Pathology of postprimary tuberculosis in humans and mice: Contradiction of long-held beliefs

Hunter, Robert L.; Jagannath, Chinnaswamy; Actor, Jeffrey K.

doi:10.1016/j.tube.2006.11.003

Cited by 168 publications

(190 citation statements)

References 48 publications

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“…Although the resolution of these studies precludes us from determining whether cholesterolcontaining membranes are directly adjacent to the pathogen, it seems likely that mycobacteria have access to adequate local stores of cholesterol during intracellular growth. This compound may be even more abundant in tuberculosis lesions in vivo, where M. tuberculosis is often found within cholesterol-laden foamy macrophages or in extracellular spaces in which cholesterol is deposited as insoluble crystals (6).…”

Section: Discussionmentioning

confidence: 99%

“…The result of this biological impasse is chronic tuberculosis, which is characterized by slowly replicating bacteria, and progressive immunopathology. In these chronic tuberculosis lesions, both intra-and extracellular bacteria are apparent (6). Thus, to maintain a persistent infection, M. tuberculosis must adapt to a heterogeneous and continually changing host environment.…”

mentioning

confidence: 99%

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Mycobacterial persistence requires the utilization of host cholesterol

Pandey

Sassetti²

2008

Proc. Natl. Acad. Sci. U.S.A.

941

1,039

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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.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Mycobacterial persistence requires the utilization of host cholesterol

Pandey

Sassetti²

2008

Proc. Natl. Acad. Sci. U.S.A.

941

1,039

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“…Foamy macrophages containing multiple cholesterol loaded lipid bodies constitute a distinct trait of tuberculous granulomas and a safe haven for mycobacteria, since they have been found to harbor multiple bacilli [150,151]. Induction by mycolic acids of macrophages rich in lipid bodies was further confirmed on human monocyte-derived macrophages [152].…”

Section: Cholesteroid Nature Of Mycolic Acidsmentioning

confidence: 87%

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

Verschoor

Baird

Grooten

2012

Progress in Lipid Research

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Mycolic acids constitute the waxy layer of the outer cell wall of Mycobacterium spp and a few other genera. They are diverse in structure, providing a unique chromatographic foot-print for almost each of the more than seventy Mycobacterium species. Although mainly esterified to cell wall arabinogalactan, trehalose or glucose, some free mycolic acid is secreted during in vitro growth of M. tuberculosis. In M. tuberculosis, alpha-, keto-and methoxy-mycolic acids are the main classes, each differing in their ability to attract neutrophils, induce foamy macrophages or adopt an antigenic structure for antibody recognition. Of interest is their particular relationship to cholesterol, discovered by their ability to attract cholesterol, to bind Amphotericin B or to be recognised by monoclonal antibodies that cross-react with cholesterol. The structural elements that determine this diverse functionality include the carboxylic acid in the mycolic motif, as well as the nature and stereochemistry of the two functional groups in the merochain. The functional diversity of mycolic acid classes implies that much information may be contained in the selective expression and secretion of mycolic acids to establish tuberculosis after infection of the host. Their cholesteroid nature may relate to how they utilize host cholesterol for their persistent survival.

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“…Implication of TDM as a major contributor to primary tuberculosis pathology has been "validated" through use of these animal models [22][23][24][25][26][27] [47,48]. This now gives TDM a foothold as a mediator of adaptive functions leading to post primary tuberculosis and cavitary lesion development [7].…”

Section: Biological Properties Associated With Cord Factormentioning

confidence: 99%

“…In contrast, post primary tuberculosis (also referred to as secondary or adult tuberculosis) was recently redefined as a caseating pathology arising in immune competent individuals whereby organisms evade strong and effective systemic specific immunity [4][5][6]. In modern day cases, post primary tuberculosis is often associated with a lipid pneumonia, challenging long held beliefs that cavities arise from expansion of caseating granulomas [7].…”

Section: Introductionmentioning

confidence: 99%

Mycobacterial TDM: A Coat to Modulate Post Primary Pathogenesis?

Actor¹

2012

Mycobact Diseases

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Pathology of postprimary tuberculosis in humans and mice: Contradiction of long-held beliefs

Cited by 168 publications

References 48 publications

Mycobacterial persistence requires the utilization of host cholesterol

Mycobacterial persistence requires the utilization of host cholesterol

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

Mycobacterial TDM: A Coat to Modulate Post Primary Pathogenesis?

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