The pathogen Mycobacterium tuberculosis (MTB) has infected approximately one third of the world’s human population. It is estimated that there is an incidence of up to 8 million new cases annually. Of those infected, only about 10% develop symptomatic tuberculosis. Tuberculosis mortality rate is over 2million each year. It is known that susceptibility can be influenced by environmental factors including malnutrition and stress, concomitant infections (HIV) or senescence. In both humans and animals genetic variation within the host population is also known to play a significant role in the degree of resistance and susceptibility, but has remained for the most part poorly understood. In the past locating individual genes responsible for innate immunity has been difficult.
A recent study mapped a new genetic locus on a mouse chromosome, and designated it sst1 (super susceptibility to tuberculosis1). It was demonstrated that in sst1 congenic mouse strains, this locus mediated an innate immunity to MTB. Within the stt1 locus, a candidate gene was identified, Intracellular Pathogen Resistance 1 (Ipr1), which was thought may be a gene that contributed to resistance. Tests showed that the in the sst1 resistant macrophages the Ipr1 gene is upregulated upon infection and activation. It was found that in the sst1 susceptible macrophages, the expression of Ipr1 limits the multiplication of MTB conferring resistance. Ipr1 induction also switches the infected macrophages cell death pathway from necrosis to apoptosis. However in sst1 susceptible macrophages, Ipr1 was not expressed. In addition to its bacteriostatic effects on MTB, Ipr1 upregulation limits the multiplication of Listeria monocytogenes, another virulent and potentially fatal pathogen. The authors of the study suggest that signals generated by intracellular pathogens with mechanisms that control pathogenesis, cell death and innate immunity may be integrated in part by the Ipr1 gene product, contributing further knowledge to the role of genes in pathogenic immunity.
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