Cholesterol-sensor initiates M. tuberculosis entry into human macrophages

Abstract

Cholesterol-mediated mycobacteria entry into and survival within macrophages has added a new dimension to Tuberculosis research. The molecular mechanism through which cholesterol initiates this process is still poorly understood. The present study addressed to resolve this mechanism revealed that Mycobacterium tuberculosis possesses cholesterol-specific Receptor 'Ck'-like molecule responsible for mycobacterial entry into macrophages. Further human Receptor-Ck was found to regulate transcriptional expression of a gene that codes for Tryptophan-Aspartate containing coat (TACO) protein responsible for survival of mycobacteria within cells. Based upon these results, we propose that interaction of Receptor-Ck with cholesterol-rich membrane domains helps to create a 'Synaptic-junction' between mycobacteria and macrophage resulting in signalling events that are responsible for mycobacterium entry into and survival within macrophages.

Uptake and Persistence of Mycobacterium avium subsp. paratuberculosis in Human Monocytes

“…paratuberculosis associates with and is internalized into THP-1 monocytes in a cholesteroldependent manner and at cholesterol-rich areas of the membrane. This, coupled with our finding of cholesterol-dependent M. bovis uptake by THP-1 cells, is consistent with other studies of pathogenic mycobacteria (12,22,32). Intriguingly, significantly fewer E. coli bacteria associated with cells as cellular cholesterol levels fell.…”

“…In addition, cellular cholesterol may actively affect processes associated with normal bacterial clearance. One example is the cholesterol-dependent binding of the mycobacterial protein lipoamide dehydrogenase C (LpdC) to coronin-1 (also known as TACO) on the phagosomal membrane (10,12,22). Binding aids retention of the coronin-1 protein (8), which, in turn, facilitates phagosome maturation arrest (10) by blocking lysosomal delivery (21).…”

“…paratuberculosis survival, as has been reported for pathogenic mycobacteria such as M. tuberculosis and M. bovis. These species have been reported to use receptor-mediated association with cholesterol-rich areas of the plasma membrane (22) to enter cells and traffic to cholesterol-rich compartments (12), where they persist by utilizing host cholesterol (30) and blocking normal phagosome maturation. This is demonstrated by reduced fusion of bacterium-containing phagosomes with lysosomes (6) and the absence of RILP (Rab7-interacting lysosomal protein) in Rab7-staining phagosomes that contain live mycobacteria (38).…”

DNAzymes Targeting theiclGene Inhibit ICL Expression and DecreaseMycobacterium tuberculosisSurvival in Macrophages

“…Kaul et al (2004) found that there are cholesterol receptors on the M. tuberculosis cell wall. For guiding DNAzymes to M. tuberculosis and improving the uptake of DNAzymes, we ligated a cholesterol molecular at the 3Ј-end of DZ4, but we did not observe the expected improvement.…”

The Mycobacterium Tuberculosis Cytochromes P450: Physiology, Biochemistry & Molecular Intervention

“…Molecular genetics and micro biology have shown multiple important roles for cholesterol in Mtb pathogenesis. Cholesterol is a major sterol of the mammalian plasma mem brane and is abundant in the macrophage [41].…”