Mycobacterial persistence requires the utilization of host cholesterol

Abstract

A hallmark of tuberculosis is the ability of the causative agent, Mycobacterium tuberculosis , to persist for decades despite a vigorous host immune response. Previously, we identified a mycobacterial gene cluster, mce4 , that was specifically required for bacterial survival during this prolonged infection. We now show that mce4 encodes a cholesterol import system that enables M. tuberculosis to derive both carbon and energy from this ubiquitous component of host membranes. Cholesterol import is not required for establishing infection in mice or for growth in resting macrophages. However, this function is essential for persistence in the lungs of chronically infected animals and for growth within the IFN-γ-activated macrophages that predominate at this stage of infection. This finding indicates that a major effect of IFN-γ stimulation may be to sequester potential pathogens in a compartment devoid of more commonly used nutrients. The unusual capacity to catabolize sterols allows M. tuberculosis to circumvent this defense and thereby sustain a persistent infection.

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

“…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. Mycolic acids may in fact constitute a direct means by which intracellular M.…”

Characterization of the KstR-dependent promoter of the gene for the first step of the cholesterol degradative pathway in Mycobacterium smegmatis

“…Interestingly, it has been described that only fast-growing non-pathogenic mycobacteria were able to grow on cholesterol as a sole carbon source (Av-Gay & Sobouti, 2000); however, more recent results have demonstrated that cholesterol is also used as a carbon source during infection of M. tuberculosis (Pandey & Sassetti, 2008). Although recent biochemical and structural studies have assigned a role for some of the mycobacterial genes in cholesterol catabolism, the complete degradative pathway and its specific regulation remain to be fully established (Capyk et al, 2009;Knol et al, 2008;Lack et al, 2010;Yam et al, 2009).…”

Mce3R, a TetR-type transcriptional repressor, controls the expression of a regulon involved in lipid metabolism in Mycobacterium tuberculosis

“…Based on the identification of conserved domains in many Mce proteins, previous studies strongly suggest that the mce and yrbE genes encode components of ABC transport systems (Kumar et al, 2005;Casali & Riley, 2007). Moreover, it has recently been demonstrated that mce4 encodes a cholesterol import system that enables M. tuberculosis to derive both carbon and energy from host cholesterol (Pandey & Sassetti, 2008). Interestingly, Kendall et al (2007) have shown that the mce4 operon is regulated by KstR, a TetR-type regulator, and co-regulated with other genes involved in fatty acid metabolism.…”