The ΔfbpA mutant derived from Mycobacterium tuberculosis H37Rv has an enhanced susceptibility to intracellular antimicrobial oxidative mechanisms, undergoes limited phagosome maturation and activates macrophages and dendritic cells

Katti, Muralidhar K.; Dai, Guixiang; Armitige, Lisa Y.; Marrero, C Rivera; Daniel, Sundarsingh; Singh, Christopher R.; Lindsey, Devin R.; Dhandayuthapani, Subramanian; Hunter, Robert L.; Jagannath, Chinnaswamy

doi:10.1111/j.1462-5822.2008.01126.x

Cited by 59 publications

(74 citation statements)

References 87 publications

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“…To further characterize the ⌬secA2 mutantcontaining phagosome for evidence of phagosome/lysosome fusion, we immunostained infected macrophages for markers of late-endosomal/lysosomal fusion (CD63 and Rab7). Wild-type M. tuberculosis is reported to prevent phagosomes from maturing to a CD63-and Rab7-positive state (12,31,65). In comparison to phagosomes containing H37Rv or the complemented strain, a higher percentage of ⌬secA2 mutant-containing phagosomes stained positive for CD63 and Rab7.…”

Section: Resultsmentioning

confidence: 98%

The Mycobacterium tuberculosis SecA2 System Subverts Phagosome Maturation To Promote Growth in Macrophages

et al. 2012

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The ability of Mycobacterium tuberculosis to grow in macrophages is critical to the virulence of this important pathogen. One way M. tuberculosis is thought to maintain a hospitable niche in macrophages is by arresting the normal process of phagosomes maturing into acidified phagolysosomes. The process of phagosome maturation arrest by M. tuberculosis is not fully understood, and there has remained a need to firmly establish a requirement for phagosome maturation arrest for M. tuberculosis growth in macrophages. Other intracellular pathogens that control the phagosomal environment use specialized protein export systems to deliver effectors of phagosome trafficking to the host cell. In M. tuberculosis, the accessory SecA2 system is a specialized protein export system that is required for intracellular growth in macrophages. In studying the importance of the SecA2 system in macrophages, we discovered that SecA2 is required for phagosome maturation arrest. Shortly after infection, phagosomes containing a ⌬secA2 mutant of M. tuberculosis were more acidified and showed greater association with markers of late endosomes than phagosomes containing wild-type M. tuberculosis. We further showed that inhibitors of phagosome acidification rescued the intracellular growth defect of the ⌬secA2 mutant, which demonstrated that the phagosome maturation arrest defect of the ⌬secA2 mutant is responsible for the intracellular growth defect. This study demonstrates the importance of phagosome maturation arrest for M. tuberculosis growth in macrophages, and it suggests there are effectors of phagosome maturation that are exported into the host environment by the accessory SecA2 system.

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Section: Resultsmentioning

confidence: 98%

The Mycobacterium tuberculosis SecA2 System Subverts Phagosome Maturation To Promote Growth in Macrophages

et al. 2012

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“…M. tuberculosis also secretes superoxide dismutase encoded by sodA (24) which may protect against ROI, although conclusive data on this function are lacking in M. tuberculosis. Various cell wall components (25,26), reductases (27,28), and the genes responsible for mycothiol production (29) also appear to play a protective role. Lsr2 appears to use a different mechanism to protect mycobacteria against oxidative stress that requires direct protein-DNA binding.…”

Section: Discussionmentioning

confidence: 99%

The multifunctional histone-like protein Lsr2 protects mycobacteria against reactive oxygen intermediates

Colangeli

Haq

Arcus

et al. 2009

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

120

112

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Mycobacterium tuberculosis has evolved a number of strategies to survive within the hostile environment of host phagocytes. Reactive nitrogen and oxygen intermediates (RNI and ROI) are among the most effective antimycobacterial molecules generated by the host during infection. Lsr2 is a M. tuberculosis protein with histonelike features, including the ability to regulate a variety of transcriptional responses in mycobacteria. Here we demonstrate that Lsr2 protects mycobacteria against ROI in vitro and during macrophage infection. Furthermore, using macrophages derived from NOS ؊/؊ and Phox ؊/؊ mice, we demonstrate that Lsr2 is important in protecting against ROI but not RNI. The protection provided by Lsr2 protein is not the result of its ability to either bind iron or scavenge hydroxyl radicals. Instead, electron microscopy and DNAbinding studies suggest that Lsr2 shields DNA from reactive intermediates by binding bacterial DNA and physically protecting it. Thus, Lsr2 appears to be a unique protein with both histone-like properties and protective features that may be central to M. tuberculosis pathogenesis. In addition, evidence indicates that lsr2 is an essential gene in M. tuberculosis. Because of its essentiality, Lsr2 may represent an excellent candidate as a drug target.Mycobacterium tuberculosis ͉ ROI ͉ DPS ͉ DNA

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“…This is combined, in part, by additional interactions with MARCO, TLR2 and/or CD14 which are critical for mediating activity [56] with internalized signaling events that possibly function through Card9-dependent mechanisms [57,58]. What is currently clear is that once internalized, Mycobacterium tuberculosis blocks maturation of phagosomes [59][60][61], altering molecular events critical for destruction of organisms [62] and development of intra-phagosome events critical for antigen processing [63]. TDM is directly linked to this process [64,65] and elimination of critical enzymes for TDM production [eg.…”

Section: Tdm Influence On Immune Functionmentioning

confidence: 99%

Mycobacterial TDM: A Coat to Modulate Post Primary Pathogenesis?

Actor¹

2012

Mycobact Diseases

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The ΔfbpA mutant derived from Mycobacterium tuberculosis H37Rv has an enhanced susceptibility to intracellular antimicrobial oxidative mechanisms, undergoes limited phagosome maturation and activates macrophages and dendritic cells

Abstract: Summary Mycobacterium tuberculosis

Cited by 59 publications

References 87 publications

The Mycobacterium tuberculosis SecA2 System Subverts Phagosome Maturation To Promote Growth in Macrophages

The Mycobacterium tuberculosis SecA2 System Subverts Phagosome Maturation To Promote Growth in Macrophages

The multifunctional histone-like protein Lsr2 protects mycobacteria against reactive oxygen intermediates

Mycobacterial TDM: A Coat to Modulate Post Primary Pathogenesis?

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