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Mycobacterial Lipid Bodies and the Chemosensitivity and Transmission of Tuberculosis

  • Natalie J. Garton
  • Michael R. Barer
Living reference work entry
Part of the Handbook of Hydrocarbon and Lipid Microbiology book series (HHLM)

Abstract

Just over a quarter of humanity is infected with the tubercle bacillus and risks developing active disease that routinely requires 6-month treatment. The impact of this scourge cannot be underestimated, and reducing the global burden of tuberculosis is the focus of much research. In addition to the need for improved chemotherapy regimens and monitoring thereof, understanding the risk and processes involved in transmission, a critical step in the life cycle of the organism, has even greater potential to impact the burden of disease. Our chance observation that lipid bodies (LBs) were present in Mycobacterium tuberculosis in sputum, but not in growing cultures of the lab strain in vitro, led us and others to examine this phenomenon further. Transcriptional analysis of the bacilli in sputum identified that upregulation of tgs1, a triacylglycerol synthase, was likely responsible for the presence of these LBs. Strikingly, in contrast to the then established view that tubercle bacilli in sputum arose directly from rapidly replicating populations, further transcriptional and cytological analyses led us to link the M. tuberculosis sputum phenotype to slow or non-growing persisters. As a result, we and others have directed research to further understanding the biological and clinical significance of LBs and neutral lipids in mycobacteria. There is now greater insight into the biosynthetic pathways and role of neutral lipids during infection, for both growing and dormant M. tuberculosis. Links have been made between tgs1-related triacylglycerol LB accumulation and growth arrest and with antibiotic tolerance potentially underpinning the need for protracted chemotherapy. The possible clinical significance of this is reflected in the finding that sustained high frequencies of LB-positive M. tuberculosis in sputum during treatment are associated with unsatisfactory outcomes. LB-positivity may also support transmission of the organism. Greater understanding of the significance of this “fat and lazy” population will open up new approaches to the combat of this long-standing foe.

Abbreviations

ACSL

Long-chain acyl-CoA synthase

DAG

Diacylglycerol

DC

Differentially culturable

DGAT

Diacylglycerol acyl transferase

FACS

Fatty acyl CoA synthase

FCR

Fatty acyl long-chain CoA reductase

ILI

Intracellular lipophilic inclusion

LB

Lipid body

LCFA

Long-chain fatty acid

LD

Lipid droplet

NO

Nitric oxide

PBMC

Peripheral blood mononuclear cell

RIF

Rifampicin

TAG

Triacylglycerol

TB

Tuberculosis

TCA

Tricarboxylic acid

TGS

Triacylglycerol synthase

THL

Tetrahydrolipstatin

WE

Wax ester

WS

Wax ester synthase

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Authors and Affiliations

  1. 1.Department of Infection, Immunity and InflammationUniversity of LeicesterLeicesterUK
  2. 2.Department of Clinical MicrobiologyUniversity Hospitals Leicester NHS TrustLeicesterUK

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