Differential Requirement for IRGM Proteins During Tuberculosis Infection in Mice

Mycobacterium tuberculosis () is a bacterium that exclusively resides in human hosts and remains a dominant cause of morbidity and mortality among infectious diseases worldwide. Host protection against infection is dependent on the function of immunity-related GTPase clade M (IRGM) proteins. Polymorphisms in human associate with altered susceptibility to mycobacterial disease, and human IRGM promotes the delivery of into degradative autolysosomes. Among the three murine IRGM orthologs, has been singled out as essential for host protection during infections in cultured macrophages and . However, whether the paralogous murine genes, and , play roles in host defense against or exhibit functional relationships with during infection remains undetermined. Here, we report that mice are indeed acutely susceptible to aerosol infection with , yet the additional deletion of the paralogous gene restores protective immunity to infections in -deficient animals. Mice lacking all three genes (pan) are characterized by shifted lung cytokine profiles at 5 and 24 weeks postinfection, but control disease until the very late stages of the infection, when pan mice display increased mortality compared to wild-type mice. Collectively, our data demonstrate that disruptions in the balance between isoforms is more detrimental to the -infected host than total loss of -mediated host defense, a concept that also needs to be considered in the context of human susceptibility linked to polymorphisms.