Mycobacterium tuberculosis Is Able To Accumulate and Utilize Cholesterol

Abstract

It is expected that the obligatory human pathogen Mycobacterium tuberculosis must adapt metabolically to the various nutrients available during its cycle of infection, persistence, and reactivation. Cholesterol, which is an important part of the mammalian cytoplasmic membrane, is a potential energy source. Here, we show that M. tuberculosis grown in medium containing a carbon source other than cholesterol is able to accumulate cholesterol in the free-lipid zone of its cell wall. This cholesterol accumulation decreases the permeability of the cell wall for the primary antituberculosis drug, rifampin, and partially masks the mycobacterial surface antigens. Furthermore, M. tuberculosis was able to grow on mineral medium supplemented with cholesterol as the sole carbon source. Targeted disruption of the Rv3537 (kstD) gene inhibited growth due to inactivation of the cholesterol degradation pathway, as evidenced by accumulation of the intermediate, 9-hydroxy-4-androstene-3,17-dione. Our findings that M. tuberculosis is able to accumulate cholesterol in the presence of alternative nutrients and use it when cholesterol is the sole carbon source in vitro may facilitate future studies into the pathophysiology of this important deadly pathogen.Mycobacterium tuberculosis, the causative agent of tuberculosis, is a very successful pathogen that infects one-third of the human population (21). Only 10% of primary infected individuals develop active disease during their lifetimes. Tubercle bacilli are able to persist in a dormant state, from which they may reactivate and induce the contagious disease state (13). In asymptomatic hosts, M. tuberculosis exists in reservoirs called granulomas, which are cellular aggregates that restrict bacterial spreading (40). Granulomas are organized collections of mature macrophages that exhibit a certain typical morphology and that arise in response to persistent intracellular pathogens (1, 4). Pathogenic mycobacteria can induce the formation of foamy macrophages filled with lipid-containing bodies; these have been postulated to act as a secure, nutrient-rich reservoir for tubercle bacilli (31). Moreover, M. tuberculosis DNA has been detected in fatty tissues surrounding the kidneys, as well as those of the stomach, lymph nodes, heart, and skin. Tubercle bacilli are able to enter adipocytes, where they accumulate within intracytoplasmic lipid inclusions and survive in a nonreplicating state (26). In vivo, it is expected that M. tuberculosis adapts metabolically to nutrient-poor conditions characterized by glucose deficiency and an abundance of fatty acids (25,26). The presence of a complex repertoire of lipid metabolism genes in the genome of M. tuberculosis suggests that lipids, including steroids, are important alternative carbon and energy sources for this pathogen (7).One attractive potential alternative nutrient that is readily available in the mammalian host is cholesterol, a major sterol of the plasma membrane. The presence of cholesterol in lipid rafts is required in order for microorga...

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

“…This property gave Rhodococcus species potential for industrial application to clean up sites of oil pollution [137]. In Mycobacterium tuberculosis, this property is manifested as an ability to attract cholesterol into the lipid-free zone that surrounds the cell wall mycolic acid layer [146] and is at the basis of the requirement for host cell membrane cholesterol to enable entry of the bacillus into its host macrophage [139,147]. Besides being essential for the phagocytosis of the bacterium by the macrophage, cholesterol is also used by the bacilli as an energy and carbon source that is critically linked with mycobacterial persistence [148,149] and depends on a sufficient availability of the sterol within the host cell.…”

Mycobacterium smegmatis is a suitable cell factory for the production of steroidic synthons

“…Brzostek et al . (2009) have identified six putative KstD enzymes within the M. smegmatis genome and a targeted disruption of one of them (KstD1) resulted in partial inactivation of the cholesterol degradation pathway and the consequent accumulation of AD. More recently, Wei et al .…”

Mycobacterium tuberculosis Mce1 protein complex initiates rapid induction of transcription of genes involved in substrate trafficking

“…To ensure sufficient availability of cholesterol, the mycobacteria rely on lipid import by the host macrophage 17 and M. tuberculosis has been demonstrated to stimulate the accumulation of cholesterol in the cell wall. 18 The storage of cholesterol in the cell wall of the bacterium has been shown to result in altered cell wall permeability and decreased uptake of rifampin. 18 The transcription of Abca1 is tightly Figure 2.…”

“…18 The storage of cholesterol in the cell wall of the bacterium has been shown to result in altered cell wall permeability and decreased uptake of rifampin. 18 The transcription of Abca1 is tightly Figure 2. Expression profiles of co-transcribed genes.…”