MTOR deficiency reveals an immunological trade-off in innate resistance to mycobacterial infection in vivo

Abstract

Abstract The Mechanistic Target of Rapamycin (mTOR) has been implicated in myeloid cell development and survival. As adequate myelopoiesis has been recently shown to be a resistance factor in tuberculosis, mTOR deficiency would be expected to increase mycobacterial growth and thus host susceptibility to this disease. In contrast, mTOR inhibition decreases Mycobacterium tuberculosis infection burdens in cultured macrophages, an effect attributed to the triggering of autophagy. Which of these contradictory effects of mTOR deficiency influences infection outcome in vivo is unknown. We have examined the effects of mTOR on mycobacterial infection using the optically transparent and genetically tractable Mycobacterium marinum-zebrafish model of tuberculosis. A forward genetic screen in zebrafish initially identified an mtor mutant as being hypersusceptible to M. marinum, a phenotype that mapped to mTOR complex 1 and was reproduced with rapamycin. However, using very low inoculums typical of human tuberculosis (1–3 mycobacteria) revealed mTOR’s dichotomous role: mTOR-deficient animals were more likely to clear infection early, but those that did not clear the infection progressed rapidly to more severe disease characterized by the death of infected macrophages and subsequent release of mycobacteria into the more growth-permissive extracellular space. Thus, mTOR supports macrophage homeostasis at the expense of a transient enhancement in microbicidal capacity that could reduce the likelihood of mycobacterial colonization but would inevitably thwart long-term immunity.