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Physiol Rev
83: 417– 432, 2003; 10.1152/physrev.00030.2002.
Interaction of Mycoplasmas With Host Cells
SHLOMO ROTTEM
Department of Membrane and Ultrastructure Research,
The Hebrew University-Hadassah Medical School, Jerusalem, Israel
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I. Introduction
II. Adherence to Host Tissues
A. Adhesins
B. Accessory proteins
C. Receptors
III. Invasion Into Host Cells
A. Invasins and receptors
B. Changes in the host cell cytoskeleton
C. Signal transduction
D. Survival and multiplication within host cells
IV. Fusion With Host Cells
A. Factors mediating fusion
B. Molecules implicated in fusion
V. Possible Mechanisms of Damage to Host Cells
A. Competition for precursors
B. Damage induced by adherence
C. Damage induced by fusion
D. Cytopathic effects
VI. Circumventing the Host Immune System
VII. Modulating the Immune System
A. Modulatory effects on monocytes and macrophages
B. Characterization of modulins
C. Lipoproteins
D. Superantigens
E. Membrane lipids
F. Signaling pathways by modulins
G. Mitogenic activity
H. Oncogenic activity
VIII. Conclusions
Rottem, Shlomo. Interaction of Mycoplasmas With Host Cells. Physiol Rev 83: 417– 432, 2003; 10.1152/physrev.00030.2002.—-The mycoplasmas form a large group of prokaryotic microorganisms with over 190 species
distinguished from ordinary bacteria by their small size, minute genome, and total lack of a cell wall. Owing to their
limited biosynthetic capabilities, most mycoplasmas are parasites exhibiting strict host and tissue specificities. The
aim of this review is to collate present knowledge on the strategies employed by mycoplasmas while interacting with
their host eukaryotic cells. Prominant among these strategies is the adherence of mycoplasma to host cells,
identifying the mycoplasmal adhesins as well as the mammalian membrane receptors; the invasion of mycoplasmas
into host cells including studies on the role of mycoplasmal surface molecules and signaling mechanisms in the
invasion; the fusion of mycoplasmas with host cells, a novel process that raises intriguing questions of how
microinjection of mycoplasma components into eukaryotic cells subvert and damage the host cells. The observations of diverse interactions of mycoplasmas with cells of the immune system and their immunomodulatory effects
and the discovery of genetic systems that enable mycoplasmas to rapidly change their surface antigenic composition
have been important developments in mycoplasma research over the past decade, showing that mycoplasmas
possess an impressive capability of maintaining a dynamic surface architecture that is antigenically and functionally
versatile, contributing to the capability of the mycoplasmas to adapt to a large range of habitats and cause diseases
that are often chronic in nature.
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0031-9333/03 $15.00 Copyright © 2003 the American Physiological Society
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I. INTRODUCTION
A. Adhesins
M. pneumoniae is the most extensively studied system with respect to the adhesins and receptors. This
organism has a polar, tapered cell extension at one of the
poles containing an electron-dense core in the cytoplasma
(Fig. 1). This structure, termed the tip organelle, functions
both as an attachment organelle and as the leading end in
gliding-type motility. A surface 169-kDa protein designated P1 (47) and a 30-kDa protein designated P30 (19)
are densely clustered at the tip organelle of virulent M.
pneumoniae (Fig. 2), providing polarity to the cytadherence event. Both proteins elicit a strong immunological
response in convalescent-phase sera from humans and
experimentally infected hamsters, and anti-P1 or anti-P30
monoclonal antibodies block this cytadherence (4, 81).
Neither P1 nor P30 mutants cytadhere (50, 103). At
present, it is apparent that P1 is the adhesin of M. pneumoniae and P30 is a protein associated with the adherence process. Nonetheless, the exact role of P30 in ad-
II. ADHERENCE TO HOST TISSUES
Many animal mycoplasmas depend on adhesion to
host tissues for colonization and infection. In these mycoplasmas adherence is the major virulence factor, and
adherence-deficient mutants are avirulent (6, 81). The
best studied adherence systems are those of M. pneumoniae, the causative agent of primary atypical pneumoPhysiol Rev • VOL
FIG. 1. Adherence of Mycoplasma pneumoniae to host cells. A:
scanning electron microscopy of filamentous M. pneumoniae grown in
broth medium. (Micrograph courtesy of S. Razin, The Hebrew University-Hadassah Medical School.) B: transmission electron microscopy of
flask-shaped M. pneumoniae (M) attached by the terminal tip organelle
(arrow) to ciliated mucosal cells. (Micrograph courtesy of A. M. Collier,
The University of North Carolina School of Medicine.) Magnification: A,
⫻10,000; B, ⫻36,000.
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Mycoplasmas (class Mollicutes) are the smallest and
simplest self-replicating bacteria (82). These microorganisms lack a rigid cell wall and are bound by a single
membrane, the plasma membrane. Wall-less bacteria
were first described 100 years ago, and now over 190
species, widely distributed among humans, animals, insects and plants, are known (88). The lack of a cell wall is
used to distinguish these microorganisms from ordinary
bacteria and to include them in a separate class named
Mollicutes. Most human and animal mollicutes are Mycoplasma and Ureaplasma species of the family Mycoplasmataceae. Because mycoplasmas have an extremely small
genome (0.58 –2.20 Mb compared with the 4.64 Mb of
Escherichia coli), these organisms have limited metabolic
options for replication and survival. Phylogenetically, the
mollicutes are related to Gram-positive bacteria from
which they developed by genome reduction (43). Therefore, the mollicutes are not at the root of the phylogenetic
tree but are most probably late evolutionary products (43,
61). The smallest genome of a self-replicating organism
known at present is the genome of Mycoplasma genitalium (0.58 Mb; Ref. 34). Comparative genomic studies
suggested that the genome of this organism still carries
almost double the number of genes included in the minimal gene set essential for cellular function (61, 74).
Owing to their limited biosynthetic capabilities, most
mycoplasmas are parasites exhibiting strict host and tissue specificities (82, 89). The mycoplasmas enter an appropriate host in which they multiply and survive for long
periods of time. These microorganisms have evolved molecular mechanisms needed to deal with the host immune
response and the transfer and colonization in a new host.
These mechanisms include mimicry of host antigens, survival within phagocytic and nonphagocytic cells, and generation of phenotypic plasticity. The major question is
whether mycoplasmas cause damage to the host cells and
to what extent the damage is clinically apparent. Mycoplasmas have long resisted detailed analyses because of
complex nutritional requirements, poor growth yields,
and a paucity of useful genetic tools. Although questions
still far outnumber answers, significant progress has been
made in identifying the mechanisms by which mycoplasmas interact and damage eukaryotic host cells.
nia in humans, which inhabits the respiratory tract, and
M. genitalium, which preferentially colonize the urogenital tract. These organisms exhibit the typical polymorphism of mycoplasmas, with the most common flask and
filamentous shaped (Fig. 1). Cytadherence of these organisms to cells in the respiratory or urogenital epithelium is
an initial and essential step in tissue colonization and
subsequent disease pathogenesis (5).
INTERACTIONS OF MYCOPLASMAS WITH HOST CELLS
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FIG. 2. Schematic diagram of the location of the
major cytadherence and accessory proteins in M.
pneumoniae. [Modified from Balish and Krause (4).]
B. Accessory Proteins
The isolation and characterization of M. pneumoniae
mutants that possess P1 and P30, yet fail to cytadhere,
suggest that the tip-mediated adherence of M. pneumoniae to eukaryotic target cells is more complex (50,
81). Two groups of accessory proteins, the first including
a 40-kDa and a 90-kDa proteins (P40 and P90), and the
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second, proteins HMW1-HMW3, were described (25, 50,
51). These proteins are not adhesins, but the loss of one of
them is associated with the inability of M. pneumoniae to
cytadhere, whereas its regain results in reversion to a
cytadherence-positive phenotype (81). P40 and P90 were
found to be surface proteins localized mainly at the tip
organelle (Fig. 2). These proteins are closely associated
with P1 (53, 54) but are not directly involved in receptor
binding. Although P1 is present on the surface of strains
lacking P40 and/or P90, it is not clustered at the tip
organelle, but scattered on the surface of the mycoplasma
(50). Since P40 and P90 were responsible for the association of P1 with M. pneumoniae Triton shell, it has been
suggested that the P1 is kept in the membrane by P40 and
P90 in a way that allows it to closely interact with the
cytoskeleton forming or associated proteins.
In certain noncytadhering mutant strains another
group of proteins, designated HMW1, HMW2, and HMW3,
is missing, while in the corresponding revertants, cytadherence was regained. These proteins are coded by two
unlinked genetic loci in the M. pneumoniae chromosome.
HMW1 (112 kDa) and HMW3 (74 kDa) are members of a
family of mycoplasma proteins that share acidic residues
and an internal proline-rich domain in repeated motifs
(25, 50). The proline-rich domains probably impart an
extended conformation to the protein backbone, while
the hydrophobic surface provided by the proline residues
may contribute to interactions with other mycoplasma
proteins. Similar to their counterparts lacking P40 and
P90, mutants devoid of HMW1-HMW3 are avirulent, cytadhere very poorly, and fail to cluster P1 at the tip organelle
(40, 79). Furthermore, their tip organelle lacks the characteristic truncated appearance seen in wild-type M.
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herence is not yet fully understood. The P30 mutants
appear to localize the adhesin P1 to the tip organelle,
suggesting that P30 is required for P1 function rather than
trafficking to the tip. Recently, it has been shown that P30
plays a role in cell development because its absence leads
to morphological abnormalities, notably ovoid or multilobed cells (85). These cells, having poorly defined tip
organelles, were associated with the loss of P30 (85). It is
reasonable to assume that mutations in P30 will confer a
defect in cell development, motility, and the potential to
cytadhere to respiratory epithelium. Most importantly,
the homologies predicted to be shared between P30 and
mammalian structural proteins are implicating molecular
mimicry as a basis for mycoplasma-mediated postinfectious autoimmunity (20). Recent findings demonstrate
that M. pneumoniae interacts in the respiratory system
also with the surfactant protein D (SP-D, Ref. 15), a major
constituent of the alveolar environment that acts to keep
alveoli from collapsing during the expiratory phase of the
respiratory cycle. The primary mycoplasmal determinants
participating in the interaction of M. pneumoniae with
human SP-D were membrane glycolipids (15), suggesting
that there is more than one type of adhesin on the cell
surface of M. pneumoniae.
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C. Receptors
The role of host cell surface sialoglycoconjugates as
receptors for mycoplasmas has long been established
(81). The carbohydrate moiety of the glycoprotein, which
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serves as a receptor for M. pneumoniae on human erythrocytes, has been identified as having a terminal
NeuAc(␣2–3)Gal(␤1– 4)GlcNAc sequence (84). Nevertheless, neuraminidase treatment has frequently failed to
abolish the ability of various eukaryotic cells to bind M.
pneumoniae (36). A sialic acid-free glycoprotein, isolated
from cultured human lung fibroblasts, which serves as a
receptor for M. pneumoniae, has been isolated by Geary
et al. (37). Sulfated glycolipids containing terminal
Gal(3SO4)␤1 residues were also found to function as receptors (52). Clearly, there is more than one type of
receptor for M. pneumoniae and apparently for other
adhering mycoplasmas as well. It is interesting to note
that at the primary site of M. pneumoniae infection, the
apical microvillar border and the cilia carry the sialoglycoconjugate-type receptors, whereas the secretory cells
and mucus lack them, favoring attachment of M. pneumoniae to the ciliated cells (59).
III. INVASION INTO HOST CELLS
Current theory holds that mycoplasmas remain attached to the surface of epithelial cells (82), although
some mycoplasmas have evolved mechanisms for entering host cells that are not naturally phagocytic. The intracellular location is obviously a privileged niche, well protected from the immune system and from the action of
many antibiotics. The ability of M. penetrans, isolated
from the urogenital tract of acquired immunodeficiency
syndrome (AIDS) patients (56, 57), to invade and survive
within host cells has been intensively studied. This microorganism has invasive properties and localizes in the cytoplasm and perinuclear regions (2, 12, 38). Other mycoplasmas known to be surface parasites such as M. fermentans (100, 105), M. pneumoniae (4), M. genitalium
(48), and M. gallisepticum (110), under certain circumstances, reside within nonphagocytic cells.
In studying bacterial invasion, it is essential to differentiate between microorganisms adhering to a host cell
and those which have penetrated the cell. The early light
microscopic and electron microscopic observations of
mycoplasmas engulfed in membrane vesicles lead to conflicting interpretations. Are the mycoplasmas intracytoplasmatic, or are they at the bottom of crypts formed by
the invagination of the cell membrane (117)? A more
sophisticated ultrastructural study was based on a combined immunochemistry and electron microscopy approach. Staining surface polysaccharides of the host cell
with ruthenium red allows a better differentiation between intracellular and extracellular mycoplasmas (105).
Currently, the gentamicin resistance assay is the most
common assay to differentiate intracellular from extracellular bacteria (28, 94). In this assay, the extracellular
bacteria are killed by gentamicin, but the intracellular
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pneumoniae, suggesting that one or more of the HMW
proteins is required both to anchor P1 at the attachment
organelle and to maintain the proper architecture of the
tip organelle (102). Consistent with this interpretation is
the observation that these proteins are components of the
Triton X-100-insoluble mycoplasma cytoskeleton and as
such may have a structural role in the localization of P1
(90, 101). The deduced amino acid sequence of HMW3
shows that this protein is largely hydrophilic. Results of
whole cell radioimmunoprecipitation experiments revealed that HMW3 is not exposed on the surface of M.
pneumoniae cells (50; Fig. 2).
Because the tip organelle in mutants having reduced
levels of HMW3 lacks the truncated tip appearance characteristic of wild-type M. pneumoniae (102), and loss of
HMW3 resulted in subtle changes in morphology, inability
to cluster the adhesion P1 and reduced cytadherence
(109), it has been suggested that HMW3 contribute to the
architecture and stability of the tip organelle (50, 109).
Similar to HMW3, HMW1 has an unusual subcellular distribution. This protein is a peripheral membrane protein
that is antibody accessible on the outer surface of wildtype M. pneumoniae, (3, Fig. 2). The subcellular location
of HMW2 is yet unknown, but there are suggestions that
this protein is present near the base of the tip organelle
(40).
How do the accessory proteins promote adherence?
As already mentioned, clustering of P1 at the tip organelle
appears to be necessary to attachment providing a critical
concentration of the adhesion molecule required for securing a stable primary association with receptor molecules on the host cells. In the nonadhering mutants, P1
fails to cluster at the tip organelle (4). It is conceivable
that one or more of the accessory proteins plays a role in
the lateral movement and concentration of the adhesion
molecules at the tip organelle. How this is accomplished
is still not fully understood. A plausible hypothesis is that
to fulfill this role, the accessory proteins must be associated with the mycoplasma cytoskeleton, which is responsible not only for the lateral movement and proper orientation of P1, but also for changes in cell shape, cell
division, and motility (82, 88). Recent studies showed that
the loss of HMW2 from wild-type M. pneumoniae cells
resulted in accelerated turnover of HMW1 and other
cytadherence-accessory proteins, probably by proteolysis
(3). These findings suggest a role for HMW2 in promoting
the export of HMW1 to the cell surface, where it is stable
and fully functional (3).
INTERACTIONS OF MYCOPLASMAS WITH HOST CELLS
surface proteins that enables invasion (14, 26). Fibronectin binding activity was detected in M. penetrans. This
organism, which contains a 65-kDa fibronectin binding
protein, binds selectively immobilized fibronectin (38). An
increase in the invasive capacity of M. fermentans, which
arises from the potential of this organism to bind plasminogen and activate it by urokinase to plasmin, has been
recently described (113). Plasmin, a protease with broad
substrate specificity, may alter M. fermentans-cell surface
proteins and thereby promotes its internalization. Proteolytic modification of bacterial and/or host cell surface
protein(s) is an emerging theme in the study of bacterial
pathogenicity. For example, the plasminogen activator of
Yersinia pestis degrades bacterial outer membrane proteins
triggering virulence (98). Similarly, a secreted protease was
shown to stimulate the fibronectin-dependent uptake of
Streptococcus pyogenes into eukaryotic cells (14).
B. Changes in the Host Cell Cytoskeleton
Almost all invasive bacteria that come into contact
with the host cell surface trigger cytoskeletal rearrangements that facilitate bacterial internalization (31, 39, 75).
M. penetrans invasion of HeLa cells depends on the
capacity of the cells to assemble actin microfilaments, as
treatment with cytochalasin D has a dramatic effect on
the invasion of HeLa cells by M. penetrans (2). Furthermore, both vinblastine, which disrupts microtubules, and
taxol, which freezes microtubules, virtually abolish penetration of M. penetrans (12). These findings suggest that
alterations in the polymerization dynamics and stability of
microtubules inhibits the invasion of M. penetrans into
HeLa cells. On the other hand, the entry of M. gallisepticum into chicken embryo fibroblasts is inhibited by the
microtubule inhibitor nocodazole, but not by cytochalasin
D, suggesting that M. gallisepticum may use a different
strategy from that of M. penetrans for reaching the intracellular space (110).
A. Invasins and Receptors
C. Signal Transduction
Bacterial invasion of eukaryotic cells involves complex bacterial and host cell processes. Invasion is associated with adhesins as well as host cell receptors that
mediate interaction of the bacteria with the host cell (14,
94). It is likely that surface molecules (proteins and lipids)
that facilitate the adhesion process will have an effect on
the invasion. Nevertheless, adherence to the surface of
host cells is not sufficient to trigger events that lead to
invasion. The signals generated by the interaction of host
cells with invasive mycoplasmas have yet to be investigated. Bacterial invasion is based on the ability of several
bacteria to bind fibronectin (27) or sulfated polysaccharides (26, 27). These compounds form a molecular bridge
between the bacteria and different types of host cell
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Involvement of the host cell cytoskeleton in internalization is considered to be the result of a host cell signal
transduction cascade induced by the invasive bacterium.
As in many signal transduction processes initiated by
bacteria, kinases and/or phosphatases are usually involved (75, 83). The invading mycoplasmas generate uptake signals that trigger the assembly of highly organized
cytoskeletal structures in the host cells (38). Yet, the
nature of these signals and the mechanisms used to transduce them are not fully understood. Specific activation of
protein kinases occurs during the internalization of most
of the bacteria taken up by microtubule-dependent mechanisms (86). It has been shown that invasion of HeLa cells
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bacteria are shielded from the antibiotic because of the
limited penetration of the gentamicin into eukaryotic
cells. The gentamicin procedure was successfully adapted
to mycoplasma systems (2, 110). M. penetrans and M.
gallisepticum are relatively susceptible to gentamicin. In
the case of M. penetrans, the susceptibility to the antibiotic can be markedly increased by adding low concentrations of Triton X-100 to the medium (2). For example, a
combination of 200 ␮g gentamicin and 0. 01% Triton X-100
resulted in an 8 log decrease in CFU within 1 h of incubation at 37°C. The low Triton X-100 concentrations affected neither the viability of the host cells nor their
permeability to gentamicin. Low Triton X-100 concentrations have only a slight effect on the viability of M. penetrans or on the binding of M. penetrans to HeLa cells (2).
Usually the number of intracellular bacteria is determined
by washing the host cells free of the antibiotic, lysing
them with mild detergents to release the bacteria and
counting the colonies (31). Because mycoplasmas are as
susceptible to detergent lysis as the host cells, dilutions of
the mycoplasma-infected host cells should be plated directly onto solid mycoplasma media without lysing them
beforehand. Each mycoplasma colony represents one
infected host cell rather than a single intracellular
mycoplasma (28).
Immunofluorescent staining of internalized bacteria
and of those remaining on the cell surface, combined with
confocal laser scanning microscopy, has demonstrated
that M. penetrans penetrates eukaryotic cells (6, 12). This
nondestructive, high-resolution method allowed infected
host cells to be optically sectioned after fixation and
immunofluorescent labeling. Imaging single infected HeLa
cells revealed that invasion is both time and temperature
dependent. Penetration of HeLa cells has been observed
as early as 20 min after infection (12), whereas invasion of
cultured HEp-2 cells by M. penetrans has been shown to
begin after 2 h of infection (6).
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D. Survival and Multiplication Within Host Cells
The intracellular fate of invading bacteria can vary
greatly. Most invasive bacteria appear to be able to sur-
vive intracellularly for extended periods of time, at least if
they have reached a suitable host cell (29). Other engulfed
bacteria are degraded intracellularly via phagosome-lysosome fusion. The invasive bacteria either remain and
multiply within the endosomes after invasion or are released via exocytocis and/or the lysis of the endosomes
which may allow multiplication within the cytoplasm.
Most ultrastructural studies performed with engulfed mycoplasmas revealed mycoplasmas within membranebound vesicles (48, 100, 105). Persistence of M. penetrans
within NIH/3T3 cells, Vero cells, human endothelial cells,
HeLa cells, WI-38 cells, and HEp-2 cells has been observed
over a 48 –96 h postinfection (38, 57). M. gallisepticum
remains viable within HeLa cells during 24 – 48 h of intracellular residence (110). The observation of vesicles
stuffed with M. penetrans in various host cells was taken
as an indication that M. penetrans is able to divide within
intracellular vesicles of the host cells (57). Nonetheless,
the intracellular multiplication of mycoplasmas remains
to be convincingly demonstrated.
IV. FUSION WITH HOST CELLS
The lack of a rigid cell wall allows direct and intimate
contact of the mycoplasma membrane with the cytoplasmic membrane of the host cell. Under appropriate conditions, such contact may lead to cell fusion (Fig. 3). Fusion
of mycoplasmas with eukaryotic host cells has been first
observed in electron microscopic studies (88). The development of energy transfer and fluorescence methods has
enabled investigation of the fusion process on a quantitative basis in an experimental cell culture-mycoplasma
system and has also allowed the identification of fusogenic mycoplasmas.
FIG. 3. Schematic diagram of the fusion of a mycoplasma with a eukaryotic
cell.
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by M. penetrans is associated with tyrosine phosphorylation of a 145-kDa host cell protein (2). Tyrosine phosphorylation activates phospholipase C to generate two second
messengers: phosphatidylinositol metabolites and diacylglycerol (DAG). Changes in host cell lipid turnover occur
as a result of M. penetrans binding and/or invasion of
Molt-3 lymphocytes (91). These changes include the accumulation of DAG and the release of unsaturated fatty
acids, predominantly long-chain polyunsaturated ones
such as docosahexanoic acid (C22:6, Ref. 91). Nonetheless,
metabolites of phosphatidylinositol were not detected.
These observations support the hypothesis that M. penetrans stimulates host phospholipases to cleave membrane phospholipids, thereby initiating the signal transduction cascade. Because in HeLa cells, which are invaded by M. penetrans, DAG is generated, it is likely that
the protein kinase C is activated in the host cells. Indeed,
transient protein kinase C activation was demonstrated in
invaded HeLa cells by several methods, including translocation to the plasma membrane and enzymatic activity
(12). However, activation was weak and transient, peaking at 20 min postinfection. How any of these different
signal transduction events lead to specific microtubule
activity resulting in mycoplasmal internalization is unknown. The role of these signals in the penetration, survival, and proliferation of mycoplasmas within host cells,
as well as the involvement of the lipid intermediates in the
pathobiological alterations taking place in the host cells,
merit further investigation.
INTERACTIONS OF MYCOPLASMAS WITH HOST CELLS
A. Factors Mediating Fusion
B. Molecules Implicated in Fusion
Among the Mycoplasma species, the human mycoplasma, M. fermentans, is highly fusogenic, capable of
fusing with a variety of cells (33). Furthermore, it has
been shown that the polar lipid fraction of this organism
is capable of enhancing the fusion of small, unilamellar
phosphatidylcholine-cholesterol (1:1 molar ratio) vesicles
with Molt-3 lymphocytes in a dose-dependent manner,
suggesting that a lipid component acts as a fusogen (11,
92). In an attempt to identify the fusogen, detailed lipid
analyses of M. fermentans membranes were performed
(23, 92, 114), revealing that the polar lipid fraction of this
organism is dominated by the presence of unusual choline-containing phosphoglycolipids (Fig. 4). The major
type (MfGL-II) has been identified as 6⬘-O-(3⬙-phosphorylcholine-2⬙-amino-1⬙phospho-1⬙,3⬙-propanediol)-␣-D-glucopyranosyl (1⬘-3)-1,2-diacyl-glycerol with hexadecanoyl
(16:0) and octadecanoyl (18:0) in a molar ratio of 3.6:1
constituting the major acyl residues (114). Other cholinecontaining lipids identified are MfGL-I (65, 66), which is
similar to MfGL-II but without the 2-amino-1,3-propanediol-1,3-bisphosphate, and the ether lipids 1-O-alkyl-/alkenyl-2-O-acyl-glycero-3-phosphocholine (MfEL) and its lysoform 1-O-alkyl-/alkenyl-glycero-3-phosphocholine (lysoMfEL) (108).
It has been proposed that MfGL-II is the fusogenic
component in M. fermentans strain PG18 (92), yet a
recent study showed that despite the fact that the respiratory isolates of M. fermentans, strains M39 and M52,
have no MfGL-II, these strains fused with Molt-3 cells at
almost the same rate and to about the same extent as
PG18, suggesting that in these strains MfGL-II is not the
fusogenic component (11). It is widely accepted that the
reorganization of the membrane structure that occurs
during fusion requires that the lipid bilayer is broken up
and that other inverted configurations, such as reversed
FIG. 4. Structure of the major choline-containing
phospholipids of M. fermentans. The MfEL contains a
hexadecyl residue. R, acyl. [From Ben-Menachem et al.
(11).]
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In all the fusogenic Mycoplasma species tested, fusogenicity is dependent on the unesterified cholesterol
content of the cell membrane (104). Fusogenic activity
can be found only among mycoplasmas requiring unesterified cholesterol for growth, whereas Acholeplasma species, which do not require cholesterol, are nonfusogenic.
Furthermore, adaptation of M. capricolum to grow in the
absence of cholesterol results in a marked reduction in
membrane-cholesterol content and renders the organism
nonfusogenic (104). Fusogenicity of M. fermentans with
Molt-3 cells is markedly stimulated by Ca⫹2 and depends
on the proton gradient across the mycoplasma cell membrane, decreasing markedly when the proton gradient is
collapsed by proton ionophores (24).
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V. POSSIBLE MECHANISMS OF DAMAGE
TO HOST CELLS
A. Competition for Precursors
Genomic analyses of mycoplasmas have revealed the
limited biosynthetic capabilities of these microorganisms
(45, 46, 78). Mycoplasmas apparently lost almost all the
genes involved in the biosynthesis of amino acids, fatty
acids, cofactors, and vitamins and therefore depend on
the host microenvironment to supply the full spectrum of
biochemical precursors required for the biosynthesis of
macromolecules (78, 82). Competition for these biosynthetic precursors by mycoplasmas may disrupt host cell
integrity and alter host cell function. Nonfermenting Mycoplasma spp. utilize the arginine dihydrolase pathway
for generating ATP (78) and rapidly deplete the host’s
arginine reserves affecting protein synthesis, host cell
division, and growth (87). Certain strains of arginineutilizing Mycoplasma spp. have been shown to induce
chromosomal aberrations in host cells, most commonly
chromosomal breakage, multiple translocations, a reduction in chromosome number, and the appearance of new
and/or additional chromosome varieties (5, 67). Because
histones are rich in arginine, it has been suggested that
arginine utilization by mycoplasmas inhibits histone synthesis and causes chromosomal damage (5, 67, 87). M.
fermentans infection of rat astrocytes has been shown
recently to result in a choline-deficient environment and
in the induction of apoptosis (9). Choline is an essential
dietary component that ensures the structural integrity
and signaling functions of the cell membranes; it is the
major source of methyl groups in the diet, and it directly
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affects cholinergic neurotransmission, transmembrane
signaling, and lipid transport and metabolism (115).
B. Damage Induced by Adherence
The attachment of mycoplasmas to the surface of
host cells may interfere with membrane receptors or alter
transport mechanisms of the host cell. The disruption of
the K⫹ channels of ciliated bronchial epithelial cells by
Mycoplasma hyopneumoniae that resulted in ciliostasis
has been described (21). The host cell membrane is also
vulnerable to toxic materials released by the adhering
mycoplasmas. Although toxins have not been associated
with mycoplasmas, the production of cytotoxic metabolites and the activity of cytolytic enzymes is well established. Oxidative damage to the host cell membrane by
peroxide and superoxide radicals excreted by the adhering mycoplasmas appears to be experimentally well-substantiated (1). The intimate contact of the mycoplasma
with the host cell membrane may also result in the hydrolysis of host cell phospholipids catalyzed by the potent
membrane-bound phospholipases present in many mycoplasma species (96). This could trigger specific signal
cascades (86) or release cytolytic lysophospholipids capable of disrupting the integrity of the host cell
membrane (92, 93).
C. Damage Induced by Fusion
During the fusion process, mycoplasma components
are delivered into the host cell and affect the normal
functions of the cell. A whole array of potent hydrolytic
enzymes has been identified in mycoplasmas (82, 95, 96).
Most remarkable are the mycoplasmal nucleases (76, 77,
82) that may degrade host cell DNA. It has recently been
shown that M. fermentans contains a potent phosphoprotein phosphatase (95). Phosphorylation of cellular constituents by interacting cascades of serine/threonine and tyrosine protein kinases and phosphatases is a major means
by which a eukaryotic cell responds to exogenous stimuli
(86). The delivery of an active phosphoprotein phosphatase into the eukaryotic cell upon fusion may interfere
with the normal signal transduction cascade of the host
cell. In addition to delivery of the mycoplasmal cell content into the host cell, fusion also allows insertion of
mycoplasmal membrane components into the membrane
of the eukaryotic host cell. This could alter receptor
recognition sites as well as affect the induction and expression of cytokines and alter the cross-talk between the
various cells in an infected tissue.
D. Cytopathic Effects
Contamination of a cell culture by mycoplasmas may
go undetected because mycoplasma infections do not
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nonbilayer aggregates, are being formed (18, 60, 97). Nevertheless, analyses of the phase behavior of MfGL-II/H2O
mixtures by solid state 31P and pulsed-field gradient diffusion NMR spectroscopy revealed that MfGL-II is a bilayer stabilizing lipid incapable of undergoing a phase
transition from a lamellar to an inverted configuration (8).
This property of MfGL-II is difficult to reconcile with a
role in membrane fusion. On the other hand, it is well
established that lysolipids can substantially enhance the
rate of fusion in model membranes as well as in biomembranes (18), and it is plausible that the lyso ether lipid
found in all M. fermentans strains (108) may act as a
fusogen. Very little is known about the role of membrane
proteins in the fusion process. The observation that fusion of M. fermentans with Molt-3 cells was inhibited by
pretreatment of intact M. fermentans with proteolytic
enzymes (24) implies that this organism possesses a proteinase-sensitive receptor(s) responsible for binding
and/or the establishment of tight contact with the cell
surface of the host cell involved in fusion.
INTERACTIONS OF MYCOPLASMAS WITH HOST CELLS
VI. CIRCUMVENTING THE HOST IMMUNE
SYSTEM
Circumvention of the host immune system is of utmost importance to the survival of a mycoplasma within
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its host. The major mechanisms that have been studied at
length are molecular mimicry and phenotypic plasticity,
which ensure that the mycoplasmas are not fully or efficiently recognized by the host’s immune system. Molecular mimicry refers to antigenic epitopes that have been
shown to be shared by different mycoplasmas and host
cells and were proposed as putative factors involved in
evasion of host defense mechanisms and/or induction of
autoantibodies observed during infections with certain
mycoplasmas. Mycoplasmas are also endowed with phenotypic plasticity defined as the ability of a single genotype to change its antigenic make-up producing more than
one alternative form of morphology, physiological state,
and/or behavior in response to environmental condition.
Phenotypic plasticity can be accomplished by two distinct
mechanisms: a response to environmental signals or random changes of expression of single or multiple genes.
The use of signal transduction pathways to sense signals
in the host environment and respond accordingly by expressing gene products is necessary for survival in the
host (107, 112). The apparent scarcity in mycoplasmas of
regulatory genes functioning as sensors to environmental
stimuli and of genes encoding transcriptional factors suggests, but does not rule out, that adaptation of mycoplasmas to the changing environment is not per se a response
to signals. The common way to achieve phenotypic plasticity in mycoplasmas is by “antigenic variation,” a term
that refers to the reversible high-frequency gain or loss of
surface components that is a common survival strategy
used by bacterial pathogens (62, 112). These surface components that in microorganisms include components of
flagella, pili, outer membrane, or capsules are the major
targets for the host antibody response. Therefore, the
ability of a microorganism to rapidly change the surface
antigenic repertoire and consequently vary the immunogenicity of these components allows the microorganism
to avoid detection or to outpace a host’s immune system.
Lacking a cell wall, locomotive organelles, or pili, most of
the variable surface components of mycoplasmas are
membrane proteins. These proteins are mature, processed prokaryotic lipoproteins anchored to the membrane by DAG and amide-linked fatty acids (13). A mycoplasma population may spontaneously and randomly generate distinct lipoprotein populations with a variety of
antigenic phenotypes, “heterotypes,” that will survive the
specific host response capable of eliminating the predominant “homotypes.” Notably, the molecular switching
events leading to the generation of these heterotypes are
reversible, and the escape variants produced through random genetic variation must inherit the ability to produce,
at a high frequency, a wide range of antigenic phenotypes.
A considerable evolutionary dividend to the microbial
pathogen of such random phenotypic switching can be
achieved even before the onset of a specific immune
response. For example, by “fine tuning” of the specificities
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produce overt turbid growth commonly associated with
bacterial and fungal contamination. The morphological
cellular changes can be minimal or unapparent. Frequently, the cellular changes are similar to those caused
by nutritional effects such as the depletion of amino
acids, sugars, or nucleic acid precursors. These morphological effects can be reversed by changing the medium or
by replenishing the medium with fresh nutrients.
Mycoplasmal attachment to eukaryotic cells may
sometimes lead to a pronounced cytopathic effect. Attachment permits the mycoplasma contaminant to release
noxious enzymatic and cytolytic metabolites directly onto
the tissue cell membrane. Some mycoplasmas selectively
colonize defined areas of the cell culture. This results in
microcolony formation producing microlesions and small
foci of necrosis, e.g., M. pulmonis, or form plaques, e.g., M.
gallisepticum, in an agar overlay system (5). Microcolonization suggests that mycoplasma-specific receptors are localized in defined areas of the cell monolayer. However, other
fermenting mycoplasmas, e.g., M. hyorhinis, attach to every
cell and destroy the entire monolayer, producing a generalized cytopathic effect. With HeLa cells infected by the invasive M. penetrans, the most pronounced effect was the
vacuolation of the host cells (12). The vacuoles appeared to
be empty, differing from the described membrane-bound
vesicles containing clusters of bacteria (57). The number
and size of the vacuoles depended on duration of infection.
Because vacuolation is not obtained with M. penetrans cell
fractions (12), it is unlikely that a necrotizing cytotoxin is
involved in the generation of the cellular lesions. A possible
mechanism that leads to vacuolation may be associated with
the accumulation of organic peroxides upon invasion of
HeLa cells by M. penetrans. Indeed, when HeLa cells were
grown with the antioxidant ␣-tocopherol, the level of accumulated organic peroxides was extremely low, and vacuolation was almost completely abolished (12).
Being unable to synthesize nucleotides, mycoplasmas developed potent nucleases, either soluble ones secreted into the extracellular medium or membrane-bound
nucleases (7, 68, 82) apparently as a means of producing
nucleic acid precursors required for metabolism. It has
been shown that, occasionally, secreted mycoplasmal
nucleases are taken up by the host cells (76, 77). Thus it
was suggested that the cytotoxicity of M. penetrans is
mediated at least in part to a secreted mycoplasmal endonuclease that is cleaving DNA and/or RNA of the host
cells (7), and the endonuclease activity of M. bovis was
implicated in the increased sensitivity of lymphocytic cell
lines to various inducers of apoptosis (99).
425
426
SHLOMO ROTTEM
VII. MODULATING THE IMMUNE SYSTEM
A. Modulatory Effects on Monocytes
and Macrophages
It is increasingly recognized that for many bacteria
induction of cytokines is a major virulence mechanism
(41, 112). The induced cytokines have a wide range of
effects on the eukaryotic host cell and are recognized as
important mediators of tissue pathology in infectious diseases. It appears that although mycoplasmas circumvent
phagocytosis, they interact with mononuclear and polymorphonuclear phagocytes stimulating the synthesis of
cytokines with proinflammatory action (88, 92). These
immunomodulatory influences depend on both the immune cells and the Mycoplasma spp. involved. Macrophage-mediated cytolysis of fibrosarcoma A9HT induced
by whole cells of M. orale was first described by Lowenstein et al. (58). Cytolysis of the neoplastic cells was
obtained even with macrophages from the lipopolysaccharide (LPS)-unresponsive C3H/HeJ mice, suggesting
that the mechanism of activation is different from that of
LPS (53). Since then over 20 Mycoplasma spp. have been
shown to activate monocytes, macrophages, and brain
astrocytes and induce secretion of the proinflammatory
Physiol Rev • VOL
cytokines tumor necrosis factor (TNF)-␣, interleukin
(IL)-1 and IL-6, chemokines, such as IL-8, monocyte chemoattractant protein 1 (MCP-1), macrophage inflamatory
protein 1 (MIP-1␣), granulocyte-monocyte colony stimulating factors (GM-CSFs), as well as prostaglandins and
nitric oxide (82, 92). More recent observations suggest
that the mechanisms underlying macrophage activation
by whole cells are in many cases identical to those employed by their purified membrane lipoproteins, supporting the notion that lipoproteins are the principle component of intact mycoplasmas activating monocytes/macrophages and playing an important role in the inflammatory
response during infection (13, 41).
The potent molecules and mediators released by
cells responding to mycoplasmas and mycoplasma-derived cell components enhance expression of major histocompatibility complex (MHC) class I and class II antigens and of costimulatory end cell adhesion molecules in
leukocytes and endothelial cells, induce recruitment and
extravasation of leukocytes to the site of infection and
cause local tissue damage (41, 82, 90). It is interesting to
note that mycoplasmal infections are not necessarily associated with a strong inflammatory response, and some
mycoplasmas colonize the respiratory and urogenital
tracts with no apparent clinical symptoms. It is therefore
tempting to speculate that in addition to triggering the
production of proinflammatory cytokines, certain organisms have the capacity to downregulate NF␬B or to induce anti-inflammatory cytokines such as IL-4, IL-10,
IL-13, or transforming growth factor-␤, contributing to
the complex network of synergistic and antagonistic influences induced by mycoplasmas on cells of the
immune system.
B. Characterization of Modulins
The term modulin has been proposed to describe
components and products of bacteria that have the capacity to stimulate cytokine synthesis. The first and most
widely studied modulin was the LPS of Gram-negative
bacteria (41). During the past decade it has been shown
that in addition to LPS, other bacterial components,
mainly those associated with the cell wall, such as peptidoglycan fragments, lipoteichoic acid, and murein
lipoproteins can stimulate mammalian cells to produce
cytokines (41). Recent attempts to identify mycoplasmal
cytokine-inducing moieties have targeted membrane lipoproteins (13, 70, 90), superantigens (16, 17), and choline-containing phosphoglycolipids (10, 92).
C. Lipoproteins
Lipoproteins are found in the cytoplasmic membrane
and in the outer membrane of many Gram-positive and
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of variant receptors or adhesion factors throughout the
cell population, there is a better chance that a given
variant will succeed in finding the preferred receptors on
the mosaic of different tissues displayed by the host. It
may also provide the mycoplasma, during the course of
parasitic life, the flexibility to reach and adapt to different
niches within the host where distinctive receptors may be
required for colonization. Despite the very limited genetic
information that mycoplasmas contain, the number of
mycoplasmal genes involved in diversifying the antigenic
nature of their cell surface is unexpectedly high. The
utilization of multiple variable genes organized as gene
families, allowing the generation of an extensive repertoire of antigenic variants, is a common theme in pathogenic bacteria and parasites for maintaining surface variability (107, 112). By oscillating at a high frequency, these
genes allow numerous combinatorial antigenic repertoires to be generated. Genetic mechanisms of antigenic
variation emerging from the mycoplasma studies can be
broadly divided into three categories: 1) variation by homopolymeric repeats, 2) variation by chromosomal rearrangements, and 3) variation by reiterated coding
sequence domains. Comprehensive and comparative
reviews on the genetic mechanisms generating antigenic
variation of surface proteins in mycoplasmas and other
bacteria and on the role of antigenic variation in bacteriahost cell interactions have been recently published (13,
82, 89, 107, 111, 112)
INTERACTIONS OF MYCOPLASMAS WITH HOST CELLS
427
FIG. 5. Schematic structure of the lipoylated amino
terminus of bacterial lipoproteins. I: mycoplasmal lipoprotein with the amino-terminal cysteinyl residue lipoylated
by a diacylglyceryl (DAG) but not N-acylated. II: lipoprotein of Escherichia coli lipoylated by both a DAG and a
fatty acyl moiety. a.a., amino acid.
Physiol Rev • VOL
tained by analyzing the cytokine-inducing potency of a
number of synthetic peptides, which are analogs of the
MALP-2 of M. fermentans (35, 71). These studies clearly
demonstrated that the macrophage-activating agents
carry a fatty acid-substituted amino-terminal S-(2,3bisacyloxypropyl) cysteinyl group, but lack the N-acyl
long-chain fatty acid present in bacterial lipoproteins.
This feature renders these compounds exceptionally active as macrophage stimulators in vitro (72, 73).
D. Superantigens
Superantigens (SAg) are potent immunoregulatory
proteins produced by bacteria, viruses, and mycoplasmas
(32, 63, 69). These proteins are able to activate large
proportions of the peripheral T-lymphocyte population,
inducing them to secrete a large panel of cytokines both
in vivo and in vitro (32, 42). The SAg are presented
directly to T cells in association with various class II
major histocompatibility complex molecules on accessory cell surfaces, usually without the need for processing
(22, 32), and are recognized predominantly by T cells
bearing specific V-chain segments of the T-cell receptor
for antigen (TCR) (42, 63). Because recognition is dependent on fewer restricting elements that are required for
traditional antigens, large numbers of naive T cells may be
activated. This response contributes to the marked inflammation seen after in vivo administration of SAg,
which has clear implications for disease pathogenesis
(69). The superantigen of M. arthritidis (MAM) was most
thoroughly studied (16). MAM has been cloned and sequenced, and the functional regions of the molecule were
described (17). There is currently no evidence that other
mycoplasmas have SAg.
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Gram-negative bacteria. All membrane-anchored bacterial
lipoproteins contain a lipoylated amino-terminal cysteinyl
residue which, in some cases, is N-acylated (Fig. 5). Lipoproteins are extremely abundant in the cell membrane
of mycoplasmas. In M. pneumoniae, for example, of an
estimated number of 150 membrane proteins, 46 open
reading frames encoding putative lipoprotein genes have
been identified (46). Chemical analyses of mycoplasmal
lipoproteins have revealed that their lipoylation mechanism is similar to that of Gram-negative and Gram-positive bacteria (13). However, in many mycoplasmas, the
lipoproteins are not N-acylated (Fig. 3), nor has an Nacyltransferase gene been found in the genome (34, 45,
46). The first reports on the cytokine-inducing ability of
mycoplasmal lipoproteins showed that a lipoprotein from
M. fermentans (49, 70) or M. arginini (44) is capable of
stimulating the release of proinflammatory cytokines
such as IL-1␤, IL-6, and TNF-␣ from human peripheral
blood monocytes in a dose-dependent manner. Comparison of the effects of intact lipoproteins with those of
proteinase-K-treated lipoproteins reveals that the lipoylated amino terminus is responsible for the immunostimulating properties of the lipoproteins (13, 29). However, it
is not certain whether all naturally occurring mycoplasmal membrane lipoproteins are potent macrophage activators. The importance of the lipid residue has been
emphasized by the isolation and characterization of naturally occurring lipopeptides with macrophage-activating
potential from two mycoplasmas. A macrophage-activating lipopeptide with a molecular mass of 2 kDa (MALP-2)
has been identified in the cell membrane of M. fermentans (73), and two lipopeptides, derived from the variable
lipoproteins VlpA and VlpC, respectively, were characterized in M. hyorhinis (72). Further information on the
functionally important lipopeptide moieties has been ob-
428
SHLOMO ROTTEM
E. Membrane Lipids
F. Signaling Pathways by Modulins
The monocyte surface molecule CD14 is part of the
receptor complex for several microbial products. This 50to 55-kDa glycoprotein is expressed predominantly on
myeloid cells, and in addition to being a high-affinity
receptor for LPS, it has been implicated in the response to
peptidoglycan and other bacterial cell wall components
(41). The failure of anti-CD14 monoclonal antibodies to
block cytokine induction by M. fermentans lipoproteins
(49, 80) indicates that cytokine induction by M. fermentans lipoproteins does not proceed through CD14 (49).
This was further supported by the finding that cytokine
synthesis by a human monocyte cell line induced by M.
fermentans lipoproteins was not affected by pretreatment of the cells with vitamin D3, known to increase
CD14 expression on the cell surface (80). In contrast to
CD14, the toll-like receptors (TLRs) contain all of the
characteristics that one would expect from a true pattern
recognition receptor, including the presence of a true
signal-transducing intracellular domain (35). Although
only recently described, the list of putative ligands for
TLR2 and TLR4 is already impressively large. Both TLR2
and TLR4 have been reported to function as LPS signal transducers (35). However, lipoproteins/lipopeptides
from M. fermentans activated cells expressing TLR2 but
not those expressing TLR4, suggesting that TLR2 is a
central pattern recognition receptor in host response to
M. fermentans invasion (35).
The downstream signaling events that follow the
TLR-mediated activation by mycoplasmal lipoprotreins
and lead to cytokine synthesis seem to be similar to the
intracellular events induced by LPS. The TLRs have a
cytoplasmic domain that is homologous to the IL-1 receptor. Thus it is likely that TLR2 activates the NF-␬B pathway, and perhaps other proinflammatory pathways as
Physiol Rev • VOL
G. Mitogenic Activity
Numerous reports describe the mitogenic stimulation of lymphocytes by mycoplasmas in a nonspecific
polyclonal manner both in vitro and in vivo (90), yet many
of these mitogenic effects were not immunologically well
characterized. These effects may be indirect and due
primarily to cytokine release by macrophages and monocytes. Different Mycoplasma spp. have been shown to
stimulate B cells, T cells, or both nonspecifically. Antibodies of different specificities, with no affinity for mycoplasmal antigens, are generated both in vitro and in vivo,
following exposure of lymphoid cells to different mycoplasmas possessing B cell mitogens (82, 88, 90). It is
worth noting that there is a clear distinction between
mycoplasma-induced DNA synthesis and differentiation
of activated B cells into antibody-producing cells. Thus,
on the one hand, stimulation of DNA synthesis is not
always a prerequisite for the induction of polyclonal
immunoglobulin secretion by B cells exposed to mycoplasmas. On the other hand, stimulation of mitosis by
mycoplasmas does not necessarily trigger subsequent
differentiation of the dividing lymphocytes into plasma cells
(92). Various Mycoplasma spp. are potent stimulators of
T-cell-derived cytokines such as IL-2, interferon-␣, or IL-4.
They exert multiple amplifying effects on phagocytes and
lymphocytes and affect the balance between Th1 and Th2
populations of CD4⫹ T cells, thereby influencing the direction of the subsequent effector phases of the immune response, and augmenting natural killer cell activity (82, 88).
Our present knowledge of the biochemical nature of
mycoplasma mitogens is very limited. It appears that
mycoplasmal B-cell mitogens differ from bacterial LPS in
their ability to activate lymphocytes from C3H/HeJ mice
that are poor responders to LPS and their inducing potential is unaffected by polymyxin B (82). Furthermore, there
are indications that a single mycoplasma may carry more
than one cell constituent interacting with lymphocytes.
Thus the AIDS-associated M. penetrans mitogens appear
to include a glycolipid as well as a major membrane
lipoprotein (88).
H. Oncogenic Activity
Mycoplasmas can grow in close interaction with
mammalian cells, often silently for a long period of time.
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Very few mycoplasmal lipids have been investigated
for cytokine stimulating activity. MfGL-II, the major choline-containing phosphoglycolipid of M. fermentans (Fig.
4), has been found to be associated with the secretion of
inflammatory mediators by human monocytes (92) and by
rat cells of the central nervous system (10). Stimulation of
primary rat astrocytes by MfGL-II caused activation of
protein kinase C, secretion of nitric oxide and prostagalandine E2, in a dose-dependent manner (10). Deacylation
of MfGL-II or treatment with monoclonal anti-phosphocholine antibodies pronouncedly reduced the stimulatory
activity, suggesting that the fatty acyl residues are essential for activity and that the terminal phosphocholine moiety plays an important role in MfGL-IIs
stimulation (10).
well, via their interactions with IL-1 receptor signaling
genes (55). Indeed, M. fermentans lipoproteins or the
lipoprotein-derived MALP-2 lipopeptide activate NF-␬B
and AP-1, the two transcription factors playing a central
role in the induction of proinflammatory cytokines, as
well as the mitogen-activated protein kinase family members including extracellular signal-regulated kinases 1 and
2, c-Jun amino-terminal kinase, and p38 (35, 80).
INTERACTIONS OF MYCOPLASMAS WITH HOST CELLS
However, prolonged interactions with mycoplasmas with
seemingly low virulence could, through a gradual and
progressive course, induce chromosomal instability as
well as malignant transformation, promoting tumorous
growth of mammalian cells (30, 106, 116). This mycoplasmamediated transformation of cells has a long latency and
demonstrates distinct multistage progression (106). Overexpression of H-ras and c-myc oncogenes was found to
be closely associated with both the initial reversible and
the subsequent irreversible states of the mycoplasmamediated transformation of cells (116).
VIII. CONCLUSIONS
Physiol Rev • VOL
ganisms possess an impressive capability of maintaining a
surface architecture that is antigenically and functionally
versatile. These variable surface antigens undoubtedly
contribute to the capability of the mycoplasmas to adapt
to a large range of habitats and to cause diseases, which
are often chronic in nature. Although mycoplasmas circumvent phagocytosis, they interact with mononuclear
and polymorphonuclear phagocytes, suppressing or stimulating them by a combination of direct and indirect
cytokine-mediated effects. It appears that for many mycoplasmas, induction of cytokines is a major virulence
mechanism. The induced cytokines have a wide range of
effects on the eukaryotic host cell and are recognized
as important mediators of tissue pathology in infectious
diseases.
Address for reprint requests and other correspondence: S.
Rottem, Dept. of Membrane and Ultrastructure Research, The
Hebrew University-Hadassah Medical School, PO Box 12272,
Jerusalem 91120, Israel (E-mail: [email protected]).
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Over the last decade, intensive studies have been
carried out to understand the strategy employed by a
mycoplasma pathogen to interact with host cells and to
avoid or subvert host protective measures. The identification of mycoplasmal membrane components that participate in the adhesion process will shape and direct
future efforts toward understanding the molecular organization of adhesion-associated proteins and to further
identify mammalian membrane receptors for mycoplasmas and mycoplasma products. The finding that some
mycoplasmas can reside intracellularly opens up new
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its antigenic characteristics has been one of the major
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