Pneumocystis organisms were first reported by Chagas in 1909 (10), but he mistook them for a morphologic form of Trypanosoma cruzi. Within a few years of this first report, further studies established that the microbe in question was not a trypanosome but a new species altogether, named Pneumocystis carinii (11).

From the time of its discovery, until late in the 1980s, Pneumocystis was widely thought to be a protozoan. These views were based on several criteria: 1) strong similarities in microbe morphology and host pathology, 2) absence of some phenotypic features typical of fungi, 3) presence of morphologic features typical of protozoa, 4) ineffectiveness of antifungal drugs, and 5) effectiveness of drugs generally used to treat protozoan infections. Some investigators pointed out that Pneumocystis organisms exhibit morphologic similarities to fungi (2). Nevertheless, the protozoan hypothesis remained predominant until 1988, when DNA analysis demonstrated that Pneumocystis is a fungus, albeit an odd one, lacking in ergosterol and very difficult to grow in culture (12,13).

Soon after the proper classification of Pneumocystis had been determined at the kingdom level, additional DNA data showed that Pneumocystis organisms in different mammals are quite different. These data led to interim name changes (14), but it was not until 1999 that the first valid new binomial appeared. The organism that causes human PCP is now named Pneumocystis jiroveci Frenkel 1999 (pronounced “yee row vet zee”), in honor of the Czech parasitologist Otto Jirovec, who is credited with describing the microbe in humans (15). The primary purpose of this article is to explain what led to the name change and why the new name is necessary, useful, and workable for all concerned. For a more extensive review of the systematics and nomenclature of Pneumocystis, see Stringer’s review of workshops on the subject (16). The DNA sequence information that led to the renaming of Pneumocytsis organisms also provided the tools needed to better understand the relationships between these microbes and the hosts they inhabit. Thus, the secondary purpose of this article is to summarize data on these relationships, focusing on current views on the relationship between P. jiroveci and humans.

Phenotypic differences between P. jiroveci and other species of Pneumocystis were noted decades ago (19). More recent descriptions echo these reports (20). On the basis of phenotypes, Frenkel first proposed the name Pneumocystis jiroveci in 1976. The name was not validly published, however, under the then-prevailing specifications of the International Code of Zoological Nomenclature. Thus, the name did not gain acceptance at that time.

The first indication of a molecular difference between P. jiroveci and Pneumocystis from laboratory animals came from analyses of protein sizes (21,22). However, the importance of these differences was difficult to judge because the Pneumocystis was prepared directly from the lung of the host, leaving open the possibility that differences could have been due to extrinsic factors such as contamination with host proteins, host-mediated modification of Pneumocystis proteins, or presence of dead Pneumocystis organisms.

DNA analysis provided the information needed to clarify the issue and to establish that the organisms from humans and other animals are quite different (23). The most powerful approach has been to use polymerase chain reaction (PCR). Wakefield developed primers that amplify DNA from all known species of Pneumocystis (24,25). When these primers have been used on human-derived samples of Pneumocystis, the only DNA found has been that of P. jiroveci. Moreover, P. jiroveci DNA has not been found in lung samples from any other mammals, including nonhuman primates (26). The PCR data are supported by the results of sequencing cloned genes. Several genes or gene fragments have been cloned from human-derived Pneumocystis (27–30). In all cases, the gene sequence is very different from its orthologues in Pneumocystis organisms from other host species. Genetic divergence data also argue that P. jiroveci is a distinct species. The 18S rRNA sequences from P. jiroveci (i.e., human-derived) and P. carinii (i.e., rat-derived) differ by 5%. This level of divergence is comparable with that between Pneumocystis organisms and Taphrina deformans (a plant fungal pathogen), whose 18S rRNA sequences differ by approximately 6%. In contrast, species in the genus Saccharomyces can differ by as little as 1% at the 18S rRNA locus.

The genetic divergence between P. jiroveci and other Pneumocystis organisms is typical of the genus. When Pneumocystis from different host species are compared by DNA sequence analysis, they always differ (23,25,31–33). In addition, experiments with rats, mice, ferrets, and monkeys have demonstrated host-species specificity (34–36). For example, when Pneumocystis organisms were taken from a rat and transferred to a mouse, proliferation was not evident, and no disease resulted (34). In contrast, when Pneumocystis organisms from a rat were transferred to another rat, they proliferated to a very high number and caused severe disease. Transfer experiments that seem to show lack of specificity have been reported, but these reports did not show that the proliferating organisms were the same species of Pneumocystis as those introduced, leaving open the possibility that endogenous organisms were responsible for the infection.

Pneumocystis organisms might be obligate parasites that have evolved to survive in a particular host species. Co-evolution of parasite and host might be expected in such a case. Note, in this regard, that P. jiroveci is most similar to organisms isolated from other primates (37). This finding fits with the obligate parasite conjecture. However, the host specificity data also fit with an alternative scenario: there could be many free-living species of Pneumocystis, one of which is capable of invading humans, others of which are capable of invading nonhuman primates, and the like. In this scenario, the similarity between P. jiroveci and the Pneumocystis organisms found in nonhuman primates would reflect the similarities between humans and other primates. If P. jiroveci is not an obligate parasite, finding it outside the human body should be possible. P. jiroveci DNA has been detected in samples of airborne fungal spores (24) and in a sample of pond water (38). However, the number of P. jiroveci in the environment seems to be very low, leaving open the possibility that these “free forms” of the organism may have been deposited by humans. P. jiroveci could be an obligate parasite, spores of which can survive in the environment long enough to infect a new host, should one be encountered. Resolving this question awaits the availability of a system capable of detecting infectious Pneumocystis organisms in the air, water, or soil.

Soon after DNA sequence data began to appear, name changes were suggested (14,39). However, naming new species seemed premature to many because of concerns about the possibility of creating false species by misinterpreting the importance of a limited amount of DNA sequence data. Consequently, a provisional trinomial nomenclature was adopted. This system referred to the different kinds of Pneumocystis organisms as special forms of P. carinii Under this system, P. jiroveci was called P. carinii formae specialis hominis (P. carinii f. sp. hominis). After these provisional nomenclature were instituted, more DNA sequence data were obtained, and by 2001, it became clear that the organism causing PCP in humans should be recognized as a distinct species. The name P. jiroveci had already been published in a valid manner in 1999 (15); however, publication of a name does not necessarily lead to its use. Therefore, at the 2001 International Workshop on Opportunistic Protists held in Cincinnati, Ohio, approximately 50 researchers from around the world, including clinicians, epidemiologists, and laboratory scientists, met to discuss the desirability and appropriateness of retaining the currently used trinomial nomenclature system, as opposed to assigning (or using) new species names. The group unanimously endorsed a proposal to rename the organisms currently known as special forms of P. carinii as species in the genus Pneumocystis and drew up guidelines for the creation of the new species names (16). Consequently, in keeping with the International Code of Botanical Nomenclature, it is no longer correct, either biologically or taxonomically, to refer to the human Pneumocystis organism as P. carinii. P. carinii now refers exclusively to the organism formerly known as P. carinii f. sp. carinii, one of the two Pneumocystis species found only in rats.

The consensus achieved at the workshop will help to make published reports on Pneumocystis more uniform with respect to nomenclature. Such uniformity will clarify communication among all who are interested in this genus and the disease caused by its members. Hopefully, all future reports pertaining to P. jiroveci will use its new name.

Given the compelling evidence that the human form of Pneumocystis is a separate species, the most important objection to designating it as such has been the problem that this name change could create in the medical literature, where the disease caused by P. jiroveci is widely known as PcP, or PCP. This problem can be avoided by taking the species name out of the disease name. Under this system, PCP would refer to Pneumocystis pneumonia. This simple modification in the vernacular accommodates the name change pertaining to the Pneumocystis species that infects humans. Furthermore, adopting this change makes the acronym appropriate for describing the disease in every host species, none of which, except rats, is infected by P. carinii.

DNA sequence polymorphisms are often observed in isolates of P. jiroveci, suggesting that numerous strains of this species exist. Loci that have been favorite targets for sequence analysis include the mitochondrial large subunit ribosomal RNA gene, the mitochondrial small subunit rRNA gene, the internal transcribed spacer regions of the nuclear rRNA gene (ITS), the arom gene, and the dihydropteroate synthase (DHPS) gene. The first three of these loci are considered to be under little if any selective pressure and presumably serve as indicators of genetic changes that are phenotypically neutral. The changes in the arom gene may also be considered neutral because they effect no change in the amino acid sequence of the enzyme. By contrast, the polymorphisms in the DHPS gene may be due to selection (see below). Techniques other than DNA sequencing have been used to detect genotypic variation. These include the use of type-specific oligonucleotide probes to detect variation at the ITS regions (40) and detection of single-strand conformation polymorphism (SSCP) at multiple loci (41).

Genotyping has produced data from hundreds of P. jiroveci samples. Most studies have targeted one locus for analysis, but several multilocus studies have been reported (41–44). The allelic sequence polymorphism common in P. jiroveci is not seen in P. carinii (rat-derived Pneumocystis). However, P. carinii populations differ with respect to chromosome size, and several different strains have been identified by analysis of chromosome sizes (45,46). The possibility of chromosome size variation in P. jiroveci has not been adequately addressed because this analysis requires more organisms than are typically available from patients.