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

Automated summary

Cell-intrinsic immune mechanisms play a role in controlling intracellular pathogens. Mycobacterium tuberculosis (Mtb) has evolved to resist cell-autonomous immunity and cause persistent infections. The cytokine IFN gamma induces cell-autonomous immunity, but Mtb can evade certain antimicrobial responses mediated by IFN gamma. The Guanylate binding proteins (GBPs), key host defense proteins, are able to control intracellular infections. While GBPs can restrict M. bovis BCG, their role in Mtb infection was unclear. This study reveals a novel function of the ESX1 virulence system in evading GBP-mediated immunity.