Key Points
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Pneumocystis pneumonia (PCP) remains the most prevalent opportunistic infection in patients with AIDS and is a significant cause of severe pneumonia in immunocompromised patients with cancer, organ transplant recipients or those receiving immunosuppressant medications.
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Pneumocystis is an intractable fungal pathogen classified phylogenetically with the Ascomycetes. Pneumocystis has pathways involved in cell-cycle control, signal transduction and metabolism that are analogous to the pathways in these yeast.
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Pneumocystis has a unique life cycle alternating between small trophic forms and cysts, which contain 2, 4 or 8 intracystic bodies. The airborne route of transmission is currently the favoured model for the spread of infection.
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Pneumocystis interacts with the lung epithelium and immune cells of the lower respiratory tract, resulting in inflammation, which is hazardous to the host. This is a complex interaction involving surface antigens of the organism and host surfactant proteins, adhesion molecules, macrophages, neutrophils, lymphocytes, and cytokine and chemokine responses.
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Drug targets for the treatment of PCP include metabolic pathways for dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR), DNA and protein synthesis inhibition, sterol metabolism, cytochrome b complex and cell-wall construction through inhibition of the GSC1 glucan synthetase.
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Mutations in DHPS, DHFR, and cytochrome b have raised the concern of emerging resistance to the medications currently in use. The efforts of the Pneumocystis research community have contributed substantially to the current understanding of the complex biology of Pneumocystis and the intricate association with the host. Continued research is essential to continue investigating the biology of this organism in the hope of developing novel treatment strategies for PCP.
Abstract
The fungal infection Pneumocystis pneumonia is the most prevalent opportunistic infection in patients with AIDS. Although the analysis of this opportunistic fungal pathogen has been hindered by the inability to isolate it in pure culture, the use of molecular techniques and genomic analysis have brought insights into its complex cell biology. Analysis of the intricate relationship between Pneumocystis and the host lung during infection has revealed that the attachment of Pneumocystis to the alveolar epithelium promotes the transition of the organism from the trophic to the cyst form. It also revealed that Pneumocystis infection elicits the production of inflammatory mediators, culminating in lung injury and impaired gas exchange. Here we discuss these and other recent findings relating to the biology and pathogenesis of this intractable fungus.
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References
Thomas, C. F. Jr & Limper, A. H. Pneumocystis pneumonia. N. Engl. J. Med. 350, 2487–2498 (2004).
HIV/AIDS surveillance supplemental report. Centers for Disease Control and Prevention 9, 1–20 [online] (2003).
Sepkowitz, K. A. Opportunistic infections in patients with and patients without acquired immunodeficiency syndrome. Clin. Infect. Dis. 34, 1098–1107 (2002).
Chagas, C. Nova tripanozomiata humana. Mem. Inst. Oswaldo Cruz 1, 159–218 (1909).
Carinii, A. Formas de eschizogonia do Trypanozoma lewisi. Comm. Soc. Med. Sao Paolo 16, 204 (1910).
Delanoë, P. and Delanoë, M. Surles rapporte des kystos de carinii le Trypanosoma lewisi. Compt. Rend. Acad. Sci. 155, 658 (1912).
Edman, J. C. et al. Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the fungi. Nature 334, 519–522 (1988).
Gigliotti, F., Harmsen, A. G., Haidaris, C. G. & Haidaris, P. J. Pneumocystis carinii is not universally transmissible between mammalian species. Infect. Immun. 61, 2886–2890 (1993).
Stringer, J. R., Beard, C. B., Miller, R. F. & Cushion, M. T. A new name (Pneumocystis jiroveci) for Pneumocystis from humans (response to Hughes). Emerg. Infect. Dis. 9, 277–279 (2003).
Limper, A. H. Pneumocystis nomenclature. Clin. Infect. Dis. 42, 1210–1211; author reply 1212–1214 (2006).
Gigliotti, F. Pneumocystis carinii nomenclature: response to Cushion and Stringer. Clin. Infect. Dis. 42, 1208–1209 (2006).
Gigliotti, F. Pneumocystis carinii: has the name really been changed? Clin. Infect. Dis. 41, 1752–1755 (2005).
Hughes, W. T. Pneumocystis carinii versus Pneumocystis jirovecii (jiroveci) Frenkel. Clin. Infect. Dis. 42, 1211–1212; author reply 1212–1214 (2006).
Wakefield, A. E. Detection of DNA sequences identical to Pneumocystis carinii in samples of ambient air. J. Euk. Microbiol. 41, 116S (1994).
Casanova-Cardiel, L. & Leibowitz, M. J. Presence of Pneumocystis carinii DNA in pond water. J. Euk. Microbiol. 44, 28S (1997).
Vargas, S. L. et al. Search for primary infection by Pneumocystis carinii in a cohort of normal, healthy infants. Clin. Infect. Dis. 32, 855–861 (2001).
Chen, W., Gigliotti, F. & Harmsen, A. G. Latency is not an inevitable outcome of infection with Pneumocystis carinii. Infect. Immun. 61, 5406–5409 (1993).
Morris, A. M., Swanson, M., Ha, H. & Huang, L. Geographic distribution of human immunodeficiency virus-associated Pneumocystis carinii pneumonia in San Francisco. Am. J. Respir. Crit. Care Med. 162, 1622–1626 (2000).
Morris, A., Beard, C. B. & Huang, L. Update on the epidemiology and transmission of Pneumocystis carinii. Microbes Infect. 4, 95–103 (2002).
Morris, A. et al. Current epidemiology of Pneumocystis pneumonia. Emerg. Infect. Dis. 10, 1713–1720 (2004).
Helweg-Larsen, J. et al. Clinical correlation of variations in the internal transcribed spacer regions of rRNA genes in Pneumocystis carinii f. sp. hominis. AIDS 15, 451–459 (2001).
Lundgren, B. et al. Transmission of Pneumocystis carinii from patients to hospital staff. Thorax 52, 422–424 (1997).
Miller, R. F., Ambrose, H. E. & Wakefield, A. E. Pneumocystis carinii f. sp. hominis DNA in immunocompetent health care workers in contact with patients with P. carinii pneumonia. J. Clin. Microbiol. 39, 3877–3882 (2001).
Vargas, S. L. et al. Transmission of Pneumocystis carinii DNA from a patient with P. carinii pneumonia to immunocompetent contact health care workers. J. Clin. Microbiol. 38, 1536–1538 (2000).
Hughes, W. T. Natural mode of acquisition for de novo infection with Pneumocystis carinii. J. Infect. Dis. 145, 842–848 (1982).
Wakefield, A. E., Lindley, A. R., Ambrose, H. E., Denis, C. M. & Miller, R. F. Limited asymptomatic carriage of Pneumocystis jiroveci in human immunodeficiency virus-infected patients. J. Infect. Dis. 187, 901–908 (2003).
Manoloff, E. S. et al. Risk for Pneumocystis carinii transmission among patients with pneumonia: a molecular epidemiology study. Emerg. Infect. Dis. 9, 132–134 (2003).
Morris, A . et al. Association of chronic obstructive pulmonary disease severity and Pneumocystis colonization. Am. J. Respir. Crit. Care Med. 170, 408–413 (2004).
Limper, A. H. & Martin, W. J. Pneumocystis carinii: inhibition of lung cell growth mediated by parasite attachment. J. Clin. Invest. 85, 391–396 (1990).
Afessa, B., Green, W., Chiao, J. & Frederick, W. Pulmonary complications of HIV infection: autopsy findings. Chest 113, 1225–1229 (1998).
Wyder, M. A., Rasch, E. M. & Kaneshiro, E. S. Quantitation of absolute Pneumocystis carinii nuclear DNA content. Trophic and cystic forms isolated from infected rat lungs are haploid organisms. J. Euk. Microbiol. 45, 233–239 (1998).
Matsumoto, Y. & Yoshida, Y. Sporogony in Pneumocystis carinii: synaptonemal complexes and meiotic nuclear divisions observed in precysts. J. Protozool. 31, 420–428 (1984).
Huang, L., Morris, A., Limper, A. H. & Beck, J. M. An official ATS workshop summary: recent advances and future directions in Pneumocystis pneumonia (PCP). Proc. Am. Thorac. Soc. 3, 655–664 (2006).
Sloand, E. et al. The challenge of Pneumocystis carinii culture. J. Euk. Microbiol. 40, 188–195 (1993).
Keely, S. P. et al. Gene arrays at Pneumocystis carinii telomeres. Genetics 170, 1589–1600 (2005).
Stringer, J. R. & Cushion, M. T. The genome of Pneumocystis carinii. FEMS Immunol. Med. Microbiol. 22, 15–26 (1998).
Thomas, C. F. Jr, Leof, E. B. & Limper, A. H. Analysis of Pneumocystis carinii introns. Infect. Immun. 67, 6157–6160 (1999).
Gigliotti, F., Stokes, D. C., Cheatham, A. B., Davis, D. S. & Hughes, W. T. Development of murine monoclonal antibodies to Pneumocystis carinii. J. Infect. Dis. 154, 315–322 (1986).
Gigliotti, F., Ballou, L. R., Hughes, W. T. & Mosley, B. D. Purification and initial characterization of a ferret Pneumocystis carinii surface antigen. J. Infect. Dis. 158, 848–854 (1988).
Vuk-Pavlovic, Z., Standing, J. E., Crouch, E. C. & Limper, A. H. Carbohydrate recognition domain of surfactant protein D mediates interactions with Pneumocystis carinii glycoprotein A. Am. J. Respir. Cell. Mol. Biol. 24, 475–484 (2001).
O'Riordan, D. M., Standing, J. E. & Limper, A. H. Pneumocystis carinii glycoprotein A binds macrophage mannose receptors. Infect. Immun. 63, 779–784 (1995).
Linke, M. J., Cushion, M. T. & Walzer, P. D. Properties of the major antigens of rat and human Pneumocystis carinii. Infect. Immun. 57, 1547–1555 (1989).
Lundgren, B., Koch, C., Mathiesen, L., Nielsen, J. O. & Hansen, J. E. Glycosylation of the major human Pneumocystis carinii surface antigen. Apmis 101, 194–200 (1993).
Kovacs, J. A. et al. Multiple genes encode the major surface glycoprotein of Pneumocystis carinii. J. Biol. Chem. 268, 6034–6040 (1993).
Stringer, J. R. & Keely, S. P. Genetics of surface antigen expression in Pneumocystis carinii. Infect. Immun. 69, 627–639 (2001).
Gigliotti, F. Host species-specific antigenic variation of a mannosylated surface glycoprotein of Pneumocystis carinii. J. Infect. Dis. 165, 329–336 (1992).
Kovacs, J. A. et al. Monoclonal antibodies to Pneumocystis carinii: identification of specific antigens and characterization of antigenic differences between rat and human isolates. J. Infect. Dis. 159, 60–70 (1989).
Wada, M. & Nakamura, Y. Chromosomal organization of MSG antigen genes of rat Pneumocystis carinii: tandem repeat and unique 5′UTR sequence encoding intron. J. Euk. Microbiol. 41, 115S (1994).
Wada, M. & Nakamura, Y. Type-II major-surface-glycoprotein family of Pneumocystis carinii under the control of novel expression elements. DNA Res. 6, 211–217 (1999).
Kutty, G. & Kovacs, J. A. A single-copy gene encodes Kex1, a serine endoprotease of Pneumocystis jiroveci. Infect. Immun. 71, 571–574 (2003).
Lee, L. H. et al. Molecular characterization of KEX1, a kexin-like protease in mouse Pneumocystis carinii. Gene 242, 141–150 (2000).
Lugli, E. B., Allen, A. G. & Wakefield, A. E. A Pneumocystis carinii multi-gene family with homology to subtilisin-like serine proteases. Microbiology 143, 2223–2236 (1997).
Lugli, E. B., Bampton, E. T., Ferguson, D. J. & Wakefield, A. E. Cell surface protease PRT1 identified in the fungal pathogen Pneumocystis carinii. Mol. Microbiol. 31, 1723–1733 (1999).
Douglas, C. M. Fungal β(1,3)-D-glucan synthesis. Med. Mycol. 39, 55–66 (2001).
Vassallo, R., Standing, J. E. & Limper, A. H. Isolated Pneumocystis carinii cell wall glucan provokes lower respiratory tract inflammatory responses. J. Immunol. 164, 3755–3763 (2000).
Kottom, T. J. & Limper, A. H. Cell wall assembly by Pneumocystis carinii. Evidence for a unique gsc-1 subunit mediating β-1,3-glucan deposition. J. Biol. Chem. 275, 40628–40634 (2000).
Schmatz, D. M. et al. Treatment of Pneumocystis carinii pneumonia with 1,3-β-glucan synthesis inhibitors. Proc. Natl Acad. Sci. USA 87, 5950–5954 (1990).
Powles, M. A. et al. Efficacy of MK-991 (L-743, 872), a semisynthetic pneumocandin, in murine models of Pneumocystis carinii. Antimicrob. Agents Chemother. 42, 1985–1989 (1998).
Thomas, C. F., Anders, R. A., Gustafson, M. P., Leof, E. B. & Limper, A. H. Pneumocystis carinii contains a functional cell-division-cycle Cdc2 homologue. Am. J. Respir. Cell. Mol. Biol. 18, 297–306 (1998).
Gustafson, M. P., Thomas, C. F. Jr, Rusnak, F., Limper, A. H. & Leof, E. B. Differential regulation of growth and checkpoint control mediated by a Cdc25 mitotic phosphatase from Pneumocystis carinii. J. Biol. Chem. 276, 835–843 (2001).
Johnson, G. L. & Lapadat, R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 1911–1912 (2002).
Bardwell, L., Cook, J. G., Inouye, C. J. & Thorner, J. Signal propagation and regulation in the mating pheromone response pathway of the yeast Saccharomyces cerevisiae. Dev. Biol. 166, 363–379 (1994).
Vohra, P. K., Puri, V. & Thomas, C. F. Jr . Complementation and characterization of the Pneumocystis carinii MAPK, PCM. FEBS Lett. 551, 139–146 (2003).
Thomas, C. F. Jr, Kottom, T. J., Leof, E. B. & Limper, A. H. Characterization of a mitogen-activated protein kinase from Pneumocystis carinii. Am. J. Physiol. 275, L193–L199 (1998).
Vohra, P. K., Puri, V., Kottom, T. J., Limper, A. H. & Thomas, C. F. Jr. Pneumocystis carinii STE11, an HMG-box protein, is phosphorylated by the mitogen activated protein kinase PCM. Gene 312, 173–179 (2003).
Vohra, P. K., Park, J. G., Sanyal, B. & Thomas, C. F. Jr. Expression analysis of PCSTE3, a putative pheromone receptor from the lung pathogenic fungus Pneumocystis carinii. Biochem. Biophys. Res. Commun. 319, 193–199 (2004).
Kottom, T. J., Kohler, J. R., Thomas, C. F. Jr, Fink, G. R. & Limper, A. H. Lung epithelial cells and extracellular matrix components induce expression of Pneumocystis carinii STE20, a gene complementing the mating and pseudohyphal growth defects of STE20 mutant yeast. Infect. Immun. 71, 6463–6471 (2003).
Fox, D. & Smulian, A. G. Mitogen-activated protein kinase Mkp1 of Pneumocystis carinii complements the slt2δ defect in the cell integrity pathway of Saccharomyces cerevisiae. Mol. Microbiol. 34, 451–462 (1999).
Fox, D. & Smulian, A. G. Mkp1 of Pneumocystis carinii associates with the yeast transcription factor Rlm1 via a mechanism independent of the activation state. Cell. Signal. 12, 381–390 (2000).
Vohra, P. K., Sanyal, B. & Thomas, C. F. Jr. Biochemical requirements for PCBCK1 kinase activity, the Pneumocystis carinii MEKK involved in cell wall integrity. FEMS Microbiol. Lett. 235, 153–156 (2004).
Thomas, C. F. Jr et al. Pneumocystis carinii BCK1 functions in a mitogen-activated protein kinase cascade regulating fungal cell-wall assembly. FEBS Lett. 548, 59–68 (2003).
Kottom, T. J., Thomas, C. F. Jr & Limper, A. H. Characterization of Pneumocystis carinii PHR1, a pH-regulated gene important for cell wall integrity. J. Bacteriol. 183, 6740–6745 (2001).
Kottom, T. J. & Limper, A. H. Pneumocystis carinii cell wall biosynthesis kinase gene CBK1 is an environmentally responsive gene that complements cell wall defects of cbk-deficient yeast. Infect. Immun. 72, 4628–4636 (2004).
Smulian, A. G., Sesterhenn, T., Tanaka, R. & Cushion, M. T. The ste3 pheromone receptor gene of Pneumocystis carinii is surrounded by a cluster of signal transduction genes. Genetics 157, 991–1002 (2001).
Smulian, A. G., Ryan, M., Staben, C. & Cushion, M. Signal transduction in Pneumocystis carinii: characterization of the genes (pcg1) encoding the α subunit of the G protein (PCG1) of Pneumocystis carinii carinii and Pneumocystis carinii ratti. Infect. Immun. 64, 691–701 (1996).
Limper, A. H., Offord, K. P., Smith, T. F. & Martin, W. J. 2nd. Pneumocystis carinii pneumonia. Differences in lung parasite number and inflammation in patients with and without AIDS. Am. Rev. Respir. Dis. 140, 1204–1209 (1989).
Ezekowitz, R. A. et al. Uptake of Pneumocystis carinii mediated by the macrophage mannose receptor. Nature 351, 155–158 (1991).
Steele, C. et al. Alveolar macrophage-mediated killing of Pneumocystis carinii f. sp. muris involves molecular recognition by the Dectin-1 β-glucan receptor. J. Exp. Med. 198, 1677–1688 (2003).
Neese, L. W., Standing, J. E., Olson, E. J., Castro, M. & Limper, A. H. Vitronectin, fibronectin, and gp120 antibody enhance macrophage release of TNF-α in response to Pneumocystis carinii. J. Immunol. 152, 4549–4556 (1994).
Limper, A. H., Hoyte, J. S. & Standing, J. E. The role of alveolar macrophages in Pneumocystis carinii degradation and clearance from the lung. J. Clin. Invest. 99, 2110–2117 (1997).
Koziel, H. et al. Reduced binding and phagocytosis of Pneumocystis carinii by alveolar macrophages from persons infected with HIV-1 correlates with mannose receptor downregulation. J. Clin. Invest. 102, 1332–1344 (1998).
Lasbury, M. E. et al. Suppression of alveolar macrophage apoptosis prolongs survival of rats and mice with pneumocystis pneumonia. J. Immunol. 176, 6443–6453 (2006).
Vassallo, R., Standing, J. E. & Limper, A. H. Isolated Pneumocystis carinii cell wall glucan provokes lower respiratory tract inflammatory responses. J. Immunol. 164, 3755–3763 (2000).
Benfield, T. L. et al. The major surface glycoprotein of Pneumocystis carinii induces release and gene expression of interleukin-8 and tumor necrosis factor α in monocytes. Infect. Immun. 65, 4790–4794 (1997).
Carmona, E. M. et al. Pneumocystis cell wall β-glucans induce dendritic cell costimulatory molecule expression and inflammatory activation through a Fas-Fas ligand mechanism. J. Immunol. 177, 459–467 (2006).
Hahn, P. Y. et al. Pneumocystis carinii cell wall β-glucan induces release of macrophage inflammatory protein-2 from alveolar epithelial cells via a lactosylceramide-mediated mechanism. J. Biol. Chem. 278, 2043–2050 (2003).
Lebron, F., Vassallo, R., Puri, V. & Limper, A. H. Pneumocystis carinii cell wall β-glucans initiate macrophage inflammatory responses through NF-κB activation. J. Biol. Chem. 278, 25001–25008 (2003).
McCann, F., Carmona, E., Puri, V., Pagano, R. E. & Limper, A. H. Macrophage internalization of fungal β-glucans is not necessary for initiation of related inflammatory responses. Infect. Immun. 73, 6340–6349 (2005).
Vetvicka, V., Thornton, B. P. & Ross, G. D. Soluble β-glucan polysaccharide binding to the lectin site of neutrophil or natural killer cell complement receptor type 3 (CD11b/CD18) generates a primed state of the receptor capable of mediating cytotoxicity of iC3b-opsonized target cells. J. Clin. Invest. 98, 50–61 (1996).
Brown, G. D. & Gordon, S. Immune recognition. A new receptor for β-glucans. Nature 413, 36–37 (2001).
Evans, S. E. et al. Pneumocystis cell wall β-glucans stimulate alveolar epithelial cell chemokine generation through nuclear factor-κB-dependent mechanisms. Am. J. Respir. Cell. Mol. Biol. 32, 490–497 (2005).
Zhang, C. et al. Toll-like receptor 2 mediates alveolar macrophage response to Pneumocystis murina. Infect. Immun. 74, 1857–1864 (2006).
Vassallo, R., Kottom, T. J., Standing, J. E. & Limper, A. H. Vitronectin and fibronectin function as glucan binding proteins augmenting macrophage responses to Pneumocystis carinii. Am. J. Respir. Cell. Mol. Biol. 25, 203–211 (2001).
Saijo, S . et al. Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans. Nature Immunol. 8, 39–46 (2007).
Hoffman, O. A., Standing, J. E. & Limper, A. H. Pneumocystis carinii stimulates tumor necrosis factor-α release from alveolar macrophages through a β-glucan-mediated mechanism. J. Immunol. 150, 3932–3940 (1993).
Chen, W., Havell, E. A. & Harmsen, A. G. Importance of endogenous tumor necrosis factor α and γ interferon in host resistance against Pneumocystis carinii infection. Infect. Immun. 60, 1279–1284 (1992).
Wright, T. W. et al. TNF receptor signaling contributes to chemokine secretion, inflammation, and respiratory deficits during Pneumocystis pneumonia. J. Immunol. 172, 2511–2521 (2004).
Kolls, J. K. et al. Exacerbation of murine Pneumocystis carinii infection by adenoviral- mediated gene transfer of a TNF inhibitor. Am. J. Respir. Cell. Mol. Biol. 16, 112–118 (1997).
McAllister, F. et al. CXCR3 and IFN protein-10 in Pneumocystis pneumonia. J. Immunol. 177, 1846–1854 (2006).
Benfield, T. L. et al. Prognostic value of interleukin-8 in AIDS-associated Pneumocystis carinii pneumonia. Am. J. Respir. Crit. Care Med. 151, 1058–1062 (1995).
Swain, S. D., Wright, T. W., Degel, P. M., Gigliotti, F. & Harmsen, A. G. Neither neutrophils nor reactive oxygen species contribute to tissue damage during Pneumocystis pneumonia in mice. Infect. Immun. 72, 5722–5732 (2004).
Swain, S. D., Meissner, N. N. & Harmsen, A. G. CD8 T cells modulate CD4 T-cell and eosinophil-mediated pulmonary pathology in Pneumocystis pneumonia in B-cell-deficient mice. Am. J. Pathol. 168, 466–475 (2006).
Phair, J. et al. The risk of Pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. Multicenter AIDS Cohort Study Group. N. Engl. J. Med. 322, 161–165 (1990).
Shellito, J. et al. A new model of Pneumocystis carinii infection in mice selectively depleted of helper T lymphocytes. J. Clin. Invest. 85, 1686–1693 (1990).
Roths, J. B., Marshall, J. D., Allen, R. D., Carlson, G. A. & Sidman, C. L. Spontaneous Pneumocystis carinii pneumonia in immunodeficient mutant scid mice. Natural history and pathobiology. Am. J. Pathol. 136, 1173–1186 (1990).
Wright, T. W. et al. Immune-mediated inflammation directly impairs pulmonary function, contributing to the pathogenesis of Pneumocystis carinii pneumonia. J. Clin. Invest. 104, 1307–1317 (1999).
Harmsen, A. G. & Stankiewicz, M. Requirement for CD4+ cells in resistance to Pneumocystis carinii pneumonia in mice. J. Exp. Med. 172, 937–945 (1990).
Beck, J. M. & Harmsen, A. G. Lymphocytes in host defense against Pneumocystis carinii. Semin. Respir. Infect. 13, 330–338 (1998).
Lund, F. E., Schuer, K., Hollifield, M., Randall, T. D. & Garvy, B. A. Clearance of Pneumocystis carinii in mice is dependent on B cells but not on P. carinii-specific antibody. J. Immunol. 171, 1423–1430 (2003).
Lund, F. E. et al. B cells are required for generation of protective effector and memory CD4 cells in response to Pneumocystis lung infection. J. Immunol. 176, 6147–6154 (2006).
Marcotte, H. et al. Pneumocystis carinii infection in transgenic B cell-deficient mice. J. Infect. Dis. 173, 1034–1037 (1996).
Wright, T. W., Johnston, C. J., Harmsen, A. G. & Finkelstein, J. N. Chemokine gene expression during Pneumocystis carinii-driven pulmonary inflammation. Infect. Immun. 67, 3452–3460 (1999).
Beck, J. M. et al. Reduction in intensity of Pneumocystis carinii pneumonia in mice by aerosol administration of g interferon. Infect. Immun. 59, 3859–3862 (1991).
Chen, W., Havell, E. A. & Harmsen, A. G. Importance of endogenous tumor necrosis factor α and γ interferon in host resistance against Pneumocystis carinii infection. Infect. Immun. 60, 1279–1284 (1992).
Meissner, N. N., Swain, S., Tighe, M. & Harmsen, A. Role of type I IFNs in pulmonary complications of Pneumocystis murina infection. J. Immunol. 174, 5462–5471 (2005).
Beck, J. M. et al. Inflammatory responses to Pneumocystis carinii in mice selectively depleted of helper T lymphocytes. Am. J. Respir. Cell. Mol. Biol. 5, 186–197 (1991).
Beck, J. M. et al. Interaction of rat Pneumocystis carinii and rat alveolar epithelial cells in vitro. Am. J. Physiol. 275, L118–L125 (1998).
Beck, J. M. et al. Pneumocystis pneumonia increases the susceptibility of mice to sublethal hyperoxia. Infect. Immun. 71, 5970–5978 (2003).
Sepkowitz, K. A. Pneumocystis carinii pneumonia in patients without AIDS. Clin. Infect. Dis. 17, S416–S422 (1993).
Bhagwat, S. P., Gigliotti, F., Xu, H. & Wright, T. W. Contribution of T cell subsets to the pathophysiology of Pneumocystis-related immunorestitution disease. Am. J. Physiol. Lung Cell. Mol Physiol (2006).
Walzer, P. D. Attachment of microbes to host cells: relevance of Pneumocystis carinii. Lab. Invest. 54, 589–592 (1986).
Limper, A. H., Standing, J. E., Hoffman, O. A., Castro, M. & Neese, L. W. Vitronectin binds to Pneumocystis carinii and mediates organism attachment to cultured lung epithelial cells. Infect. Immun. 61, 4302–4309 (1993).
Benfield, T. L., Prento, P., Junge, J., Vestbo, J. & Lundgren, J. D. Alveolar damage in AIDS-related Pneumocystis carinii pneumonia. Chest 111, 1193–1199 (1997).
Beck, J. M. et al. Interaction of rat Pneumocystis carinii and rat alveolar epithelial cells in vitro. Am. J. Physiol. 275, L118–L125 (1998).
Limper, A. H., Edens, M., Anders, R. A. & Leof, E. B. Pneumocystis carinii inhibits cyclin-dependent kinase activity in lung epithelial cells. J. Clin. Invest. 101, 1148–1155 (1998).
Zimmerman, P. E., Voelker, D. R., McCormack, F. X., Paulsrud, J. R. & Martin, W. J 2nd. 120-kD surface glycoprotein of Pneumocystis carinii is a ligand for surfactant protein A. J. Clin. Invest. 89, 143–149 (1992).
O'Riordan, D. M. et al. Surfactant protein D interacts with Pneumocystis carinii and mediates organism adherence to alveolar macrophages. J. Clin. Invest. 95, 2699–2710 (1995).
Beers, M. F., Atochina, E. N., Preston, A. M. & Beck, J. M. Inhibition of lung surfactant protein B expression during Pneumocystis carinii pneumonia in mice. J. Lab. Clin. Med. 133, 423–433 (1999).
Williams, M. D., Wright, J. R., March, K. L. & Martin, W. J. 2nd. Human surfactant protein A enhances attachment of Pneumocystis carinii to rat alveolar macrophages. Am. J. Respir. Cell. Mol. Biol. 14, 232–238 (1996).
Koziel, H. et al. Surfactant protein-A reduces binding and phagocytosis of Pneumocystis carinii by human alveolar macrophages in vitro. Am. J. Respir. Cell. Mol. Biol. 18, 834–843 (1998).
Yong, S. J., Vuk-Pavlovic, Z., Standing, J. E., Crouch, E. C. & Limper, A. H. Surfactant protein D-mediated aggregation of Pneumocystis carinii impairs phagocytosis by alveolar macrophages. Infect. Immun. 71, 1662–1671 (2003).
Wright, T. W., Notter, R. H., Wang, Z., Harmsen, A. G. & Gigliotti, F. Pulmonary inflammation disrupts surfactant function during Pneumocystis carinii pneumonia. Infect. Immun. 69, 758–764 (2001).
Edman, J. C. et al. Isolation and expression of the Pneumocystis carinii dihydrofolate reductase gene. Proc. Natl Acad. Sci. USA 86, 8625–8629 (1989).
Ma, L., Jia, Q. & Kovacs, J. A. Development of a yeast assay for rapid screening of inhibitors of human-derived Pneumocystis carinii dihydrofolate reductase. Antimicrob. Agents Chemother. 46, 3101–3103 (2002).
Achari, A. et al. Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase. Nature Struct. Biol. 4, 490–497 (1997).
Johnson, T., Khan, I. A., Avery, M. A., Grant, J. & Meshnick, S. R. Quantitative structure-activity relationship studies of a series of sulfa drugs as inhibitors of Pneumocystis carinii dihydropteroate synthetase. Antimicrob. Agents Chemother. 42, 1454–1458 (1998).
Anderson, A. C., Perry, K. M., Freymann, D. M. & Stroud, R. M. The crystal structure of thymidylate synthase from Pneumocystis carinii reveals a fungal insert important for drug design. J. Mol. Biol. 297, 645–657 (2000).
Vestereng, V. H. & Kovacs, J. A. Inability of Pneumocystis organisms to incorporate bromodeoxyuridine suggests the absence of a salvage pathway for thymidine. Microbiology 150, 1179–1182 (2004).
Morales, I. J. et al. Characterization of a lanosterol 14 α-demethylase from Pneumocystis carinii. Am. J. Res. Cell & Mol. Biol. 29, 232–238 (2003).
Kaneshiro, E. S. et al. The Pneumocystis carinii drug target S-adenosyl-L-methionine:sterol C-24 methyl transferase has a unique substrate preference. Mol. Microbiol. 44, 989–999 (2002).
Masur, H., Kaplan, J. E. & Holmes, K. K. Guidelines for preventing opportunistic infections among HIV-infected persons — 2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. Ann. Intern. Med. 137, 435–478 (2002).
Sepkowitz, K. A., Brown, A. E., Telzak, E. E., Gottlieb, S. & Armstrong, D. Pneumocystis carinii pneumonia among patients without AIDS at a cancer hospital. JAMA 267, 832–837 (1992).
Yale, S. H. & Limper, A. H. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy. Mayo Clin. Proc. 71, 5–13 (1996).
Pareja, J. G., Garland, R. & Koziel, H. Use of adjunctive corticosteroids in severe adult non-HIV Pneumocystis carinii pneumonia. Chest 113, 1215–1224 (1998).
Nahimana, A., Rabodonirina, M., Bille, J., Francioli, P. & Hauser, P. M. Mutations of Pneumocystis jirovecii dihydrofolate reductase associated with failure of prophylaxis. Antimicrob. Agents Chemother. 48, 4301–4305 (2004).
Kessl, J. J. et al. Molecular basis for atovaquone resistance in Pneumocystis jirovecii modeled in the cytochrome bc(1) complex of Saccharomyces cerevisiae. J. Biol. Chem. 279, 2817–2824 (2004).
Huang, L. et al. Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance. Emerg. Infect. Dis. 10, 1721–1728 (2004).
Beard, C. B. et al. Genetic differences in Pneumocystis isolates recovered from immunocompetent infants and from adults with AIDS: epidemiological implications. J. Infect. Dis. 192, 1815–1818 (2005).
Crothers, K. et al. Severity and outcome of HIV-associated Pneumocystis pneumonia containing Pneumocystis jirovecii dihydropteroate synthase gene mutations. AIDS 19, 801–805 (2005).
Hauser, P. M., Sudre, P., Nahimana, A. & Francioli, P. Prophylaxis failure is associated with a specific Pneumocystis carinii genotype. Clin. Infect. Dis. 33, 1080–1082 (2001).
Helweg-Larsen, J., Benfield, T. L., Eugen-Olsen, J., Lundgren, J. D. & Lundgren, B. Effects of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of AIDS-associated P. carinii pneumonia. Lancet 354, 1347–1351 (1999).
Takahashi, T. et al. Relationship between mutations in dihydropteroate synthase of Pneumocystis carinii f. sp. hominis isolates in Japan and resistance to sulfonamide therapy. J. Clin. Microbiol. 38, 3161–3164 (2000).
Nahimana, A. et al. Sulfa resistance and dihydropteroate synthase mutants in recurrent Pneumocystis carinii pneumonia. Emerg. Infect. Dis. 9, 864–867 (2003).
Navin, T. R. et al. Effect of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of P. carinii pneumonia in patients with HIV-1: a prospective study. Lancet 358, 545–549 (2001).
Cushion, M. T. in Topley and Wilson's Microbiology and Microbial Infections 9th edn Vol. 4 (eds Collier, L., Balows, A. & Sussman, M.) (Arnold Publishing, New York, 1998).
Acknowledgements
C.F.T. and A.H.L. have National Institutes of Health funding. We appreciate the many helpful discussions of P. K. Vohra, B. Sanyal, R. Vassallo, Z. Vuk-Pavlovic and T. J. Kottom. We apologize to our colleagues whose work we could not reference owing to space limitations.
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Supplementary information
Supplementary information S1 (table)
Selected characterized Pneumocystis genes* (PDF 106 kb)
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DATABASES
Entrez Genome
Entrez Genome Project
FURTHER INFORMATION
Broad Institute status of Fungal Genome Initiative projects
Wellcome Trust Sanger Institute Pneumocystis carinii telomeric clone sequencing project
Glossary
- Surfactant
-
A surface-active lipoprotein produced by type II alveolar epithelial cells that results in a reduction of surface tension in the alveoli.
- Donor consensus site
-
The recognition sequence at the 5′-end of the intron required for intron splicing.
- Acceptor consensus site
-
The recognition sequence at the 3′-end of the intron required for intron splicing.
- Branch-site sequence
-
An internal recognition sequence in an intron that is necessary for intron splicing.
- Chitin
-
A long-chain polymeric polysaccharide that is a component of the fungal cell wall.
- Degenerate PCR
-
A PCR technique to clone genes based on protein-domain homology. The PCR primer sequence is called degenerate if some of its positions (typically encoding the third codon) have several possible bases.
- Cell-division cycle (Cdc) molecules
-
A conserved family of molecules in eukaryotes that include cyclins and cyclin-dependent kinases.
- Cyclin
-
A cell-cycle protein that has a fluctuating (or cycling) concentration during growth. It interacts with a cyclin-dependent kinase to promote cell-cycle progression.
- DNA damage checkpoint
-
A DNA damage checkpoint is an essential control point in the cell cycle ensuring effective damage repair. When cells have DNA damage that needs to be repaired, cells activate DNA damage checkpoints that arrest the cell cycle.
- DNA replication checkpoint
-
When DNA replication is disrupted, cells activate DNA replication checkpoints that arrest the cell cycle at the G2/M transition until DNA replication is complete. The loss of checkpoint functions leads to loss of genomic integrity and allows accumulation of genetic damage in the daughter cells.
- Ascus
-
The spore-containing structure of the fungi Ascomycota.
- Opsonic protein
-
A protein that functions as a binding enhancer for a cell.
- RAG−/−
-
(RAG−/− mice). A genetic strain of mice that lack the recombination activation gene and are severely immunodeficient owing to a lack of functional B cells and T cells.
- Alveolar type I epithelial cell
-
The most distal portion of the lung, the alveoli, participate in gas exchange and metabolic functions. The alveolar structure includes long, flat, type I pneumocytes, which encompass approximately 95% of the surface area of the alveoli.
- Alveolar type II epithelial cell
-
The alveolar structure also includes cuboidal type II pneumocytes. Type II pneumocytes secrete surfactant proteins and are believed to be regenerative cells involved in alveolar repair.
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Thomas, C., Limper, A. Current insights into the biology and pathogenesis of Pneumocystis pneumonia. Nat Rev Microbiol 5, 298–308 (2007). https://doi.org/10.1038/nrmicro1621
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DOI: https://doi.org/10.1038/nrmicro1621
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