Abstract
ABSTRACTMycobacterium tuberculosis(Mtb) is a bacterium that exclusively resides in human hosts and remains a dominant cause of morbidity and mortality among infectious diseases worldwide. Host protection againstMtbinfection is dependent on the function of immunity-related GTPase clade M (IRGM) proteins. Polymorphisms in humanIRGMassociate with altered susceptibility to mycobacterial disease, and human IRGM promotes the delivery ofMtbinto degradative autolysosomes. Among the three murine IRGM orthologs,Irgm1has been singled out as essential for host protection duringMtbinfections in cultured macrophages andin vivo. However, whether the paralogous murineIrgmgenes,Irgm2andIrgm3, play roles in host defense againstMtbor exhibit functional relationships withIrgm1duringMtbinfection remains undetermined. Here, we report thatIrgm1-/-mice are indeed acutely susceptible to aerosol infection withMtb, yet the additional deletion of the paralogousIrgm3gene restores protective immunity toMtbinfections inIrgm1-deficient animals. Mice lacking all threeIrgmgenes (panIrgm-/-) are characterized by shifted lung cytokine profiles at 4 and 24 weeks post infection, but control disease until the very late stages of the infection, when panIrgm-/-mice display increased mortality compared to wild type mice. Collectively, our data demonstrate that disruptions in the balance betweenIrgmisoforms is more detrimental to theMtb-infected host than total loss ofIrgm-mediated host defense, a concept that also needs to be considered in the context of humanMtbsusceptibility linked toIRGMpolymorphisms.
Publisher
Cold Spring Harbor Laboratory