Host Factors Identified That Regulate Latency of Mycobacterium tuberculosis
Key findings
- Mycobacterium tuberculosis (Mtb) has a remarkable ability to switch phenotypic states, allowing it to persist in infected macrophages, where host-derived lipid droplets form that aid its survival
- Lack of phenotype-specific models of Mtb infection and knowledge of contributing host factors have hindered the development of effective interventions for latent infection
- In this study, a novel multi-fluorescent reporter was used to identify three distinct Mtb phenotypes—survival, active replication, and stressed non-replication—and the host transcriptome of infected macrophages in those states
- A combination of transcriptomics and genome-wide screens identified the MMGT1–GPR156 axis as a previously unrecognized regulator of Mtb latency via lipid droplet accumulation
- Targeting these host factors is likely to be an efficient approach to force phenotypic switching in Mtb, with consequences for drug susceptibility
Mycobacterium tuberculosis (Mtb) infection progresses to active tuberculosis in only 5%–10% of cases. The remarkable ability of Mtb to persist in infected hosts for decades and then reactivate upon sensing favorable conditions makes it an exceptionally successful pathogen.
Subscribe to the latest updates from Digestive Health Advances in Motion
To date, no drug is available that targets latent Mtb directly. As an alternative, host-directed therapy is being investigated, which requires more knowledge about how the host contributes to the phenotype switching capability of Mtb.
Massachusetts General Hospital researchers have engineered a multi-fluorescent Mtb strain that captures the various phenotypic states of Mtb. Building on those findings, they identified a targetable axis that regulates Mtb persistence.
Ramnik J. Xavier, MD, PhD, director of the Center for the Study of IBD at Mass General and Kurt J. Isselbacher professor of Medicine in the Field of Gastroenterology at Harvard Medical School, Haroon Kalam, PhD, research associate in Medicine, and colleagues published their findings in Cell Host & Microbe.
Background
When Mtb infects macrophages, host-derived lipid droplets form that aid its survival. A large portion of the Mtb genome codes for enzymes involved in lipolysis, reflecting the pathogen's ability to use complex lipids as a source of nutrition.
Paradoxically, once infected macrophages are full of lipid droplets, Mtb replication diminishes and its phenotype switches toward a non-replicating state. Lipid droplets are now regarded as a component of innate immunity and a regulator of the host's metabolic state upon infection.
Distinct Mtb Phenotypes
In this new study, using a triple reporter to examine Mtb-infected macrophages, the researchers observed three distinct phenotypic states:
- Survival—No replication and low stress (further research is needed to understand the functional relevance of this state)
- Active replication (AR)—Metabolically active and relatively susceptible to first-line anti-tuberculosis antibiotics
- Stressed non-replication (SNR)—Higher drug tolerance and metabolically dormant, corresponding to a persistent phenotype
Transcriptomics analysis identified distinct sets of functional pathways active in AR or SNR-infected macrophages.
Host Regulators of Mtb Phenotypes
A genome-wide CRISPR screen was conducted to identify host factors whose knockout significantly influenced the AR or SNR states. Membrane magnesium transporter 1 (MMGT1) was prioritized for more detailed investigation.
Further analysis showed Mtb infection of MMGT1-deficient macrophages promoted a switch to persistence, upregulation of lipid metabolism genes, and accumulation of lipid droplets. Targeting triacylglycerol synthesis reduced both droplet formation and Mtb persistence.
The expression and activity of the G protein-coupled receptor GPR156 were regulated in Mtb-infected MMGT1-deficient macrophages. MMGT1–GPR156 signaling regulated the lipid drop formation exploited by Mtb.
Targeting these host factors is likely an efficient approach to force phenotypic switching in Mtb, with consequences for drug susceptibility and interactions with host cells.
view original journal article Subscription may be required
Visit the Digestive Healthcare Center
Learn more about the Center for the Study of IBD