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Abstract

The progression of tuberculosis from a latent, subclinical infection to active disease that culminates in the transmission of infectious bacilli is determined locally at the level of the granuloma. This progression takes place even in the face of a robust immune response that, although it contains infection, is unable to eliminate the bacterium. The factors or environmental conditions that influence this progression remain to be determined. Recent advances have indicated that pathogen-induced dysregulation of host lipid synthesis and sequestration serves a critical role in this transition. The foamy macrophage seems to be a key participant in both sustaining persistent bacteria and contributing to the tissue pathology that leads to cavitation and the release of infectious bacilli.

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Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase.

John McKinney, Kerstin zu Bentrup, Ernesto Muñoz-Elías … (2000)

Mycobacterium tuberculosis claims more human lives each year than any other bacterial pathogen. Infection is maintained in spite of acquired immunity and resists eradication by antimicrobials. Despite an urgent need for new therapies targeting persistent bacteria, our knowledge of bacterial metabolism throughout the course of infection remains rudimentary. Here we report that persistence of M. tuberculosis in mice is facilitated by isocitrate lyase (ICL), an enzyme essential for the metabolism of fatty acids. Disruption of the icl gene attenuated bacterial persistence and virulence in immune-competent mice without affecting bacterial growth during the acute phase of infection. A link between the requirement for ICL and the immune status of the host was established by the restored virulence of delta icl bacteria in interferon-gamma knockout mice. This link was apparent at the level of the infected macrophage: Activation of infected macrophages increased expression of ICL, and the delta icl mutant was markedly attenuated for survival in activated but not resting macrophages. These data suggest that the metabolism of M. tuberculosis in vivo is profoundly influenced by the host response to infection, an observation with important implications for the treatment of chronic tuberculosis.

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The role of the granuloma in expansion and dissemination of early tuberculous infection.

J. Muse Davis, Lalita Ramakrishnan (2009)

Granulomas, organized aggregates of immune cells, form in response to persistent stimuli and are hallmarks of tuberculosis. Tuberculous granulomas have long been considered host-protective structures formed to contain infection. However, work in zebrafish infected with Mycobacterium marinum suggests that granulomas contribute to early bacterial growth. Here we use quantitative intravital microscopy to reveal distinct steps of granuloma formation and assess their consequence for infection. Intracellular mycobacteria use the ESX-1/RD1 virulence locus to induce recruitment of new macrophages to, and their rapid movement within, nascent granulomas. This motility enables multiple arriving macrophages to efficiently find and phagocytose infected macrophages undergoing apoptosis, leading to rapid, iterative expansion of infected macrophages and thereby bacterial numbers. The primary granuloma then seeds secondary granulomas via egress of infected macrophages. Our direct observations provide insight into how pathogenic mycobacteria exploit the granuloma during the innate immune phase for local expansion and systemic dissemination.

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Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs

Andrea J Wolf, Ludovic Desvignes, Beth Linas … (2008)

The onset of the adaptive immune response to Mycobacterium tuberculosis is delayed compared with that of other infections or immunization, and allows the bacterial population in the lungs to expand markedly during the preimmune phase of infection. We used adoptive transfer of M. tuberculosis Ag85B-specific CD4+ T cells to determine that the delayed adaptive response is caused by a delay in initial activation of CD4+ T cells, which occurs earliest in the local lung-draining mediastinal lymph node. We also found that initial activation of Ag85B-specific T cells depends on production of antigen by bacteria in the lymph node, despite the presence of 100-fold more bacteria in the lungs. Although dendritic cells have been found to transport M. tuberculosis from the lungs to the local lymph node, airway administration of LPS did not accelerate transport of bacteria to the lymph node and did not accelerate activation of Ag85B-specific T cells. These results indicate that delayed initial activation of CD4+ T cells in tuberculosis is caused by the presence of the bacteria in a compartment that cannot be mobilized from the lungs to the lymph node, where initial T cell activation occurs.

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PubMed ID:: 19692995

PMC ID:: 2759071

DOI:: 10.1038/ni.1781

ScienceOpen disciplines: Chemistry

Keywords: Animals,Disease Progression,Foam Cells,physiology,Granuloma,etiology,immunology,pathology,Humans,Isocitrate Lyase,Lipids,biosynthesis,Lipoproteins, LDL,metabolism,Phagosomes,Tuberculosis,Tumor Necrosis Factor-alpha

Foamy macrophages and the progression of the human tuberculosis granuloma.

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Journal of Circulating Biomarkers

Most cited references 44

Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase.

The role of the granuloma in expansion and dissemination of early tuberculous infection.

Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs

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