular pathogens is significantly influenced by genetic polymorphisms. Using a mouse model of infection with virulent Mycobacterium tuberculosis (MTB), we have previously identified the sst1 locus as a genetic determinant of host resistance to tuberculosis. In this study we demonstrate that susceptibility to another intracellular pathogen, Listeria monocytogenes, is also influenced by the sst1 locus. The contribution of sst1 to anti-listerial immunity is much greater in immunodeficient scid mice, indicating that this locus controls innate immunity and becomes particularly important when adaptive immunity is significantly depressed. Similar to our previous observations using infection with MTB, the resistant allele of sst1 prevents formation of necrotic infectious lesions in vivo. We have shown that macrophages obtained from sst1-resistant congenic mice possess superior ability to kill L. monocytogenes in vitro. The bactericidal effect of sst1 is dependent on IFN-γ activation and reactive oxygen radical production by activated macrophages after infection, but is independent of NO production. It is possible that there is a single gene that controls common IFN-dependent macrophage function, which is important in the pathogenesis of infections caused by both MTB and L. monocytogenes. However, host resistance to the two pathogens may be controlled by two different polymorphic genes encoded within the sst1 locus. The polymorphic gene(s) encoded within the sst1 locus that controls macrophage interactions with the two intracellular pathogens remains to be elucidated.

Dominant Role of the sst1 Locus in Pathogenesis of Necrotizing Lung Granulomas during Chronic Tuberculosis Infection and Reactivation in Genetically Resistant Hosts

“…19 The sst1 locus was also implicated in innate resistance to another intracellular bacteria-Listeria monocytogenes. 33 In that model, we have observed necrosis within hepatic inflammatory lesions. We hypothesize that the sst1-mediated function is not organ-specific per se, but it is critical at the sites of maximal inflammation and bacterial replication that are pathogen-specific.…”

Relevance of Gamma Interferon, Tumor Necrosis Factor Alpha, and Interleukin-10 Gene Polymorphisms to Susceptibility to Mediterranean Spotted Fever

“…In this view, our data seem to suggest that a genetic predisposition to produce high IFN-␥ levels might have a protective effect for the clinical outcome of the disease. Data from studies of intracellular infectious diseases have demonstrated that a genetically mediated reduction of the IFN-␥ response is associated with an increased susceptibility to a large arrays of pathogens (2,8,36,43). Recently, we reported, for the first time, that ϩ874T allele frequency is reduced in subjects affected by a Comparisons among the different combined genotype frequencies were performed by applying the nonparametric Mantel-Haenszel procedure.…”

Cytosolic Localization ofListeria monocytogenesTriggers an Early IFN-γ Response by CD8+ T Cells That Correlates with Innate Resistance to Infection

“…For example, in a previous study we showed that 2-5 ϫ 10 4 CFU of L. monocytogenes strain 10403s caused death of all BALB/c mice within 72 h, while C57BL/6 mice, which have an LD 50 that is at least 50-fold higher, all survived infection with this dose of L. monocytogenes (1). Complement (C5) deficiency and a sst1-dependent macrophage function have been implicated in innate host susceptibility to L. monocytogenes infection (2,3). However, host resistance appears to be a multigenic trait (1), and further genetic differences between mouse strains have yet to be identified.…”