The Biology of Pneumocystis Carinii

Smulian, A. George; Walzer, Peter D.

doi:10.3109/10408419209114558

Cited by 29 publications

(13 citation statements)

References 124 publications

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“…Initial studies of Diff-Quik-stained scid mouse lung homogenates revealed stained bodies with morphologies and sizes comparable to previously published observations describing P. carinii in rat and human samples (see Masur et al, 1989;Davey & Masur, 1990;Smulian & Walzer, 1992). That the scid mice bred by us were indeed positive for P. carinii was confirmed by the demonstration that bodies of the size and morphology of P. carinii were present in Giemsa-stained histological lung sections (not presented).…”

Section: Validation Of Cyst Enumeration Methodssupporting

confidence: 86%

“…That the scid mice bred by us were indeed positive for P. carinii was confirmed by the demonstration that bodies of the size and morphology of P. carinii were present in Giemsa-stained histological lung sections (not presented). Furthermore, as presented below, animals treated with trimethoprim/sulphamethoxazole, an agent known to be effective against P. carinii (see Masur et al, 1989;Davey & Masur, 1990;Smulian & Walzer, 1992), did not contain such bodies.…”

Section: Validation Of Cyst Enumeration Methodsmentioning

confidence: 89%

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The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

Kunz¹,

Junker²,

Blaser³

et al. 1995

J Antimicrob Chemother

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The usefulness of scid mice bearing endogenous Pneumocystis carinii infection as a model for experimental chemotherapy was examined using standard compounds known to be effective against P. carinii. Trimethoprim/sulphamethoxazole was able to reduce pulmonary P. carinii cysts in a dose-dependent manner within the dose range studied (10/50 to 100/500 TMP/SMX mg/kg/d, bd, po, 5 days per week for 30 treatments). However, alterations in associated symptoms of infection (reduced body weight, increased lung weight, increased blood leucocytes and erythrocytes), was apparently not linearly dose-dependent. Blood and lung lavage fluid levels of sulphamethoxazole one hour post administration of trimethoprim/sulphamethoxazole was dose-dependent, but not linear with dose, and was apparently correlated to cyst reduction; trimethoprim was below the limit of detection at this time. Treatment of mice with 100/500 mg/kg/day trimethoprim/ sulphamethoxazole required 2 weeks (bd for 10 days of treatment) before changes in indices of infection became significant. Pentamidine (20 mg/kg, sc, three times per week for 3 weeks) was nearly as effective as high-dose trimethoprim/ sulphamethoxazole in reducing cysts, whereas lower doses were ineffective. Despite being unable to reduce pulmonary P. carinii infection, even low doses of pentamidine (6 or 2 mg/kg, sc, three times per week for 3 weeks) were able to reduce lung weights and blood leucocyte levels. This model of pulmonary P. carinii infections is amenable to chemotherapeutic intervention in an apparently dose-dependent fashion, and can be used to evaluate the capacity of compounds to eradicate P. carinii and resolve signs of infection.

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Section: Validation Of Cyst Enumeration Methodssupporting

confidence: 86%

Section: Validation Of Cyst Enumeration Methodsmentioning

confidence: 89%

The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

Kunz¹,

Junker²,

Blaser³

et al. 1995

J Antimicrob Chemother

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“…1) is an inhibitor of ⌬ 24(25) -sterol methyltransferase (24-SMT) in fungal cells (2) and in both epimastigotes and amastigotes of the protozoan parasite Trypanosoma cruzi (23,52,53); it has also been shown that this compound is a potent antiproliferative agent against this parasite both in vitro and in vivo (52,53). Pneumocystis carinii, an opportunistic fungal pathogen which, in contrast to other fungi, is completely resistant to azoles and ampthotericin B (3,4,13,27,45), is also susceptible to 22,26-azasterol in vitro (55).…”

mentioning

confidence: 99%

Ultrastructural and Biochemical Alterations Induced by 22,26-Azasterol, a Δ ²⁴⁽²⁵⁾ -Sterol Methyltransferase Inhibitor, on Promastigote and Amastigote Forms of Leishmania amazonensis

Rodrigues

Attias

Rodríguez

et al. 2002

Antimicrob Agents Chemother

117

110

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We report on the antiproliferative effects and the ultrastructural and biochemical alterations induced in vitro by 22,26-azasterol, a sterol ⌬ 24(25) -methyltransferase (24-SMT) inhibitor, on Leishmania amazonensis. When promastigotes and amastigotes were exposed to 100 nM 22,26-azasterol, complete growth arrest and cell lysis ensued after 72 (promastigotes) or 120 (amastigotes) h. Exposure of parasites to this azasterol led to the complete depletion of parasite endogenous sterols (episterol and 5-dehydroepisterol) and their replacement by 24-desalkyl sterols (zymosterol, cholesta-5,7,24-trien-3␤-ol, and cholesta-7,24-dien-3␤-ol), while 14-methylzymosterol and 4,14-dimethyl-zymosterol accumulated as a result of simultaneous incubation of the parasites with 22,26-azasterol and ketoconazole, a known inhibitor of the parasite's sterol C14-demethylase. These results confirmed that 24-SMT is the primary site of action of the azasterol. Profound changes were also observed in the phospholipid compositions of treated cells, in which a twofold reduction in the content of phosphatidylserine was observed; this was accompanied by a concomitant increase in the content of phosphatidylinositol. Transmission electron microscopy showed that 22,26-azasterol induced marked morphological changes, including mitochondrial swelling, invaginations of the inner mitochondrial membrane, and the appearance of large bodies containing concentric membranes. Other modifications included increases in the numbers of acidocalcisomes, megasomes, and lipid inclusions and the appearance of typical autophagic structures and cell body protrusions toward the flagellar pocket. We conclude that the dramatic alteration of the lipid composition of the parasite's membranes induced by the drug underlies the ultrastructural alterations that lead to the loss of cell viability and that 24-SMT inhibitors could be useful as selective antileishmanial agents.

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“…Pneumocystis carinii is one of the leading causes of opportunistic infection in AIDS patients (30). Despite the importance of this microorganism as an opportunistic pathogen, much basic information about the parasite is lacking.…”

mentioning

confidence: 99%

“…In general, the arguments in favor of classifying P. carinii as a protozoan are the amoeboid appearance of the trophic form, susceptibility to antiprotozoal drugs such as pentamidine isethionate or trimethoprim-sulfamethoxazole, insusceptibility to antifungal drugs such as amphotericin B, and the lack of ergosterol in Pneumocystis cell membranes. Arguments in favor of including P. carinii among the fungi include similarities of the sporogenous state to ascospore formation in yeasts, poorly developed mitochondria which show ultrastructural similarities to fungal mitochondria, lack of the internal organelles typically found in protozoa, the encoding of the enzymes thymidylate synthase and dihydrofolate synthase by physically separate genes, and the nucleic acid sequence homologies described above (10,30).…”

mentioning

confidence: 99%

Phytosterols are present in Pneumocystis carinii

Furlong

Samia

Rose

et al. 1994

Antimicrob Agents Chemother

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Although originally classified as a protozoan, Pneumocystis carinii is now considered to have fungal characteristics. Drugs typically used for the treatment of fungal infections target ergosterol. Because P. carinii is an important pathogen in AIDS and other immunocompromised patients, knowledge of the sterol content of this organism may be useful as a basis for developing new treatment strategies or for improving diagnosis. P. carinii organisms were harvested from infected rat lungs and were purified by filtration. Control preparations from uninfected animals were identically prepared. Lipids were extracted from the organisms and control preparations and were separated into neutral lipid, glycolipid, and phospholipid fractions by silicic acid chromatography. The neutral lipid fraction was further treated by alkaline hydrolysis and was analyzed by reversed-phase high-pressure liquid chromatography (HPLC), gas chromatography (GC), and GC-mass spectrometry (GC-MS). As shown by HPLC, the neutral lipid fraction from infected rats contained a minimum of six peaks, while in control preparations a single peak with a retention time identical to that of cholesterol was observed. The predominant sterol in these preparations was positively identified by GC-MS as cholesterol and constituted 80 to 90% of the total. The remaining peaks had relative retention times similar to those of phytosterols by both HPLC and GC, and the similarity of these sterols to those derived from plants and fungi was confirmed by MS. Ergosterol, however, was not present. These results provide further evidence for a close phylogenetic relationship between P. carinii and fungi and suggest that these sterols could be used as targets for drug development and for improving diagnosis.Pneumocystis carinii is one of the leading causes of opportunistic infection in AIDS patients (30). Despite the importance of this microorganism as an opportunistic pathogen, much basic information about the parasite is lacking. While originally classified phylogenetically as a protozoan, analyses of P. carinii DNA and mitochondrial and rRNA sequences have generally shown a higher degree of homology to the mitochondrial and rRNA sequences of fungi (yeasts) than to those of protozoa (9,13,27,31,34,35). The exact relationship remains to be determined. Analyses of 5S RNA have suggested a somewhat close phylogenetic relationship to members of the Rhizopoda-Myxomycota-Zygomycota group of "protista fungi." Other studies have suggested similarities to Saccharomyces, Candida, and Neurospora spp. and "red yeast" fungi. In general, the arguments in favor of classifying P. carinii as a protozoan are the amoeboid appearance of the trophic form, susceptibility to antiprotozoal drugs such as pentamidine isethionate or trimethoprim-sulfamethoxazole, insusceptibility to antifungal drugs such as amphotericin B, and the lack of ergosterol in Pneumocystis cell membranes. Arguments in favor of including P. carinii among the fungi include similarities of the sporogenous state to ascospore format...

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The Biology of Pneumocystis Carinii

Cited by 29 publications

References 124 publications

The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

Ultrastructural and Biochemical Alterations Induced by 22,26-Azasterol, a Δ ²⁴⁽²⁵⁾ -Sterol Methyltransferase Inhibitor, on Promastigote and Amastigote Forms of Leishmania amazonensis

Phytosterols are present in Pneumocystis carinii

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The Biology of Pneumocystis Carinii

Cited by 29 publications

References 124 publications

The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

Ultrastructural and Biochemical Alterations Induced by 22,26-Azasterol, a Δ 24(25) -Sterol Methyltransferase Inhibitor, on Promastigote and Amastigote Forms of Leishmania amazonensis

Phytosterols are present in Pneumocystis carinii

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Ultrastructural and Biochemical Alterations Induced by 22,26-Azasterol, a Δ ²⁴⁽²⁵⁾ -Sterol Methyltransferase Inhibitor, on Promastigote and Amastigote Forms of Leishmania amazonensis