Mycoplasmas: Sophisticated, Reemerging, and Burdened by Their Notoriety
Joel B. Baseman and Joseph G. Tully *The University of Texas Health Science Center at San Antonio,
San Antonio, Texas, USA; National Institute of Allergy and
Infectious Diseases, Frederick Cancer Research and Development Center,
Frederick, Maryland, USA
"Sit down before fact as a little child, be prepared to give up
every preconceived notion, follow humbly wherever and to whatever abysses nature leads, or you shall learn nothing."
Thomas Henry Huxley
Mycoplasmas are most unusual self-replicating bacteria, possessing very
small genomes, lacking cell wall components, requiring cholesterol for membrane
function and growth, using UGA codon for tryptophan, passing through
"bacterial-retaining" filters, and displaying genetic economy that requires a strict dependence on the host
for nutrients and refuge. In addition, many of the mycoplasmas pathogenic for humans
and animals possess extraordinary specialized tip organelles that mediate their
intimate interaction with eucaryotic cells. This host-adapted survival is achieved through
surface parasitism of target cells, acquisition of essential biosynthetic precursors, and in
some cases, subsequent entry and survival intracellularly. Misconceptions concerning the
role of mycoplasmas in disease pathogenesis can be directly attributed to their
biological subtleties and to fundamental deficits in understanding their virulence capabilities.
In this review, we highlight the biology and pathogenesis of these procaryotes and
provide new evidence that may lead to increased appreciation of their role as human pathogens.
No other group of procaryotes has been so embroiled in controversy and in
establishing a clear pathogenic niche as the mycoplasmas.
Their virulence determinants are undeniably
complex, and their unique biological properties likely challenge the host differently
from typical bacterial pathogens (1,2). Also, numerous
Mycoplasma species appear to comprise the
commensal microbial flora of healthy persons (3), and the
association of these mycoplasmas with disease complicates the diagnosis and necessitates extensive and
highly specific serologic, nucleic acid, and epidemiologic data. Nonetheless, mycoplasmas
by themselves can cause acute and chronic diseases at multiple sites with
wide-ranging complications and have been implicated as cofactors in disease. Recently,
mycoplasmas have been linked as a cofactor to AIDS pathogenesis and to malignant
transformation, chromosomal aberrations, the Gulf War Syndrome, and other unexplained and
complex illnesses, including chronic fatigue syndrome, Crohn's disease, and various arthritides
(4-8). Even with mounting evidence of their pervasive and pathogenic potential,
mycoplasmas still evoke the image of a group of obscure or impotent microorganisms. Yet they
are evolutionarily advanced procaryotes (9-11), and their
elite status as "next generation"
bacterial pathogens necessitates new paradigms in
fully understanding their disease potential.
Mycoplasmas, which lack cell walls but possess distinctive sterol-containing plasma
membranes, are taxonomically separated from other bacteria and belong to the class Mollicutes
(mollis, soft; cutis, skin). Mollicutes, a term that includes the cell wall-less procaryotes assigned to numerous
genera under the class Mollicutes and is frequently used interchangeably with mycoplasmas, are unusual
for other biological reasons as well. They are evolutionary descendants of the low G+C containing
gram-positive bacteria and, through chromosome reduction, represent
the smallest self-replicating life forms. Their
streamlined genome size, which illustrates extreme biological gene economy, imposes
complex nutritional requirements, such as dependence on external
supplies of biosynthetic precursors, including amino acids, nucleotides, fatty acids, and sterols. This limited coding capacity dictates
for mycoplasmas a parasitic way of life that few pathogenic micro-organisms can claim. Therefore,
the view that pathogenic mycoplasmas can grow
"independently" requires an appreciation of their
fastidious nature and their intimate dependence upon the host. Because of these properties,
pathogenic mycoplasmas are among the most difficult micro-organisms to grow from clinical specimens
and remain frequent contaminants of primary and continuous eucaryotic cell lines and tissue
cultures (12). In some instances, mycoplasma contamination is obvious since infected eucaryotic cells exhibit
aberrant growth, metabolism, and morphology. However, mycoplasmas often establish covert and
chronic infections of target cells that lead to either invalid and misleading data or
introduction of mycoplasmas or their products into reagents dedicated to therapeutic or
research purposes. The recent emphasis on isolating viral
agents, such as human immunodeficiency virus (HIV)-1, from human primary
lymphocytic cells has also demonstrated the frequent cocultivation
of mycoplasmas of human origin. Often, the unwanted sources of exogenous mycoplasmas are
serum products and filter-"sterilized"(450
nm) solutions; cross-contamination by already infected
cell cultures, viral stocks, or immunologic preparations; breaks in technique, including aerosols from the
respiratory tract or by mouth pipetting; ignorance of the mycoplasma problem; or scientific indifference.
Detailed up-to-date reviews describing the biological and pathogenic properties of
mycoplasmas have been published (1,2,13,14). Our intention here is to provide a concise historical perspective of
the role of mycoplasmas in human disease; highlight the discoveries of new
Mycoplasma species and their association with human illness and host conditions that present problems in detection and
treatment; describe selected biological properties of mycoplasmas consistent with their intimate host
relationship and possible mechanisms of pathogenicity; and address recent controversies associated
with mycoplasmas as emerging infectious agents. Renewed attention to these issues may provide
the impetus to demystify mycoplasmas and improve their
standing as genuine, card-carrying pathogens.
The earliest reports of mycoplasmas as infectious agents in humans appeared in the 1930s
and 1940s. At that time, primary atypical pneumonia was associated with an infectious
agent that because of its minute size and innate biological properties unknown at that time, passed
through bacteria-retaining filters, resisted
penicillin and sulfonamide therapies, and adapted to
growth in embryonated eggs and tissue culture cells.
Correlations between the etiologic agent of "walking pneumonia"
with viruses, L-forms, and pleuropneumonia-like agents (referred to as
PPLOs in publications and textbooks of that era) were frequent and often misleading. Finally, definitive studies in the early
1960s established Mycoplasma pneumoniae as the singular cause of cold agglutinin-associated
primary atypical pneumonia (2). Today M.
pneumoniae remains an important cause of pneumonia and
other airway disorders, such as tracheobronchitis and pharyngitis
(13,14), and is associated with extrapulmonary manifestations, such as hematopoietic, exanthematic, joint, central nervous
system, liver, pancreas, and cardiovascular syndromes (15).
The confusion associated with M.
pneumoniae-mediated infections has recurred many times
with other mycoplasmas, whose detection in clinical specimens through culture, antibody, or
DNA-based testing is frequently dismissed as "only mycoplasmas" even when they appear to be the
primary pathogens. Two mycoplasmas commonly found in the urogenital tracts of healthy persons
are Mycoplasma hominis and Ureaplasma
urealyticum. However, over the years, the
pathogenic roles of these mycoplasmas have been proven in adult urogenital tract
diseases, neonatal respiratory infections, and a range of other diseases usually in immunocompromised patients (2).
Several recent examples illustrate the increasing impact of
Mycoplasma species on emerging diseases.
Mycoplasma fermentans strains were first isolated from the lower genital tract of both adult men
and women in the early 1950s, but their role in classic lower genital tract disease
has not been established (16). Reports in the
1970s of M. fermentans in the joints of rheumatoid arthritis patients and in the
bone marrow of children with leukemia raised expectations for
its pathogenic potential (17,18); these findings have not been adequately confirmed. Sufficient
evidence, however, has accumulated recently to
establish an important and emerging role for M.
fermentans in human respiratory and joint
diseases. For example, M. fermentans has been detected by specific gene amplification techniques such as polymerase
chain reaction (PCR) in the synovial fluid of patients with inflammatory arthritis, but not in the joints
of patients with juvenile or reactive arthritis (19). In two other studies using PCR,
M. fermentans was identified in the upper respiratory tract of 20% to 44% of both healthy and HIV-infected
patients (20,21) and was associated with acute respiratory distress syndrome in
nonimmunocompromised persons (22).
Mycoplasma genitalium was detected in the urogenital tract of two patients with
nongonococcal urethritis in 1981 (23), but for more than a
decade, very little was known about its host distribution
and pathogenicity. Early experimental studies established that the organism caused lower genital
tract infections in both male and female chimpanzees, with extensive urethral colonization in males
and apparent tissue invasion, eventually leading to overt bacteremia (24). However, the fastidious
growth requirements of M. genitalium from human hosts severely limited further study until the advent
of molecular detection techniques. Specific sequences in the 140 kDa adhesin protein gene of
M. genitalium were selected as targets in a PCR-based detection assay (25,26). Subsequent application
of these techniques in cases of acute nongonococcal urethritis, not including those of patients colonized
or infected with Chlamydia trachomatis, has provided mounting evidence for the
involvement of M. genitalium as an etiologic agent of
this disease (27-29). Also, M. genitalium has been
suspected in chronic nongonococcal urethritis and pelvic inflammatory disease (30).
The discovery in 1988 of M.
genitalium strains in human nasopharyngeal throat
specimens, where they were frequently mixed with strains of
M. pneumoniae, not only changed dramatically the
concept of host distribution of M.
genitalium but also prompted critical questions about the role of
this mycoplasma in human respiratory disease (31). However, the immunologic cross-reactivity
between M. genitalium and M.pneumoniae and the inability of most conventional diagnostic serologic tests
to conclusively identify M. genitalium have complicated its delineation in acute human
respiratory disease. PCR assays specific for the organism have detected
M. genitalium in throat specimens of patients infected with HIV-1 (32). However, these probes have not been applied to control groups
and patients in outbreaks of acute respiratory disease
and/or pneumonia to determine whether M.
genitalium alone is an etiologic agent in respiratory infections.
M. genitalium has been implicated as an etiologic agent in certain human joint diseases.
This clinical correlation began with the observation of a mixed infection
of M.pneumoniae and M.
genitalium in synovial fluid specimens of a nonimmunocompromised patient after an acute
respiratory infection (33). A predominant role was not established for either
Mycoplasma species in the initial
respiratory disease or in the joint manifestations, although evidence to implicate postinfectious autoimmunity
to both organisms was described. These findings prompted a PCR assay on synovial fluids from
patients with various arthritic syndromes, which presented case reports on two of 13 patients with
M. genitalium detected in joint fluids (34).
Another area of emerging mycoplasmal infections concerns immunodeficiency. Although
patients with congenital or acquired disorders of antibody production are susceptible to a wide variety
of microbial infections, the unique susceptibility of such patients to
mycoplasmal infections is a growing concern, especially considering the number of occurrences, the types of mycoplasmas involved, and
the difficulties posed in the therapeutic management of such infections. In
addition, the increased use of prolonged or permanent immunosuppressive chemotherapy required for patients undergoing tissue
or organ transplantation or treatment of various
malignant diseases has also increased the risk for mycoplasmal infections from mycoplasmas that are part of the normal human mollicute flora to
those acquired through animal contact.
The association between immunodeficiency and mycoplasmal infections was first reported in
the mid 1970s in patients with primary hypogammaglobulinemia and infection with
U. urealyticum, M. pneumoniae, Mycoplasma
salivarium, and M. hominis that localized in joint tissue, frequently
with destructive arthritis. Similar joint infections in hypogammaglobulinemic patients with
these mycoplasmal species continue to be reported (35). Since most of these mollicutes, with the
possible exception of M. pneumoniae, occur as part of the normal human flora, the origin of such joint
infections is considered endogenous. Patients with hypogammaglobulinemia and other antibody deficiencies
are also especially susceptible to mycoplasmal infections of the upper respiratory and urinary
tracts caused most frequently by M.
pneumoniae or U. urealyticum, respectively (36).
Mycoplasmal infections following organ transplantation and immunosuppressive
chemotherapy were observed in the early 1980s, with
both M. hominis and U. urealyticum reported most
often (37-39). Although these infections most likely originated from the patient's
normal microbial flora, a recent report of donor transmission
of M. hominis to two lung allograft recipients
(40) suggests that donor tissue may be a more important
factor in transplant infections than currently recognized.
While patients with antibody defects or those receiving immunosuppressive drugs appear to be
the most susceptible to infections with
mycoplasmas present in healthy tissues, emerging evidence
indicates that contact with other mycoplasmas in the environment is an important hazard. For
example, the direct isolation of a feline
mycoplasma (M. felis) from the joint of a hypogammaglobulinemic patient
with septic arthritis was recently reported (41), with suspected transmission occurring through a cat bite
6 months before the onset of arthritis. Other examples include fatal septicemia caused
by M. arginini, a common animal mycoplasma, from blood and multiple tissue sites in a slaughter
house employee who had advanced non-Hodgkin's lymphoma
and hypogammaglobulinemia (42), and a septicemic infection with
a canine mycoplasma (M. edwardii) in a patient with advanced AIDS (M.K.York, pers. comm.).
One of the most critical aspects of mycoplasmal infections in immunodeficient patients is
the frequent inability to control such infections with appropriate broad spectrum antibiotics. Although
the tetracyclines and erythromycins are effective chemotherapeutic agents for many
mycoplasmal infections, M. fermentans and
M. hominis strains are usually resistant to erythromycin,
and tetracycline-resistant strains of M.
hominis andU. urealyticum have been reported from the
lower urogenital tract of patients. However, these antibiotics and most other broad spectrum agents
have limited mycoplasmacidal activity in vivo, and their efficacy eventually depends on an intact
host immune system to eliminate the mycoplasmas. Most hypogammaglobulinemic patients lack the
ability to mount a strong antibody response. Guidelines for managing such mycoplasmal infections in
patients with immune defects should include immediate in vitro testing of the isolated mollicute against a
wide range of antibiotics; expeditious administration of
the antibiotic by the most appropriate route (intravenously, if warranted); prolonged therapy terminated only if
there is no rapid clinical or microbiological response; and possibly administration of
intravenous immunoglobulin (35,36). Clinical management of mycoplasmal infections in transplant patients is more difficult since
immunoglobulins may enhance graft or organ rejection. In the absence of suitable mycoplasmacidal
chemotherapeutic agents, vigorous and sustained chemotherapy with the most active antibiotic is the current method
Mechanisms of Pathogenicity
Many mycoplasmal pathogens exhibit filamentous or flask-shaped appearances and
display prominent and specialized polar tip organelles that mediate attachment to host target cells
(43,44). These tip structures are complex, composed of a network of interactive proteins, designated
adhesins, and adherence-accessory proteins (Figure 1, [14,43]). These proteins cooperate structurally
and functionally to mobilize and concentrate adhesins at the tip and permit mycoplasmal colonization
of mucous membranes and eucaryotic cell surfaces, probably through host sialoglycoconjugates
and sulfated glycolipids (Figure 2, [14,43,45]). It appears that mycoplasmal cytadherence-related
proteins represent a superfamily of genes and proteins that have been conserved through horizontal
gene transfer from an ancestral gene family. This protein network resembles a specialized
cytoskeleton-like apparatus, which may represent the precursor to mammalian cytoskeletal and
extracellular matrix-like complexes (14). Other
Mycoplasma species lack distinct tip structures yet are capable
of cytadherence, and they may use related genes or proteins or alternative mechanisms of
Figure 1. Transmission electron photomicrographs of the specialized tip organelle of cytadherence-positive
M. pneumoniae demonstrating a) truncated structure with nap, b) clustering of cytadherence-related proteins (P1, B, C, P30) at the tip based on
immunolabeling with ferritin and colloidal gold and crosslinking studies, and c) Triton X-100-resistant, cytoskeleton-like, structure with distinct
bleb and parallel filaments (14,43,45,46).
Figure 2. Transmission electron photomicrograph of a hamster trachea ring infected with
M. pneumoniae (43). Note the orientation of the mycoplasmas through their specialized tiplike organelle, which permits close association with the respiratory epithelium.
M, mycoplasma; m, microvillus; C, cilia.
The family of mycoplasmal genes and proteins involved in cytadherence has been studied
most extensively in M. pneumoniae (14,43,46-48). Noncytadhering phenotypes that arise
through spontaneous mutation at high frequency have been categorized into mutant classes on the basis
of distinct protein profiles. These noncytadhering mycoplasmas cannot synthesize specific
cytadherence-related proteins or are unable to stabilize
them at the tip organelle, which leads to abnormal
anatomical tip structures and avirulence (43). Spontaneous reversion to the cytadhering phenotype
is accompanied by the reappearance of the implicated proteins, restoration of structurally
and functionally intact tips, and return of full infectivity (43). Similar
cytadherence-related genes and proteins have been reported for
M. genitalium on the basis of biochemical,
immunologic, and genetic analyses (25,49,50). Furthermore, striking similarities exist in the order of operons
that comprise the cytadherence-related genes and the organization of these genes within each operon
of M. pneumoniae and M.
genitalium (14,50,51). These similarities reinforce the
unexpected coisolations of M. genitalium,
along with M. pneumoniae, from the nasopharyngeal throat swabs of patients with acute respiratory
diseases and from synovial fluids of patients with arthritis as described in the previous section (31,33).
The isolation of M. pneumoniae from the human urogenital tract (52) further suggests that
these mycoplasmas have evolved parasitic strategies that include overlapping tissue tropisms as
determined by the genetic and chemical relatedness of their cytadherence genes and proteins (14,25,43,50,51).
The recent use of transposon mutagenesis to generate
M.pneumoniae and M.
genitalium transformants displaying cytadherence-deficient phenotypes should further clarify the relationships between
the cytadherence-related genes and proteins and identify additional sites previously unlinked
to cytadherence (46,53).
An interesting feature of specific M.
pneumoniae and M. genitalium adhesins is their multiple
gene copy nature (14,43,54,55,56). Although only one full-length copy of the adhesin structural genes
exists in adhesin-related operons, precise regions of these adhesin genes are detected as single
genomic copies, while other regions occur as closely homologous, but not identical, multiple copies. In
other words, multiple truncated and sequence-related copies of the adhesin genes are dispersed
throughout the genome, which could generate adhesin variation through homologous recombination.
Consistent with this possibility is the existence of restriction fragment length polymorphisms in
the adhesin genes of human clinical isolates of
M. pneumoniae and M. genitalium, reflected by
sequence divergence in the multiple-copy regions of the adhesin genes (56-59). It appears that a repertoire
of partial adhesin-related gene regions serves as a reservoir to regulate the structural and
functional properties of mycoplasmal adhesins through recombination events, which may lead to
circumvention of the host immune response. Mechanisms of phase and antigenic variation are likely to occur in
which mycoplasmal adhesins exhibit altered specificities and affinities, as determined by the organization
of constant and variable adhesin gene sequences. Therefore, despite their small genomes,
pathogenic mycoplasmas facilitate DNA rearrangements through repetitive gene sequences, thus
promoting genetic diversity and maximizing the coding potential of their limited genomes. The
immunodominant epitopes of the mycoplasmal adhesins appear not to be identical to the adherence-mediating
domains (13). The latter are in part encoded by single copy regions of the adhesin genes and are highly
conserved, which reinforces their essential role in mycoplasmal recognition of host cell receptors and
colonization (60,61). Host immunoresponsiveness directed at the noncytadherence-mediating variable regions
is unlikely to generate effective
cytadherence-blocking antibodies, which may in part clarify the
observed high reinfection rates of patients. Thus, the grouping of clinical isolates of
M. pneumoniae into two categories, on the basis of sequence divergence in the multiple-copy regions of the adhesin gene
(56-59), along with the immune status of the population, may explain the
epidemiologic patterns of M. pneumoniae reported over the years.
Another characteristic of the cytadherence-related proteins is their proline-rich
composition, which markedly influences protein folding and binding. Several reports have established
the importance of these proline-rich domains in mycoplasmal cytadherence and virulence (47,48,62,63),
and recent evidence further suggests that mycoplasmal peptidylprolyl isomerases,
i.e., cyclophilins, are critical in regulating the conformation and function of the mycoplasmal cytadherence-related
tip organelle, colony morphology, and growth (14,64). In addition to this proline-rich property, one of
the most unusual features of the adhesins is their extensive sequence homology to
mammalian structural proteins (1,14,33,43,47,48). This molecular mimicry is especially interesting since it has been
suggested for decades that mycoplasmas provoke an antiself response that triggers immune disorders,
although the basis for the induction has been elusive (65). Patients with documented
M. pneumoniae respiratory infections demonstrate seroconversion to myosin, keratin, and fibrinogen (33) and
exhibit extrapulmonary manifestations, such as exanthems and
cardiac abnormalities. Furthermore, a classic example of bacteria-mediated
autoimmune disorders is the development of acute rheumatic
fever following streptococcal infection (66). Antistreptococcal antibodies reactive against
ahelical coiled-coil regions of the M protein crossreact with heart myosin, tropomyosin, and mycoplasmal
adhesins (14,66). In the latter case, these mycoplasmal adhesins exhibit amino acid sequence homologies
with human CD4 and class II major histocompatibility complex lymphocyte proteins, which could
generate autoreactive antibodies and trigger cell killing and immunosuppression (67,68). Also,
mycoplasmas may serve as B-cell and T-cell mitogens and induce autoimmune disease through the activation of antiself T cells or polyclonal B cells. The multiorgan protean
manifestations of mycoplasmal infections in humans are consistent with the pathogenesis of
autoimmunity. Furthermore, the ability of mycoplasmas to induce a broad range of
immunoregulatory events, mediated by cytokine production and direct effects on macrophages, B and T cells, and glial cells, is evidence that mycoplasmas
possess the attributes of primary mediators of pathogenesis (1,2,12,69). For example, cytokine production
and lymphocyte activation may either minimize disease through the activation of host
defense mechanisms or exacerbate disease through lesion development (69,70). Also, a superantigen derived
from Mycoplasma arthritidis, a mycoplasma pathogenic for rodents, induces arthritis and chronic
disease manifestations (69). It has been suggested that related superantigen-like molecules may exist
in mycoplasmas of human origin triggering autoimmune and other inflammatory pathologies.
It appears that cytadherence is the initial step in the virulence process of pathogenic
mycoplasmas (Figure 2) and precedes a spectrum of subtle or overt host cell responses. In specific instances,
distinct cytopathology correlates with the infecting
Mycoplasma species, the number of adherent mycoplasmas, the length of coincubation, the induction of proinflammatory cytokines, and the age
and immune status of the patient. For example, the exacerbation of clinical syndromes may correlate
with a history of mycoplasmal infection as observed in patients with recurrent
M. pneumoniae exposures (2,13). Also, the elevated expression of proinflammatory cytokines associated with
mycoplasmal disease pathogenesis may coincide with the intensity of the symptoms. In other cases, chronic
disease or no obvious signs or symptoms of disease accompany mycoplasmal infection.
Other biological properties of mycoplasmas have been implicated as virulence determinants
and include 1) generation of hydrogen peroxide and superoxide radicals by adhering mycoplasmas,
which induces oxidative stress, including host cell membrane damage; 2) competition for and depletion
of nutrients or biosynthetic precursors by mycoplasmas, which disrupts host cell maintenance
and function; 3) existence of capsule-like material and electron-dense surface layers or structures,
which provides increased integrity to the mycoplasma surface and confers immunoregulatory activities;
4) high-frequency phase and antigenic variation, which results in surface diversity and possible
avoidance of protective host immune defenses; 5) secretion or introduction of mycoplasmal
enzymes, such as phospholipases, ATPases, hemolysins, proteases, and nucleases into the host cell milieu,
which leads to localized tissue disruption and disorganization and chromosomal aberrations; and
6) intracellular residence, which sequesters mycoplasmas, establishes latent or chronic
states, and circumvents mycoplasmicidal immune mechanisms and selective drug therapies (1,2,71,72).
Whether pathogenic mycoplasmas enter and survive within mammalian cells has been debated for many years.
Consistent with this possibility, mycoplasmas exhibit limited biosynthetic capabilities; are
highly fastidious and dependent upon the host microenvironment and complex culture medium for
growth; have been observed in intimate contact with mammalian cell surfaces and within target cells; may
be capable of initiating fusion with host cells
through their cholesterol-containing unit membranes;
and survive long-term recommended antimicrobial treatment in humans and tissue cultures.
Recent sightings of intact mycoplasmas throughout the cytoplasm and the perinuclear regions of tissue
cells from infected patients and in cell cultures, along with evidence that mycoplasmas are capable of
long-term intracellular survival and replication in vitro, offer an additional dimension to the
pathogenic potential of mycoplasmas (4,14,72,73).
The Latest Controversies: Food for Thought or the Twilight Zone
On the basis of the above information, the virulence strategies displayed by mycoplasmas are
likely the summation of a multitude of biological activities (1). Since no obvious single or group
of mycoplasmal properties inextricably correlates with disease manifestations, the proof
that mycoplasmas are card-carrying pathogens necessitates thorough and highly specific
microbiological, epidemiologic, and diagnostic criteria; detailed descriptions of biochemical, genetic, and
immunologic characteristics that distinguish virulent and avirulent mycoplasmas; and reproducibility of
the symptoms of disease in experimental animal models or in the natural spread of
infection among susceptible populations. The portfolio of available evidence
concerning mycoplasma-mediated disease pathogenesis
is limited. These scientific shortcomings precipitate misconceptions concerning mycoplasmas
as singular agents of infectious diseases, as
putative cofactors in the progression of other diseases, and
as universal contaminants of cell cultures. Clearly, multiple pathways of interaction with target
cells appears to be the modus operandi of the
Mycoplasma species. With this conceptual
scientific framework as a background, five
recently proposed and controversial associations of mycoplasmas
to human diseases are worth noting.
The role of mycoplasmas in accelerating the progression of AIDS could not have begun under
more baffling and circuitous conditions. A virus-like agent that arose through transfection of NIH 3T3
cells with DNA from Kaposi sarcoma tissues of AIDS patients was later shown to be
M. fermentans. The spotted history of M.
fermentans in rheumatoid arthritis and leukemia and its
frequent contamination of cell cultures, along with its contemporary link to AIDS, have been considerable impediments
to overcome in its elevation to pathogenic status. However,
careful and convincing independent studies by
several laboratories have implicated M.
fermentans as a cause of systemic infections and organ
failure in AIDS patients (4,74). The isolation of
M. fermentans from blood and urine samples of
HIV-infected persons, its detection by PCR and immunohistochemistry in multiple tissue sites at various stages
of AIDS, and its ability to stimulate CD4+ lymphocytes and other
immunomodulatory activities implicate this
Mycoplasma species as a cofactor in AIDS. Consistent with this possibility,
M. fermentans has been shown to act synergistically with HIV to enhance cytopathic effects on human CD4+
lymphocytes. Coincident with these studies, a new
Mycoplasma species, Mycoplasma
penetrans, also has emerged as a potential cofactor in AIDS progression (75,76). Its isolation almost exclusively from the urine of
HIV-infected patients, the extraordinarily high prevalence of antibodies against this mycoplasma in
HIV-infected patients and not in HIV-seronegative persons, and its capacity to invade target cells
and activate the immune system of HIV-infected patients at various stages
of disease correlate with a synergistic role with HIV. Other mycoplasmas, including
M. genitalium and Mycoplasma pirum,
have also been isolated from AIDS patients and implicated as potential cofactors. However, the
proposed role of mycoplasmas as infectious agents and cofactors in AIDS-related disorders still remains
a hypothesis without definitive proof. If cofactors of HIV are essential to the development of late
stages of HIV-mediated disease, mycoplasmas possess all the prerequisite properties of the
consummate helper. Their ability to establish covert or overt chronic and persistent infections with
concomitant activation of the immune system, stimulation of cytokine production, and induction of oxidative
stress correlate with increased HIV replication and disease progression. Are mycoplasmas irrelevant
to AIDS, or are the clinical and microbiological correlations sufficient to imply intimate
relationships between HIV and mycoplasmas, especially as the infected host undergoes immunologic distress?
As early as the mid-1960s, mycoplasma-infected cell lines were associated with
chromosomal aberrations, altered morphologies, and cell transformation (77,78). These abnormal oncogenic
cell traits continued even after the apparent elimination of mycoplasmas, and
evidence implied increased tumorigenicity of these transformed cells in animals. This issue has been revisited in
studies demonstrating that longterm, persistent mycoplasmal infection of mouse embryo cells
initiated a multistage cellular process that resulted in irreversible cell transformation,
karyotypic alterations, and tumorigenicity in nude mice (6). Do these oncogenic events associated with
mycoplasma-mammalian cell coincubation relate to the ontogeny of human cancers?
Gulf War Syndrome
One of the most controversial current medical issues is whether the multiple acute and
chronic symptoms found in veterans of the Persian Gulf War were caused by chemical exposure,
infectious agents, or psychological problems, or whether a Gulf War Syndrome exists at all. The clinical
illness comprises a collection of symptoms, including chronic fatigue, joint pain, headaches, and skin
rashes. One study suggests that pathogenic mycoplasmas are responsible for a large number of cases
among veterans, on the basis of DNA hybridization and the responsiveness of veterans to prolonged
antibiotic treatment (5). Even though the experimental evidence is sparse and incomplete and
well-controlled and detailed studies by independent laboratories are needed, if the Gulf War Syndrome has
infectious causes, mycoplasmas with their requisite biological credentials are potential candidates.
Several epidemiologic studies correlate respiratory infections with exacerbation of Crohn's
disease and other chronic inflammatory bowel diseases (7,79). Acute onset gastrointestinal symptoms
in patients with these diseases are accompanied by seroconversion to specific viral or
M. pneumoniae antigens. As indicated earlier, mycoplasmas can elicit pleiotropic immune responses and are
difficult to eliminate in patients despite appropriate antibiotic treatment. Steroid therapy to
control gastrointestinal symptoms in these patients, along with the multifaceted biological
properties associated with pathogenic mycoplasmas, may precipitate the onset of acute exacerbations of
chronic inflammatory bowel disease.
Rheumatoid Arthritis and Other Human Arthritides
The occurrence of various
Mycoplasma and Ureaplasma species in joint tissues of patients
with rheumatoid arthritis, sexually transmitted reactive arthritis, and other human arthritides can
no longer be ignored (8). A clinical trial of longterm (6 to 12 months) antibiotic (doxycycline) therapy
before cartilage destruction might prove beneficial in managing such frequent and often
Extensive clinical and microbiological evidence indicates that mycoplasmas alone can elicit
a spectrum of illness for which no other agents are incriminated. The eradication of these
pathogenic mycoplasmas from various tissue sites requires an intact and functional immune system,
although persons with fully competent immune systems may have difficulty eliminating mycoplasmas,
even with recommended prolonged drug therapy. Nonetheless, mycoplasmas are still viewed
as subordinates to other infectious agents and are relegated to a category of commensals that
unwittingly cause disease in patients whose immune systems offer little resistance to microbial stress
The fundamental importance of mycoplasmas in specific diseases of humans, animals, insects,
and plants is irrefutable, and their unique biological properties are consistent with their
intimate association with host target cells. These remarkable bacteria must continue to receive the
scientific attention of mycoplasmologists, cell culturists, clinicians, immunologists, and DNA sequencers
who most recently are compiling extensive databases that may eventually dissect every
approachable mycoplasmal element that defines their biological and genetic being. Nonetheless,
mycoplasmas remain mysterious and enigmatic, and the available data and proposed hypotheses that
correlate mycoplasmas with disease pathogenesis range from definitive, provocative, and titillating to
inconclusive, confusing, and heretical. Controversy seems to be a recurrent companion
of mycoplasmas, yet good science and openmindedness should overcome the legacy that has
burdened them for decades.
Acknowledgments This study was supported in part by NIH grants AI 27873, AI 32829 and AI 41010.
Dr. Baseman is professor and chair, Department of Microbiology, University of Texas Health Science Center,
San Antonio. His research focuses on pathogen-host cell interactions with special interest in defining the biology
and virulence determinants of mycoplasmas pathogenic for humans.
Dr. Tully heads the Mycoplasma Section, Laboratory of Molecular Microbiology, National Institute of Allergy
and Infectious Diseases, Frederick, Maryland. His interest covers the host distribution, pathogenicity, and taxonomy
Address for correspondence: Joel B. Baseman, Department of Microbiology, The University of Texas
Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7758; fax: 210-567-6491;
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Mycoplasma pneumoniae and Mycoplasma
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34. Taylor-Robinson D, Gilroy CB, Horowitz S, Horowitz J.
Mycoplasmagenitalium in the joints of two patients with arthritis.
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Mycoplasma genitalium protein resembling the
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