Autophagy Gene Variant IRGM 2261T Contributes to Protection from Tuberculosis Caused by Mycobacterium tuberculosis but Not by M. africanum Strains

Autophagy is a process in which cell components are degraded by the lysosomal machinery. It has recently been described that activation of autophagy reduces the viability of M. tuberculosis in phagosomes due to an intimate autophagy-phagocytosis interaction. M. tuberculosis may also be directly accessible to autophagy, as M. tuberculosis was … See more

Autophagy is a process in which cell components are degraded by the lysosomal machinery. It has recently been described that activation of autophagy reduces the viability of M. tuberculosis in phagosomes due to an intimate autophagy-phagocytosis interaction. M. tuberculosis may also be directly accessible to autophagy, as M. tuberculosis was found to translocate into the cytoplasm. The immunityrelated GTPase IRGM is a mediator of innate immune responses and induces autophagy. We have studied genetic variants of the human IRGM gene in a Ghanaian tuberculosis case-control group and found that the IRGM variant 2261T provides relative protection against disease when the infection is caused by the Euro-American lineage of M. tuberculosis. This lineage is characterized by the pks1/15 seven base-pair (bp) deletion. The product of an intact pks1/ 15 gene, phenolic glycolipid-tb, might contribute to mycobacterial virulence by suppressing innate immune responses. It is, therefore, conceivable that only the Euro- American lineage is exposed to IRGM-triggered innate defence mechanisms. Our observations suggest that the increased frequency of the IRGM 2261TT genotype may have allowed the establishment of M. africanum as a pathogen in West Africa.

See less