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The role of cholesterol and its oxidation products in tuberculosis pathogenesis
Andrew T Roth1, Jennifer A Philips2,3, Pallavi Chandra2
1Division of Pulmonary & Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Abstract:
Mycobacterium tuberculosis causes tuberculosis (TB), one of the world's most deadly infections. Lipids play an important role in M. tuberculosis pathogenesis. M. tuberculosis grows intracellularly within lipid-laden macrophages and extracellularly within the cholesterol-rich caseum of necrotic granulomas and pulmonary cavities. Evolved from soil saprophytes that are able to metabolize cholesterol from organic matter in the environment, M. tuberculosis inherited an extensive and highly conserved machinery to metabolize cholesterol. M. tuberculosis uses this machinery to degrade host cholesterol; the products of cholesterol degradation are incorporated into central carbon metabolism and used to generate cell envelope lipids, which play important roles in virulence. The host also modifies cholesterol by enzymatically oxidizing it to a variety of derivatives, collectively called oxysterols, which modulate cholesterol homeostasis and the immune response. Recently, we found that M. tuberculosis converts host cholesterol to an oxidized metabolite, cholestenone, that accumulates in the lungs of individuals with TB. M. tuberculosis encodes cholesterol-modifying enzymes, including a hydroxysteroid dehydrogenase, a putative cholesterol oxidase, and numerous cytochrome P450 monooxygenases. Here, we review what is known about cholesterol and its oxidation products in the pathogenesis of TB. We consider the possibility that the biological function of cholesterol metabolism by M. tuberculosis extends beyond a nutritional role.
Insights
Mycobacterium tuberculosis utilizes host cholesterol for its growth and virulence, incorporating degraded products into its cell envelope. The bacterium also produces cholestenone, an oxidized metabolite found in TB patient lungs.
Area of Science:
- Microbiology
- Infectious Diseases
- Biochemistry
Background:
- Tuberculosis (TB) is a deadly infection caused by Mycobacterium tuberculosis.
- Lipids, particularly cholesterol, are crucial in M. tuberculosis pathogenesis and survival within host macrophages and granulomas.
- M. tuberculosis possesses a conserved machinery for cholesterol metabolism, inherited from environmental saprophytes.
Purpose of the Study:
- To review the role of cholesterol and its oxidation products in TB pathogenesis.
- To explore how M. tuberculosis metabolizes host cholesterol and its implications for virulence.
- To consider the broader biological functions of cholesterol metabolism beyond nutrition.
Main Methods:
- Review of existing literature on cholesterol metabolism in M. tuberculosis.
- Analysis of M. tuberculosis's enzymatic machinery for cholesterol modification (e.g., hydroxysteroid dehydrogenase, cholesterol oxidase, P450 monooxygenases).
- Discussion of host-derived oxysterols and their immune-modulating effects.
Main Results:
- M. tuberculosis degrades host cholesterol, incorporating products into its metabolism for cell envelope synthesis and virulence.
- The bacterium converts host cholesterol into cholestenone, an oxidized metabolite detected in the lungs of TB patients.
- Host-derived oxysterols influence cholesterol homeostasis and immune responses.
Conclusions:
- Cholesterol metabolism by M. tuberculosis is integral to its pathogenesis, contributing to virulence and survival.
- The bacterium's ability to modify cholesterol suggests a role beyond simple nutrient acquisition.
- Understanding cholesterol's role offers potential avenues for novel TB therapeutics.
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