Autophagy Gene Variant IRGM −261T Contributes to Protection from Tuberculosis Caused by Mycobacterium tuberculosis but Not by M. africanum Strains

Abstract

The human immunity-related GTPase M (IRGM) has been shown to be critically involved in regulating autophagy as a means of disposing cytosolic cellular structures and of reducing the growth of intracellular pathogens in vitro. This includes Mycobacterium tuberculosis, which is in agreement with findings indicating that M. tuberculosis translocates from the phagolysosome into the cytosol of infected cells, where it becomes exposed to autophagy. To test whether IRGM plays a role in human infection, we studied IRGM gene variants in 2010 patients with pulmonary tuberculosis (TB) and 2346 unaffected controls. Mycobacterial clades were classified by spoligotyping, IS6110 fingerprinting and genotyping of the pks1/15 deletion. The IRGM genotype −261TT was negatively associated with TB caused by M. tuberculosis (OR 0.66, CI 0.52–0.84, Pnominal 0.0009, Pcorrected 0.0045) and not with TB caused by M. africanum or M. bovis (OR 0.95, CI 0.70–1.30. P 0.8). Further stratification for mycobacterial clades revealed that the protective effect applied only to M. tuberculosis strains with a damaged pks1/15 gene which is characteristic for the Euro-American (EUAM) subgroup of M. tuberculosis (OR 0.63, CI 0.49–0.81, Pnominal 0.0004, Pcorrected 0.0019). Our results, including those of luciferase reporter gene assays with the IRGM variants −261C and −261T, suggest a role for IRGM and autophagy in protection of humans against natural infection with M. tuberculosis EUAM clades. Moreover, they support in vitro findings indicating that TB lineages capable of producing a distinct mycobacterial phenolic glycolipid that occurs exclusively in strains with an intact pks1/15 gene inhibit innate immune responses in which IRGM contributes to the control of autophagy. Finally, they raise the possibility that the increased frequency of the IRGM −261TT genotype may have contributed to the establishment of M. africanum as a pathogen in the West African population.

Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy

“…Furthermore, it has been shown that autophagy acts as a cell-autonomous defense mechanism against intracellular bacteria, contributing to antibacterial immunity by regulating the inflammatory immune response and routing engulfed intracellular bacteria toward lysosomal degradation (12,13). Many pathogens are able to evade autophagy, although the molecular mechanisms at play remain largely uncharacterized (14)(15)(16)(17)(18)(19)(20). Among these pathogens L. pneumophila is known to escape cellular attack by blocking autophagy defenses (21).…”

The innate immune response in human tuberculosis

“…Compared with the mouse genome (containing 23 IRG genes), the human genome contains only three IRG genes, encoding IRGC, IRGQ and IRGM, but these are not inducible by IFN‐γ. Polymorphisms in the IRGM gene, which is functional in humans, are associated with susceptibility to TB among African‐Americans (King et al ., 2011), Ghanese (Intemann et al ., 2009) and Chinese (Che et al ., 2010) populations, providing evidence that IRG proteins contribute to the control of Mtb in humans. However, functional polymorphisms in both IRGM and the autophagy gene ATG16L1 did not have a major impact on Mtb‐induced cytokine production in healthy volunteers, although a moderate effect was observed on IFN‐γ production by the ATG16L1 T300A polymorphism (Kleinnijenhuis et al ., 2011).…”

Human ULK1 Variation and Susceptibility toMycobacterium tuberculosisInfection

“…Although polymorphisms in IRGM, an autophagy gene, have been associated with tuberculosis in diverse populations [24][25][26], a study of 22 autophagy genes in an Indonesian population did not identify any associations with tuberculosis [32]. To our knowledge, ULK1 is only the second autophagy gene associated with tuberculosis in genetic studies and the first to be associated with LTBI [24,25,27].…”

“…GABARAP regulates later stages of autophagosome maturation. A number of candidate gene studies have demonstrated associations between polymorphisms in IRGM, an autophagy gene, and tuberculosis in various populations [24][25][26]. However, IRGM polymorphisms were not associated with the outcome of LTBI in one study [27].…”