An Outbreak Involving Extensive Transmission of a Virulent Strain of<i>Mycobacterium tuberculosis</i>

Valway, Sarah E.; Sanchez, Miguelle; Shinnick, T. F.; Orme, Ian M.; Agerton, Tracy B.; Hoy, Damian; Jones, J. Stephen; Westmoreland, H.; Onorato, Ida M.

doi:10.1056/nejm199803053381001

Cited by 352 publications

(230 citation statements)

References 19 publications

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“…Reversal of microbicidal activity by excess CaCl 2 supports the specificity of the Ca 2ϩ chelators and strengthens the conclusion that Ca 2ϩ is required for ATP-induced mycobacterial killing. Finally, the killing of two other well-characterized, virulent strains of M. tuberculosis, Erdman (26,27) and CDC1551 (32), by ATP e exhibited a similar Ca 2ϩ dependence (Fig. 2B, p Ͻ 0.001 for each strain and n ϭ 5).…”

Section: Atp-induced Killing Of Virulent M Tuberculosis Within Humanmentioning

confidence: 70%

ATP Stimulates Human Macrophages to Kill Intracellular Virulent Mycobacterium tuberculosis Via Calcium-Dependent Phagosome-Lysosome Fusion

Kusner

Barton²

2001

The Journal of Immunology

140

114

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Advances in therapy for tuberculosis will require greater understanding of the molecular mechanisms of pathogenesis and the human immune response in this disease. Exposure of Mycobacterium tuberculosis-infected human macrophages to extracellular ATP (ATPe) results in bacterial killing, but the molecular mechanisms remain incompletely characterized. In this study, we demonstrate that ATPe-induced bactericidal activity toward virulent M. tuberculosis requires an increase in cytosolic Ca2+ in infected macrophages. Based on our previous work with primary infection of human macrophages, we hypothesized that the Ca2+ dependence of ATP-induced killing of intracellular M. tuberculosis was linked to promotion of phagosome-lysosome fusion. Using confocal laser-scanning microscopy, we demonstrate that ATPe induces fusion of the M. tuberculosis-containing phagosome with lysosomes, defined by accumulation of three lysosomal proteins and an acidophilic dye. Stimulation of phagosome-lysosome fusion by ATPe exhibited distinct requirements for both Ca2+ and phospholipase D and was highly correlated with killing of intracellular bacilli. Thus, key signal transduction pathways are conserved between two distinct models of human macrophage antituberculous activity: primary infection of naive macrophages and physiologic stimulation of macrophages stably infected with M. tuberculosis.

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Section: Atp-induced Killing Of Virulent M Tuberculosis Within Humanmentioning

confidence: 70%

ATP Stimulates Human Macrophages to Kill Intracellular Virulent Mycobacterium tuberculosis Via Calcium-Dependent Phagosome-Lysosome Fusion

Kusner

Barton²

2001

The Journal of Immunology

140

114

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“…Outbreaks of tuberculosis present natural ''experiments'' in which the genotype of the strain responsible may be related to its propensity to cause clinical disease (8)(9)(10). In 2001, a large school-associated outbreak of tuberculosis occurred in Leicester, U.K., and both the genotype of the outbreak strain, CH, and the acquired immune responses of the exposed schoolchildren were characterized in unusual detail (10)(11)(12).…”

mentioning

confidence: 99%

A deletion defining a common Asian lineage ofMycobacterium tuberculosisassociates with immune subversion

Newton

Smith

Wilkinson

et al. 2006

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

100

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Six major lineages of Mycobacterium tuberculosis appear preferentially transmitted amongst distinct ethnic groups. We identified a deletion affecting Rv1519 in CH, a strain isolated from a large outbreak in Leicester U.K., that coincidentally defines the East African-Indian lineage matching a major ethnic group in this city. In broth media, CH grew less rapidly and was less acidic and H 2 O 2 -tolerant than reference sequenced strains (CDC1551 and H37Rv). Nevertheless, CH was not impaired in its ability to grow in human monocyte-derived macrophages. When compared with CDC1551 and H37Rv, CH induced less protective IL-12p40 and more antiinflammatory IL-10 and IL-6 gene transcription and secretion from monocyte-derived macrophages. It thus appears that CH compensates microbiological attenuation by skewing the innate response toward phagocyte deactivation. Complementation of Rv1519 , but none of nine additional genes absent from CH compared with the type strain, H37Rv, reversed the capacity of CH to elicit antiinflammatory IL-10 production by macrophages. The Rv1519 polymorphism in M. tuberculosis confers an immune subverting phenotype that contributes to the persistence and outbreak potential of this lineage.

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“…To study the role of M. tuberculosis SigH in the pathogenesis of tuberculosis, we used allelic exchange to delete and replace the sigH gene (MT3320, Rv3223c) (29) with a hygromycin-resistance gene cassette (⌬sigH mutant) in M. tuberculosis strain CDC1551 (wild type) (30). We also complemented the sigH mutation by cloning a complete copy of the sigH gene and its promoter into the singlecopy integrating plasmid pMH94.…”

Section: Construction Of the Sigh Mutant And Complemented Strainmentioning

confidence: 99%

Reduced immunopathology and mortality despite tissue persistence in aMycobacterium tuberculosismutant lacking alternative σ factor, SigH

Kaushal

Schroeder

Tyagi

et al. 2002

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

219

228

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The pathogenesis of tuberculosis involves multiple phases and is believed to involve both a carefully deployed series of adaptive bacterial virulence factors and inappropriate host immune responses that lead to tissue damage. A defined Mycobacterium tuberculosis mutant strain lacking the sigH-encoded transcription factor showed a distinctive infection phenotype. In resistant C57BL͞6 mice, the mutant achieved high bacterial counts in lung and spleen that persisted in tissues in a pattern identical to those of wild-type bacteria. Despite a high bacterial burden, the mutant produced a blunted, delayed pulmonary inflammatory response, and recruited fewer CD4 ؉ and CD8 ؉ T cells to the lung in the early stages of infection. In susceptible C3H mice, the mutant again showed diminished immunopathology and was nonlethal at over 170 days after intravenous infection, in contrast to isogenic wild-type bacilli, which killed with a median time to death of 52 days. Complete genomic microarray analysis revealed that M. tuberculosis sigH may mediate the transcription of at least 31 genes directly and that it modulates the expression of about 150 others; the SigH regulon governs thioredoxin recycling and may be involved in the maintenance of intrabacterial reducing capacity. These data show that the M. tuberculosis sigH gene is dispensable for bacterial growth and survival within the host, but is required for the production of immunopathology and lethality. This phenotype demonstrates that beyond an ability to grow and persist within the host, M. tuberculosis has distinct virulence mechanisms that elicit deleterious host responses and progressive pulmonary disease.T uberculosis is one of the leading infectious causes of death and claims Ϸ2 million lives annually (1). There is controversy over whether the disease is primarily a dysfunctional immunologic reaction to a persistent microbe or whether the bacteria themselves produce tissue damage; there is evidence that both host and bacterial factors play key roles in disease severity. In susceptible mouse strains, such as C3H, the pathogen elicits a dysregulated, necrotizing host immune response leading to tissue destruction and further bacterial replication. In resistant mice such as C57BL͞6, Mycobacterium tuberculosis survives in high numbers for many months and is contained in organized granulomatous lesions in the lung without progressive lung damage. Thus whereas mycobacteria survive in both genetic backgrounds, disease progression is delayed in resistant animals (2-4).On the bacterial side, M. tuberculosis virulence has been associated with its initial survival within macrophages and resistance to reactive oxygen and nitrogen intermediates (ROIs and RNIs) (5-8). Tubercle bacilli demonstrate inducible responses to oxidative stresses, and several M. tuberculosis genes, including katG (catalase peroxidase), ahpC (alkylhydroperoxide reductase), and sodA and sodC (superoxide dismutases) have been implicated in protection from the macrophage oxidative burst (9-11). Another potential ...

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An Outbreak Involving Extensive Transmission of a Virulent Strain ofMycobacterium tuberculosis

Cited by 352 publications

References 19 publications

ATP Stimulates Human Macrophages to Kill Intracellular Virulent Mycobacterium tuberculosis Via Calcium-Dependent Phagosome-Lysosome Fusion

ATP Stimulates Human Macrophages to Kill Intracellular Virulent Mycobacterium tuberculosis Via Calcium-Dependent Phagosome-Lysosome Fusion

A deletion defining a common Asian lineage ofMycobacterium tuberculosisassociates with immune subversion

Reduced immunopathology and mortality despite tissue persistence in aMycobacterium tuberculosismutant lacking alternative σ factor, SigH

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