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Perspective
A New Name (Pneumocystis
jiroveci) for Pneumocystis from Humans
James R. Stringer,* Charles B. Beard,† Robert F. Miller,‡ and Ann E. Wakefield§ [1]
*University of Cincinnati, Cincinnati, Ohio, USA; †Centers for Disease
Control and Prevention, Atlanta, Georgia, USA; ‡University College London,
United Kingdom; and §University of Oxford, UK
Suggested citation for this article:
Stringer JR, Beard CB, Miller RF, Wakefield AE. A new name (Pneumocystis
jiroveci) for pneumocystis from humans. Emerg Infect Dis [serial
online] 2002 Sep [date cited];8. Available from: URL: http://www.cdc.gov/ncidod/EID/vol8no9/02-0096.htm
The disease known
as Pneumocystis carinii pneumonia (PCP) is a major cause of illness
and death in persons with impaired immune systems. While the genus Pneumocystis
has been known to science for nearly a century, understanding of its
members remained rudimentary until DNA analysis showed its extensive
diversity. Pneumocystis organisms from different host species
have very different DNA sequences, indicating multiple species. In recognition
of its genetic and functional distinctness, the organism that causes
human PCP is now named Pneumocystis jiroveci Frenkel 1999. Changing
the organism's name does not preclude the use of the acronym PCP because
it can be read "Pneumocystis pneumonia." DNA sequence variation
exists among samples of P. jiroveci, a feature that allows reexamination
of the relationships between host and pathogen. Instead of lifelong
latency, transient colonization may be the rule.
Clinical
Importance of Pneumocystis
The disease known as Pneumocystis carinii pneumonia (PCP) is one
of the leading causes of illness and death in persons with impaired immunity.
The disease has been described in immunocompromised patients for many
years, including outbreaks in malnourished young children in orphanages
in Iran in the 1950s (1–6). The AIDS epidemic, however,
marked the beginning of the disease’s impact on a substantial number of
patients. PCP has long been the most common serious AIDS-defining opportunistic
infection in the United States. The introduction of highly active antiretroviral
therapy (HAART) for the treatment of HIV infection has been accompanied
by substantial reductions in mortality and the incidence of opportunistic
infections, including PCP (7). Despite these advances,
Pneumocystis remains a major pathogen in HIV-infected persons who
either are not receiving or are not responding to HAART and among those
who are unaware of their HIV status. PCP is also of clinical importance
in people immunocompromised for reasons other than HIV, such as organ
transplantation or chemotherapy for malignant diseases (8).
In addition, Pneumocystis infection has been documented recently
in persons who are mildly immunocompromised, including those with chronic
lung disease (9).
Need for a Change in Nomenclature
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.
Complexity
of the Genus
One reason that a definitive nomenclature has been slow to develop is
that Pneumocystis organisms have been difficult to study. Attempts
to develop an in vitro culture system have had limited success.
Cultivation of Pneumocystis organisms in vitro requires a large
seed population and supports rather modest increases in organism number
for a very limited period of time (17). An exception
to the rule was recently reported (18); however, this
method has not been established in other laboratories. The fastidiousness
of Pneumocystis organisms greatly hampered early efforts to understand
them. Fortunately, advances in DNA analysis technology allowed progress
in the absence of a robust culture system.
Pneumocystis
jiroveci as a Distinct
Species
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 Workshops 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.
Acronym "PCP" Retained
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.
Multiple Strains of P.
Jiroveci
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.
New Perspectives
on Infection
Genotyping samples of P. jiroveci provides a method for exploring
epidemiologic issues. For example, one study examined the possibility
that the low incidence of PCP in African HIV-infected persons might be
due to the presence or absence of certain strains of P. jiroveci.
However, samples of P. jiroveci from Zimbabwe, Brazil, the United
States, and the United Kingdom have exhibited no major differences in
genotypes (47) . Another example is a study in which
genotyping at four different genetic loci was used to compare isolates
of P. jiroveci collected before (1968–1981) and after (1982 to
present) the beginning of the AIDS pandemic (48). Pre-
and postpandemic samples were the same except for a single base polymorphism
(in the mitochondrial large subunit rRNA gene) found in the pre-pandemic
samples only. These data show that the large increase in incidence of
PCP was not accompanied by a shift in the kinds or frequencies of strains
of P. jiroveci.
Strain analysis has also led to observations that are difficult to reconcile
with the traditional view of the relationship between P. jiroveci
and humans. The traditional theory holds that clinically important
infection results from reactivation of a latent infection that was
acquired during childhood. While infection of young children appears to
be common, latent P. jiroveci has not been directly observed in
healthy adults. In addition, indirect evidence is difficult to reconcile
with lifelong latency.
The latency issue is important for several reasons. Under the reactivation
of latent infection theory, little rationale exists for instituting measures
to minimize the risk of infection during adulthood because this infection
has already occurred. On the other hand, person-to-person transmission
of the disease would have important public heath implications for medical
centers that treat HIV-infected patients or other immunocompromised persons
(42–44,49–52) . Furthermore, transmission
from patients who are undergoing treatment for PCP might enhance the opportunity
for drug resistance to arise. By contrast, the generation of drug resistance
would be less of a concern if most or all infections were due to transmission
from an immunocompetent person, such as a young child's mother, or another
child (i.e, someone who is not being treated for PCP). Under these conditions,
drug-resistant strains, if they arose, would not spread very effectively.
PCP develops in infants infected with HIV perinatally, suggesting that
P. jiroveci was present in these infants’ environments early in
their lives (53). Evidence of P. jiroveci has
also been found in some victims of sudden infant death syndrome (SIDS)
(54). In normal, healthy children, serologic
data have long indicated that infection of young children is common. Most
children develop anti-Pneumocystis antibodies early in life, and
the prevalence of these antibodies appears to increase with age (48,55).
Recently, P. jiroveci has been linked to clinical illness in normal,
healthy infants (51). P. jiroveci DNA was identified
in nasopharyngeal aspirates obtained during episodes of mild respiratory
infection in 24 (32%) of 74 infants. Seroconversion developed by 20 months
of age in 67 (85%) of 79 infants who remained in the study and occurred
in the absence of any symptoms of disease in 14 (18%). These reports confirm
previous ones showing infection of children (1,3,4) .
Young children may be a reservoir of infectious P. jiroveci in
the community.
Although infection of children seems common, little evidence exists for
lifelong latency. Using PCR, Wakefield found no evidence of P. jiroveci
in bronchoalveolar lavage fluid from 10 healthy persons (56).
Peters replicated this result in postmortem lung tissue from 15 immunocompetent
adults (56,57). (The techniques used to detect P.
jiroveci have found it in HIV-negative adults but only those with
other health problems [58].) Studies on recurrent PCP
have shown that different P. jiroveci genotypes are present during
different PCP episodes in patients with repeat episodes of PCP, a result
suggestive of infection proximal to the time of disease (42-44)
. Recent infections of adults are also suggested by the high frequency
of mutations that cause changes in the sequence of the DHPS gene, the
enzyme associated with sulfonamide resistance in other pathogens (59–61)
. These mutations have not been detected in patients in whom PCP occurred
at a time before the widespread use of sulfonamides to treat and prevent
it (62) but are common in today's patients, even in
those with no known exposure to sulfonamides (61,63).
Mutant DHPS genes have been found in a variety of P. jiroveci genetic
backgrounds, suggesting that selection for DHPS mutations is an ongoing
process (64).
An alternative approach to exploring the importance of latency is employing
population genetics and epidemiology to test the following hypothesis.
If lifelong latency is important, adult patients who reside far from their
birthplace should have the strain of P. jiroveci common in their
place of birth, not in their place of residence. Data pertaining to this
hypothesis are now available (64). The strains infecting
adult patients were more similar to those common in their place of residence
than their place of birth, suggesting that infections had been recently
acquired, rather than carried since early childhood.
Latent P. jiroveci have not been found in healthy adults, but
proving that they do not exist is practically impossible. A single organism
anywhere in the body could be sufficient to maintain a latent infection.
Therefore, the possibility of latency remains. However, latent infections
may be transitory, and humans who have eliminated the microbe may be subject
to reinfection. The observations described above seem more consistent
with this “transient colonization” scenario than with lifelong latency.
Summary
The microbe that causes PCP in humans is a distinct phylogenetic fungal
species called Pneumocystis jiroveci. This species has been difficult
to find in the environment, has not been found in nonhuman hosts, and
is either absent in healthy adults or present at very low levels. In contrast,
P. jiroveci is fairly common in humans who have depressed immune
function. The number of P. jiroveci in a person appears to be dependent
on the degree of immune dysfunction, suggesting that the species is adapted
to exploit this dysfunction, growing to very high numbers in the severely
immunodeficient and to lesser extents when immune function is less impaired.
P. jiroveci may be eliminated when immune function is optimal.
Genetic variants of the organism are common, providing markers for epidemiologic
studies. Studies using these markers have raised questions about the role
of latency in PCP. Recurrent PCP can be accompanied by shifts in genotype.
Some patients are infected by genotypes more common in their place of
residence than in their birthplace. Variable loci include the gene encoding
an enzyme targeted by sulfonamides, suggesting transmission from treated
patients to others at risk. While these observations, combined with the
scarcity of P. jiroveci in healthy adults, do not exclude latency
as a cause of PCP, they suggest that long-term latency is not the only
source of this disease.
Dr. Stringer is a professor of molecular genetics at the University of
Cincinnati. He has studied the molecular genetics of variation in the
genus Pneumocystis for 15 years.
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