Identification of host regulators of Mycobacterium tuberculosis phenotypic states uncovers a role for the MMGT1-GPR156-lipid droplet axis in the induction of persistence [THP1_MMGT1_RNAseq]

The ability of Mycobacterium tuberculosis (Mtb) to establish latency directly impacts disease and response to treatment but the host’s influence on this switch remains elusive. Using a novel Mtb reporter strain to separate macrophages infected with replicating or latent Mtb, we performed transcriptomics and genome-wide CRISPR screens. After validating the recovery of known susceptibility loci from TB GWAS as modifiers of active replication, we identified multiple pathways and novel modulators of latency. We validated multiple controllers of latency and mechanistically characterized the transporter MMGT1. MMGT1-deficient macrophages upregulated lipid metabolism genes and accumulated lipid droplets during infection. Critically, targeting triacylglycerol synthesis reduced both droplet formation and Mtb latency. We identified GPR156, an orphan GPCR as a key inducer of droplet accumulation in ΔMMGT1 cells. Altogether, our work uncovers the role of MMGT1-GPR156-lipid droplets in the induction of Mtb latency, suggesting that host-directed therapies could be used to modulate Mtb phenotypes during infection. Transcriptome profiling (RNA-seq) by high throughput sequencing of uninfected THP1, Mtb infected THP1, uninfected ΔMMGT1 and Mtb infected ΔMMGT1 macrophage