Abstract
Mycobacterium tuberculosis (M. tuberculosis) causes an enormous burden of disease worldwide. As a central aspect of its pathogenesis, M. tuberculosis grows in macrophages, and host and microbe influence each other’s metabolism. To define the metabolic impact of M. tuberculosis infection, we performed global metabolic profiling of M. tuberculosis–infected macrophages. M. tuberculosis induced metabolic hallmarks of inflammatory macrophages and a prominent signature of cholesterol metabolism. We found that infected macrophages accumulate cholestenone, a mycobacterial-derived, oxidized derivative of cholesterol. We demonstrated that the accumulation of cholestenone in infected macrophages depended on the M. tuberculosis enzyme 3β-hydroxysteroid dehydrogenase (3β-Hsd) and correlated with pathogen burden. Because cholestenone is not a substantial human metabolite, we hypothesized it might be diagnostic of M. tuberculosis infection in clinical samples. Indeed, in 2 geographically distinct cohorts, sputum cholestenone levels distinguished subjects with tuberculosis (TB) from TB-negative controls who presented with TB-like symptoms. We also found country-specific detection of cholestenone in plasma samples from M. tuberculosis–infected subjects. While cholestenone was previously thought to be an intermediate required for cholesterol degradation by M. tuberculosis, we found that M. tuberculosis can utilize cholesterol for growth without making cholestenone. Thus, the accumulation of cholestenone in clinical samples suggests it has an alternative role in pathogenesis and could be a clinically useful biomarker of TB infection.
Highlights
Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis (TB), is an intracellular pathogen that causes an enormous worldwide burden of disease
We found that the most prominent metabolic signature of M. tuberculosis infection is likely to reflect bacterial cholesterol degradation
Bacterial cholesterol metabolism results in propionyl-CoA, which is metabolized through the methyl citrate and methylmalonyl pathway, and propionyl-CoA, 2-methylcitrate, and methylmalonate are infection-induced metabolites
Summary
Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis (TB), is an intracellular pathogen that causes an enormous worldwide burden of disease. It is estimated that 1.7 billion people are latently infected with M. tuberculosis, and in 2017 there were an estimated 10 million new cases of TB and 1.4 million deaths [1]. The diagnosis of active TB is often challenging, leading to long delays in treatment. Treatment generally requires multiple antibiotics for a minimum of 6 months, and relapse occurs in 3% to 5% of treated patients [2]. Long courses of therapy expose patients unnecessarily to side effects of antibiotics, while in other patients, stopping therapy prematurely leads to relapse. There is a large unmet medical need for new therapeutics; rapid, sensitive, and affordable diagnostic methods; and biomarkers to allow tailored therapy and to guide clinical decision making
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