Pneumocystis

Kaneshiro, Edna S.

doi:10.1038/npg.els.0002101

Cited by 6 publications

(8 citation statements)

References 19 publications

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“…Recent studies with other respiratory pathogens (Yersinia pestis and Legionella pneumophila) have shown that they can invade and replicate in the type 1 pneumocyte cell line WI26 (Harb and Kwaik, 2000;Liu et al, 2006;Galvan et al, 2007). Moreover, Pneumocystis carini and Streptococcus pneumoniae have been shown to preferentially bind to and damage type I cells in vivo to achieve dissemination across the alveolar barrier (Nakamura and Wada, 1998;Kaneshiro, 2001;Garcia-Suarez Mdel et al, 2007). Preliminary studies in our lab confirmed that M. tb can invade and replicate in WI26 pneumocytes (Vir et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Potential role for ESAT6 in dissemination ofM.âtuberculosisvia human lung epithelial cells

Kinhikar

Verma

Chandra³

et al. 2010

Molecular Microbiology

111

115

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SummaryESAT6 has recently been demonstrated to cause haemolysis and macrophage lysis. Our studies demonstrate that ESAT6 causes cytolysis of type 1 and type 2 pneumocytes. Both types of pneumocytes express membrane laminin, and ESAT6 exhibits dosedependent binding to both cell types and to purified human laminin. While minimal ESAT6 was detected on the surface of Mycobacterium tuberculosis grown in vitro, exogenously provided ESAT6 specifically associated with the bacterial cell surface, and the bacterium-associated ESAT6 retained its cytolytic ability. esat6 transcripts were upregulated~4-to~13-fold in bacteria replicating in type 1 cells, and~3-to~5 fold in type 2 cells. In vivo, laminin is primarily concentrated at the basolateral surface of pneumocytes where they rest on the basement membrane, which is composed primarily of laminin and collagen. The upregulation of esat6 transcripts in bacteria replicating in pneumocytes, the specific association of ESAT6 with the bacterial surface, the binding of ESAT6 to laminin and the lysis of pneumocytes by free and bacterium-associated ESAT6 together suggest a scenario wherein Mycobacterium tuberculosis replicating in pneumocytes may utilize surface ESAT6 to anchor onto the basolateral lamininexpressing surface of the pneumocytes, and damage the cells and the basement membrane to directly disseminate through the alveolar wall.

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Section: Introductionmentioning

confidence: 99%

Potential role for ESAT6 in dissemination ofM.âtuberculosisvia human lung epithelial cells

Kinhikar

Verma

Chandra³

et al. 2010

Molecular Microbiology

111

115

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“…Pneumocystis pneumonia (PcP) remains a major opportunistic infection among AIDS patients and can also occur in those undergoing immunosuppressive treatment for cancer and solid organ transplantation (29,74). Pneumocystis is an unusual and ubiquitous fungal protist with several features unlike those of most other fungi (29,30).…”

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“…Pneumocystis is an unusual and ubiquitous fungal protist with several features unlike those of most other fungi (29,30). There is no adequate cultivation method yet developed that provides sufficient numbers of pure organism preparations suitable for many types of experiments.…”

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confidence: 99%

Ubiquinone Synthesis in Mitochondrial and Microsomal Subcellular Fractions of Pneumocystis spp.: Differential Sensitivities to Atovaquone

et al. 2005

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The lung pathogen Pneumocystis spp. is the causative agent of a type of pneumonia that can be fatal in people with defective immune systems, such as AIDS patients. Atovaquone, an analog of ubiquinone (coenzyme Q [CoQ]), inhibits mitochondrial electron transport and is effective in clearing mild to moderate cases of the infection. Purified rat-derived intact Pneumocystis carinii cells synthesize de novo four CoQ homologs, CoQ 7 , CoQ 8 , CoQ 9 , and CoQ 10 , as demonstrated by the incorporation of radiolabeled precursors of both the benzoquinone ring and the polyprenyl chain. A central step in CoQ biosynthesis is the condensation of p-hydroxybenzoic acid (PHBA) with a long-chain polyprenyl diphosphate molecule. In the present study, CoQ biosynthesis was evaluated by the incorporation of PHBA into completed CoQ molecules using P. carinii cell-free preparations. CoQ synthesis in whole-cell homogenates was not affected by the respiratory inhibitors antimycin A and dicyclohexylcarbodiimide but was diminished by atovaquone. Thus, atovaquone has inhibitory activity on both electron transport and CoQ synthesis in this pathogen. Furthermore, both the mitochondrial and microsomal fractions were shown to synthesize de novo all four P. carinii CoQ homologs. Interestingly, atovaquone inhibited microsomal CoQ synthesis, whereas it had no effect on mitochondrial CoQ synthesis. This is the first pathogenic eukaryotic microorganism in which biosynthesis of CoQ molecules from the initial PHBA:polyprenyl transferase reaction has been unambiguously shown to occur in two distinct compartments of the same cell.

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“…It has becoming evident that the high incidence of PcP in AIDS patients is global and that the organism can infect other immunodeficient people such as patients undergoing chemotherapy for cancer or solid organ transplant (1,2), children prior to becoming fully immunocompetent, and the elderly with diminished immune systems. Pneumocystis can also transiently colonize normal, healthy people and animals without causing overt symptoms of respiratory disorder.…”

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confidence: 99%

Comprehensive and definitive structural identities of Pneumocystis carinii sterols

Giner

Zhao

Beach

et al. 2002

Journal of Lipid Research

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Pneumocystis causes a type of pneumonia in immunodeficient mammals, such as AIDS patients. Mammals cannot alkylate the C-24 position of the sterol side chain, nor can they desaturate C-22. Thus, the reactions leading to these sterol modifications are particularly attractive targets for the development of drugs against fungal and protozoan pathogens that make them. In the present study, the definitive structures of 43 sterol molecular species in rat-derived Pneumocystis carinii were elucidated by nuclear magnetic resonance spectroscopy. Ergosterol, ⌬ 5,7 sterols, trienes, and tetraenes were not among them. Most (32 of the 43) were 24-alkylsterols, products of S -adenosyl-L -methionine:C-24 sterol methyl transferase (SAM:SMT) enzyme activity. Their abundance is consistent with the suggestion that SAM:SMT is highly active in this organism and that the enzyme is an excellent anti-Pneumocystis drug target. In contrast, the comprehensive analysis strongly suggest that P. carinii does not form ⌬ 22 sterols, thus C-22 desaturation does not appear to be a drug target in this pathogen. The lanosterol derivatives, 24-methylenelanost-8-en-3 ␤ -ol and ( Z )-24-ethylidenelanost-8-en-3 ␤ -ol (pneumocysterol), previously identified in human-derived Pneumocystis jiroveci , were also detected among the sterols of the rat-derived P. carinii organisms. Pneumocystis pneumonia (PcP) remains among the most prevalent opportunistic infections in immunocompromised individuals such as AIDS patients. It has becoming evident that the high incidence of PcP in AIDS patients is global and that the organism can infect other immunodeficient people such as patients undergoing chemotherapy for cancer or solid organ transplant (1, 2), children prior to becoming fully immunocompetent, and the elderly with diminished immune systems. Pneumocystis can also transiently colonize normal, healthy people and animals without causing overt symptoms of respiratory disorder. The combination of trimethoprim and sulfamethoxazole and other agents (e.g., pentamidine, atovaquone) used for prophylaxis and for clearing PcP has successfully reduced the number of deaths directly attributed to PcP. However, AIDS and other patients with prolonged immunodeficiency experience recurrent Pneumocystis jiroveci ( Pneumocystis carinii f. sp. hominis ) (3, 4) infections. Also, some individuals cannot tolerate these drugs and suffer undesirable side effects. The development of drug-resistant pathogen populations is of serious concern, making it imperative to develop a larger armamentarium of diverse drugs to circumvent these problems (5 Ϫ 7). Although the organism can be maintained in long-term, small-volume axenic cultures (8), growth is very slow and insufficient numbers of organisms are obtained for most biochemical studies. Thus, Pneumocystis remains an organism considered difficult to manipulate for experimental work. Despite this difficulty, much is now known about the organism's lipids from analyses performed on preparations purified from infected rat lungs (9 Ϫ 11...

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Pneumocystis

Cited by 6 publications

References 19 publications

Potential role for ESAT6 in dissemination ofM.âtuberculosisvia human lung epithelial cells

Potential role for ESAT6 in dissemination ofM.âtuberculosisvia human lung epithelial cells

Ubiquinone Synthesis in Mitochondrial and Microsomal Subcellular Fractions of Pneumocystis spp.: Differential Sensitivities to Atovaquone

Comprehensive and definitive structural identities of Pneumocystis carinii sterols

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Pneumocystis

Cited by 6 publications

References 19 publications

Potential role for ESAT6 in dissemination ofM.âtuberculosisvia human lung epithelial cells

Potential role for ESAT6 in dissemination ofM.âtuberculosisvia human lung epithelial cells

Ubiquinone Synthesis in Mitochondrial and Microsomal Subcellular Fractions of Pneumocystis spp.: Differential Sensitivities to Atovaquone

Comprehensive and definitive structural identities of Pneumocystis carinii sterols

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Potential role for ESAT6 in dissemination ofM.âtuberculosisvia human lung epithelial cells

Potential role for ESAT6 in dissemination ofM.âtuberculosisvia human lung epithelial cells