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Pneumocystis

For decades Pneumocystis carinii was considered a protozoan while ultrastructural investigations suggested an association with fungi. Only molecular genetic techniques could finally solve the question of phylogenetic placement for this microorganism: sequencing of rRNA [43] and rDNA [1] in the late 1980s clearly grouped P. carinii with the Fungi. All further phylogenetic marker sequences and sequences derived from the ongoing genome sequencing effort have confirmed and refined the association to the ascomycetes [44]. Recently, distinct species have been described in the genus Pneumocystis, and for the human form the species designation P. jirovecii has been suggested, while P. carinii was retained for the species infecting rats [44].

Pneumocystis is considered an opportunistic pathogen; however, unlike for other opportunists, no environmental reservoir has been identified. Cryptic infections of immune-competent mammalian hosts might be the only strategy of Pneumocys-tis species to maintain their presence, preferably in the lung as the primary niche [45, 46]. Albeit relatively rare, disseminated pneumocystosis can affect a wide variety of host sites, especially bone marrow and spleen [47]. While the complete life cycles for any Pneumocystis species are still unknown, evidence for a biphasic life cycle for P. carinii within the mammalian alveolus exists (for review see Ref. [48]): an asexual phase replicates by binary fission, and a presumed sexual phase capable of meiosis occurs in the cyst stages. Both forms remain extracellular in close contact with host cells within the lumen of the alveoli, which eventually become compromised for gas exchange. Genetic evidence for meiosis has been provided by the Pneumocystis Genome Project [49] through the identification of homologues of meiosis-specific genes from other fungi. The genome project also indicates that P. carinii may be able to synthesize cholesterol rather than take it up from the host as P. carinii lacks ergosterol as the bulk sterol (unlike most fungi), but still contains several key enzymes for sterol synthesis. Another peculiar feature of the P. carinii genome is the presence of only a single nuclear ribosomal locus [50], whereas most fungi and other eukaryotes have multiple copies (> 100). The Pneumocystis genome sequencing effort is still ongoing (see Table 18.2). The organization of the P. carinii genome reveals a remarkable reduction in size when compared to the apathogenic yeast S. cerevisiae: 13 Mbp in 16 linear chromosomes ranging from 200 to 2200 kbp [51] versus approximately 8 Mbp in 17 linear chromosomes ranging from 300 to 700kbp [52]. Concomitantly, gene numbers appear to be reduced, with approx. 6000 yeast genes versus approx. 4000 genes in P. cari-nii, while gene densities are similar at about 1 gene per 2000bp. Introns are much more common in P. carinii, 3.7 on average per gene but only about 270 total in S. cerevisiae. Chromosome ends in P. carinii present tandem arrays of genes encoding surface antigens, the "major surface glycoproteins" (MSG genes), subti-lisin-like proteases as putative processing components (PRT genes), and MSG-related proteins (MSR genes) of unknown function [53]. MSG and MSR gene families account for about 10% of the genome [54]. Their functional roles could be as surface antigens for evasion of the host immune system and/or providing adhesins for cell attachment and aggregation during mating.

Completion of the genome sequencing project for P. carinii, predicted to be by early 2005 (http://pneumocystis.cchmc.org), and the efforts of the Fungal Genome Initiative on the genomes of P.jirovecii and P. carinii f.sp. muris (http://www-genome.wi.mit.edu/annotation/fungi/fgi/) will certainly advance our understanding of the biology and pathogenesis of these enigmatic fungi.

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