Mycobacterium tuberculosis Evasion of Guanylate Binding Protein-Mediated Host Defense in Mice Requires the ESX1 Secretion System

Cell-intrinsic immune mechanisms control intracellular pathogens that infect eukaryotes. The intracellular pathogen ( ) evolved to withstand cell-autonomous immunity to cause persistent infections and disease. A potent inducer of cell-autonomous immunity is the lymphocyte-derived cytokine IFNγ. While the production of IFNγ by T cells is essential to protect against , it is not capable of fully eradicating infection. This suggests that evades a subset of IFNγ-mediated antimicrobial responses, yet what mechanisms resists remains unclear. The IFNγ-inducible Guanylate binding proteins (GBPs) are key host defense proteins able to control infections with intracellular pathogens. GBPs were previously shown to directly restrict BCG yet their role during infection has remained unknown. Here, we examine the importance of a cluster of five GBPs on mouse chromosome 3 in controlling Mycobacterial infection. While BCG is directly restricted by GBPs, we find that the GBPs on chromosome 3 do not contribute to the control of replication or the associated host response to infection. The differential effects of GBPs during versus BCG infection is at least partially explained by the absence of the ESX1 secretion system from BCG, since mutants lacking the ESX1 secretion system become similarly susceptible to GBP-mediated immune defense. Therefore, this specific genetic interaction between the murine host and reveals a novel function for the ESX1 virulence system in the evasion of GBP-mediated immunity.