Ausschuss für Hygiene

Pneumocystis carinii

Host species:
  • Laboratory animals (Smulian & Walzer 1992)
  • Wide range of domestic animals, monkeys, humans

Organotropism:
  • Lungs
  • Occasionally other organs or generalization to eyes, skin etc.

Clinical disease:
  • Inapparent in immunocompetent host
  • Slowly progressive chronic pneumonia with weight loss in immunocompromised host

Morbidity and mortality:
  • Cconventionally bred colonies may be persistently infected because of subclinical nature in immunocompetent hosts (Frenkel et al. 1966).
  • High morbidity and mortality with chronic progressive pneumonia in immunosuppressed animals

Zoonotic relevance:
  • Pneumocystis (P.) carinii is not universally transmissible between mammalian species (Gigliotti et al. 1993).
  • Respiratory mode of transmission (Hughes 1982)
  • Most common opportunistic infection and leading cause of morbidity and mortality in AIDS patients

Interference with research:

Physiology

  • P. carinii pneumonia leads to alterations in compliance and lung mechanisms (Brun-Pascaud et al. 1985, Stokes et al. 1986).
  • P. carinii may alter the amount and type of surfactant produced: P. carinii pneumonia in rats leads to a decrease in surfactant phospholipids in bronchoalveolar lavage (Kernbaum et al. 1983, Sheehan et al. 1986). P. carinii organisms can directly inhibit secrection of phosphatidylcholin from type II cells (Rice et al. 1993). Broncho-alveolar lavage phosphatidylglycerol is reduced in rats with P. carinii pneumonia (Su et al. 1996). Surfactant protein-A levels increase during P. carinii pneumonia in the rat (Phelps et al. 1996).
  • Attachment of P. carinii to alveolar macrophages occurs by a fibronectin- and calcium dependent mechanism, but does not trigger a phagocytic response (Pottratz & Martin 1990a, 1990b). P. carinii glycoprotein A binds macrophage mannose receptors, thereby mediating binding and uptake of P. carinii by alveolar macrophages (Ezekowitz et al. 1992, O’Riordan et al. 1995). Surfactant protein A can function as a ligand between P. carinii and alveolar macrophages (Williams et al. 1996).
  • Attachment of P. carinii to type I pneumocytes leads to their degeneration and to proliferation of type II pneumocytes.
  • Following attachment of P. carinii to type I cells, surface glycocalyx is decreased and alveolar-capillary permeability is increased (Lanken et al. 1980, Yoneda & Walzer 1980, 1981, 1984). As a consequence of dysplasia and disruption of the epithelium, underlying material gains access to the alveolar space and impairs normal lung function.
  • P. carinii attachment increases expression of fibronectin-binding integrins on cultured lung cells (Pottratz et al. 1994).
  • P. carinii and IFN-g induce rat alveolar macrophages to produce nitric oxide (Sherman et al. 1992).
  • The mitochondrial ATPase 6 gene is upregulated in P. carinii-infected rat lungs (Asnicar et al. 1996).
  • P. carinii infection alters GTP-binding proteins in the lung (Oz & Hughes 1997).
  • P. carinii inhibits cyclin-dependent kinase activity in lung epithelial cells (Limper et al. 1998).
  • Fibrinogen expression is induced in the lung epithelium during P. carinii pneumonia (Simpson-Haidaris et al. 1998).

Pathology

  • Slight infection: multifocal alveolar aggregates of cysts and interstitial/perivascular non-purulent infiltration (Walzer et al. 1980, Chen et al. 1990)
  • Severe infection: consolidated lungs; extensive lung areas involved with alveolar aggregates of cysts (eosinophilic, honeycombed material), proliferation of type II pneumocytes and severe interstitial fibrosis
  • Extrapulmonary manifestation of P. carinii infection by hematogenous or lymphatic spread is possible; major sites are lymph nodes, bone marrow, liver, and spleen, characterized by eosinophilic honeycombed material with inflammatory response.
  • Multinucleated giant cells in murine P. carinii pneumonia (Hanano et al. 1996)

Immunology

  • High risk for all congenitally immunodeficient hosts and for experimental models of immunosuppression.
  • P. carinii from different host species are immunologically distinct (Gigliotti & Harmsen 1997).
  • P. carinii induces activating and inhibitory innate cellular immune response mechanisms (Warschkau et al. 1998).
  • Cellular immunity is important for protection against P. carinii pneumonia (Furuta et al. 1984, 1985).
  • P. carinii-reactive CD4+ lymphocytes may contribute to the host's response via secretion of macrophage-activating cytokines (IFN-g and others) as well as by the production of signals that induce foster expansion of the antibody-forming pool of B cells and cytotoxic CD8+ lymphocytes (Beck et al. 1993).
  • Protective immunity against P. carinii is mediated by CD4+ T cells (reviewed by Hanano & Kaufmann 1998).
  • Neutrophils, alveolar type II epithelial cells, B cells, CD8+ lymphocytes, antibodies and cytokines, such as IFN-g and TNF, participate in host effector mechanisms against P. carinii (Masur & Jones 1978, Von Behren & Pesanti 1978, Shear et al. 1989, Pesanti 1989, 1991, Chen et al. 1992, Beck et al. 1996, Garvy et al. 1997, Kolls et al. 1997 Marcotte et al. 1996).
  • P. carinii induces TNF-a production from monocyte and macrophage cultures with a peak within 8 h of incubation (Tamburrini et al. 1991).
  • P. carinii glycoprotein A stimulates IL-8 production and inflammatory cell activation in alveolar macrophages and cultured monocytes (Lipschik et al. 1996).
  • P. carinii induces expression of ICAM-1 and IL-6 in lung epithelial cells (Yu & Limper 1997 Pottratz et al. 1998).

Infectiology

  • Neutrophils in bacterial pneumonia may participate in host effector mechanisms against P. carinii (Pesanti 1982).

References:

Asnicar MA, Goheen M, Bartlett MS, et al. (1996) Upregulation of host mitochondrial ATPase 6 gene in Pneumocystis carinii-infected rat lungs. Journal of Eukaryotic Microbiology 43, 38S

Beck JM, Newbury RL, Palmer BE, et al. (1996) Role of CD8+ lymphocytes in host defense against Pneumocystis carinii in mice. Journal of Laboratory and Clinical Medicine 128, 477- 487

Beck JM, Warnock ML, Kaltreider HB, et al. (1993) Host defense against Pneumocystis carinii in mice selectively depleted of CD4+ lymphocytes. Chest 103, 116S-118S

Brun-Pascaud M, Pocidalo JJ, Kernbaum S (1985) Respiratory and pulmonary alterations in experimental Pneumocystis carinii pneumonia in rats. Bulletin Europeen de Physiopathologie Respiratoire 21, 37-41

Chen W, Havell EA, Harmsen AG (1992) Importance of endogenous tumor necrosis factor-a and gamma interferon in host resistance against Pneumocystis carinii infection. Infection and Immunity 60, 1279-1284

Chen W, Mills JW, Harmsen AG (1990) Development and resolution of Pneumocystis carinii pneumonia in severe combined immunodeficient mice: a morphological study of host inflammatory responses. International Journal of Experimental Pathology 73, 709-720

Ezekowitz RA, Williams DJ, Koziel H, et al. (1991) Uptake of Pneumocystis carinii mediated by the macrophage mannose receptor. Nature 351, 155-158

Frenkel JK, Good JT, Shultz JA (1966) Latent Pneumocystis infection of rats, relapse and chemotherapy. Laboratory Investigation 15, 1559-1577

Furuta T, Ueda K, Fujiwara K (1984) Experimental Pneumocystis carinii infection in nude rats. Japanese Journal of Experimental Medicine 54, 65-72

Furuta T, Ueda K, Fujiwara K, et al. (1985) Cellular and humoral immune responses of mice subclinically infected with Pneumocystis carinii. Infection and Immunity 47, 544-548

Garvy BA, Ezekowitz RA, Harmsen AG (1997) Role of gamma interferon in the host immune and inflammatory responses to Pneumocystis carinii infection. Infection and Immunity 65, 373-379

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Hanano R, Kaufmann SH (1998) Pneumocystis carinii and the immune response in disease. Trends in Microbiology 6, 71-75

Hanano R, Reifenberg K, Kaufmann SH (1996) T- and B-lymphocyte-independent formation of alveolar macrophage-derived multinucleated giant cells in murine Pneumocystis carinii pneumonia. Infection and Immunity 64, 2821-2823

Hughes WT (1982) Natural mode of acquisition for de novo infection with Pneumocystis carinii. Journal of Infectious Diseases 145, 842-848

Kernbaum S, Masliah J, Alcindor LG, et al. (1983) Phospholipase activities of bronchoalveolar lavage fluid in rat Pneumocystis carinii pneumonia. British Journal of Experimental Pathology 64, 75-80

Kolls J K, Lei D, Vazques C, et al. (1997) Exacerbation of murine Pneumocystis carinii infection by adenoviral-mediated gene transfer of a TNF inhibitor. American Journal of Respiratory Cell and Molecular Biology 16, 112-118

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Limper AH, Edens M, Anders RA, et al. (1998) Pneumocystis carinii inhibits cyclin-dependent kinase activity in lung epithelial cells. Journal of Clinical Investigation 101, 1148-1155

Lipschik GY, Treml JF, Moore SD (1996) Pneumocystis carinii glycoprotein A stimulates interleukin-8 production and inflammatory cell activation in alveolar macrophages and cultured monocytes. Journal of Eukaryotic Microbiology 43, 14S-15S

Marcotte H, Levesque D, Delanay K, et al. (1996) Pneumocystis carinii infection in transgenic B cell-deficient mice. Journal of Infectious Diseases 173, 1034-1037

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Oz HS, Hughes WT (1997) Pneumocystis carinii infection alters GTP-binding proteins in the lung. Journal of Parasitology 83, 679-685

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Pesanti EL (1991) Interaction of cytokines and alveolar cells with Pneumocystis carinii in vitro. Journal of Infectious Diseases 163, 611-616

Phelps DS, Umstead TM, Rose RM, et al. (1996) Surfactant protein-A levels increase during Pneumocystis carinii pneumonia in the rat.

European Respiratory Journal 9, 565-570

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Pottratz ST, Reese S, Sheldon JL (1998) Pneumocystis carinii induces interleukin 6 production by an alveolar epithelial cell line. European Journal of Clinical Investigation 28, 424-429

Pottratz ST, Weir AL, Wisniowski PE (1994) Pneumocystis carinii attachment increases expression of fibronection-binding integrins on cultured lung cells. Infection and Immunity 62, 5464-5469.

Rice WR, Singleton FM, Linke MJ, et al. (1993) Regulation of surfactant phosphatidylcholine secretion from alveolar type II cells during Pneumocystis carinii pneumonia in the rat. Journal of Clinical Investigation 92, 2778-2782

Shear H, El Sadr W, Rubinstein BE, et al. (1989) Effects of steroid induced Pneumocystis carinii on alveolar macrophages in the rat. Journal of Protozoology 36, 49S-50S

Sheehan PM, Stokes DC, Yeh Y, et al. (1986) Surfactant phospholipids and lavage phospholipase A2 in experimental Pneumocystis carinii pneumonia. American Review of Respiratory Disease 134, 526-531

Sherman MP, Hidalgo HA, Aeberhard EE (1992) Pneumocystis carinii and interferon-g induce rat alveolar macrophages to produce nitric oxide. American Review of Respiratory Disease 145, A246

Simpson-Haidaris PJ, Courtney MA, Wright TW, et al. (1998) Induction of fibrinogen expression in the lung epithelium during Pneumocystis carinii pneumonia. Infection and Immunity 66, 4431-4439

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Warschkau H, Yu H, Kiderlen AF (1998) Activation and suppression of natural cellular immune functions by Pneumocystis carinii. Immunobiology 198, 343-360

Williams MD, Wright JR, March KL, et al. (1996) Human surfactant protein A enhances attachment of Pneumocystis carinii to rat alveolar macrophages. American Journal of Respiratory Cell and Molecular Biology 14, 232-238

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Yoneda K, Walzer PD (1981) Mechanism of alveolar injury in experimental Pneumocystis carinii pneumonia in the rat. British Journal of Experimental Pathology 62, 339-346

Yoneda K, Walzer PD (1984) The effect of corticosteroid treatment on the cell surface glycocalyx of the rat pulmonary alveolus: relevance to the host parasite relationship in Pneumocystis carinii infection. British Journal of Experimental Pathology 65, 347-354

Yu ML, Limper AH (1997) Pneumocystis carinii induces ICAM-1 expression in lung epithelial cells through a TNF-a-mediated mechanism. American Journal of Physiology 273, L1103- 1111
Author: Dr Gabi Pohlmeyer-Esch / Dr. M. Mähler, Hannover