The lipids of Pneumocystis carinii

Abstract

Information about a number of Pneumocystis carinii lipids obtained by the analyses of organisms isolated and purified from infected lungs of corticosteroid-immunosuppressed rats has been reported in recent years. Of the common opportunistic protists associated with AIDS (Cryptosporidium, Toxoplasma, and the microsporidia), more is currently known about the lipids of P. carinii than the others. Lipids that are synthesized by the organism but not by humans are attractive targets for drug development. Thus, the elucidation of delta 7C-24-alykylated sterol and cis-9,10-epoxystearic acid biosyntheses in P. carinii is currently being examined in detail, since these have been identified as P. carinii-specific lipids. The development of low-toxicity drugs that prevent sterol C-24 alkylation and the specific inhibition of the lipoxygenase that forms cis-9,10-epoxystearic acid might prove fruitful. Although humans can synthesize coenzyme Q10, the anti-P. carinii activity and low toxicity of ubiquinone analogs such as atovaquone suggest that the electron transport chain in the pathogen may differ importantly from that in the host. Although resistance to atovaquone has been observed, development of other naphthoquinone drugs would provide a broader armamentarium of drugs to treat patients with P. carinii pneumonia. Studies of bronchoalveolar lavage fluid and of infected lungs have demonstrated that the infection causes a number of chemical abnormalities. Bronchoalveolar lavage fluid obtained after the removal of lung cellular material and the organisms has been shown to contain larger amounts of surfactant proteins and smaller amounts of phospholipids than do comparable samples from P. carinii-free lungs. Increased phospholipase activity, inhibition of surfactant secretion by type II cells, and uptake and catabolism of lipids by the pathogen may explain this phenomenon related to P. carinii pneumonia. Although not yet thoroughly examined, initial studies on the uptake and metabolism of lipids by P. carinii suggest that the organism relies heavily on exogenous lipid nutrients.

FIG. 1

cis-9,10-Epoxyoctadecanoic acid was detected among P. carinii carinii fatty acids. (A) Structure of cis-9,10-epoxystearic acid. (B) Methyl ester derivative of the P. carinii epoxy fatty acid verified by GLC-MS. The abundant fragment at m/z 155 represents cleavage at the epoxide ring. (C) Authentic standard showing the same mass spectrum. Reprinted from reference with permission of the publisher.

FIG. 2

Sterols identified in P. carinii carinii organisms or P. carinii hominis-infected lungs. (A) Cholesterol, which is probably scavenged from the host lung, was the most abundant sterol present. (B) Fungisterol (ergost-7-en-3-ol) was among the most abundant of the P. carinii carinii-specific sterols. (C) Stigmast-7-en-3-ol was also present in high concentrations in P. carinii carinii. (D) A C₃₂ sterol, pneumocysterol, was isolated from a human lung infected with P. carinii hominis. Its structure, elucidated by MS and NMR spectroscopy, indicated that a C₂ (ethylene) group was present at C-24 of the side chain of lanosterol.

FIG. 3

CoQ homologs separated by HPLC. (A) The ubiquinone homologs CoQ₁₀ and CoQ₉ detected in P. carinii. (B) Absence of CoQ₁₀ in normal rat lungs. The presence of CoQ₈ and CoQ₉ was verified by GLC-MS. (C) Ubiquinone standards separated by HPLC. Reprinted from reference with permission of the publisher.

FIG. 4

Uptake rates of the radiolabeled fatty acids palmitic acid (16:0) and oleic acid (18:1) by P. carinii. The rates resemble first-order kinetics. Reprinted from reference with permission.