THE PATHOGENESIS AND TREATMENT
OF MYCOPLASMAL INFECTIONS
Antimicrobics and Infectious Disease
Newsletter
(Elsevier Science) 1999
Written by:
Garth L. Nicolson
The Institute for Molecular Medicine, Huntington Beach, California
Marwan Y. Nasralla
International Molecular Diagnostics, Inc., Huntington Beach, California
Nancy L. Nicolson
The Institute for Molecular Medicine, Huntington Beach, California
Summary
Pathogenic mycoplasmas have been found in the blood
or other specimens of patients with a variety of chronic clinical conditions, including
respiratory, oral cavity, genital and other infections, autoimmune, inflammatory and
immunosuppressive diseases and fatigue syndromes of unknown origin. These small bacterial
microorganisms are possible causative agents, cofactors or opportunistic infections in
these and other illnesses.
Evidence for their association or possible role in
various clinical conditions is suggested by their significantly higher incidence or degree
of infection in symptomatic patients than in non-symptomatic controls and their gradual
suppression by the appropriate antibiotics resulting in gradual patient recovery from
clinical signs and symptoms. Although they are not widely appreciated for their pathogenic
properties, certain Mycoplasma species and certain other species of bacteria (Chlamydia,
Borrelia, etc.) appear play a role in disease progression or patient morbidity in rather
large subsets of chronic illness patients.
Introduction
Certain Mycoplasma species, the smallest and
simplest, free-living, bacteria that lack a rigid cell wall, are important pathogens in
animal, plant and insect species. In humans mycoplasmal infections have only recently been
associated with certain acute and chronic illnesses where they may function as causative
agents, cofactors or opportunistic infections that cause patient morbidity. Although
various Mycoplasma species are commonly found as commensals in the oral cavity and at
other superficial sites, certain species appear to cause morbidity when they penetrate
into the blood and spread to and colonize various tissues. For example, M. hominis and
Ureaplasma urealyticum are common inhabitants of the human genital tract but they can play
an etiologic role in pyelonephritis, pelvic inflammatory diseases and post-abortion and
post-partum fevers. Some reports claim that some Mycoplasma species cause serious systemic
infections, such as septicemia, septic arthritis, neonatal meningitis and encephalitis,
and this has been confirmed in animal models. For example, M. fermentans can cause severe,
fatal neurological and respiratory signs and symptoms after injection into the cerebral
fluid of rats. Although sometimes questioned, several pathogenic Mycoplasma species have
been proposed to be etiologic agents in various acute and chronic diseases in man. Less
appreciated is the possibility that multiple chronic infections, including Mycoplasma
species, play an important role in various chronic illnesses and their progression.
Mycoplasma genomes are the smallest among bacteria
The genomes of most Mycoplasma species encode about 600 proteins. For example, The M.
genitalium and M. pneumoniae genomes contain 470 and 677 protein-coding gene sequences,
respectively, compared with 1,703 protein genes in Haemophilus influenzae and about 4,000
genes in E. Coli. The genomes of M. genitalium and M. pneumoniae have lost the genes
involved in certain biosynthetic pathways, such as the genes for amino and fatty acid and
vitamin synthesis. Since they are cell wall-deficient bacteria, there is a major reduction
in genetic information needed for cell wall biosynthesis.
Although Mycoplasma species carry a minimal set of
genes involved in energy metabolism and biosynthesis, they still have the essential genes
for DNA replication, transcription, translation, and the minimal number of rRNA and tRNA
genes. The reduction in mycoplasmal genomes explains their need for host nutritional
molecules. A significant number of mycoplasmal genes appear to be devoted to cell adhesion
and attachment organelles as well as variable membrane surface antigens to maintain
parasitism and evade host immune and nonimmune surveillance systems.
Mycoplasma species variably express structurally
heterogeneous cell surface antigens. Variations in the genes encoding cell surface
adherence molecules reveal distinct patterns of mutations capable of generating changes in
mycoplasma cell surface molecular size and antigenic diversity. Variable surface antigenic
structures and rapid changes in their expression are thought to play important roles in
the pathogenesis of mycoplasmal infections by providing altered structures for escape from
immune responses and protein structures that enhance cell and tissue colonization and
penetration of the mucosal barrier.
Mycoplasma interactions with host immune systems
Certain Mycoplasma species can either activate or
suppress host immune systems, and they may use these activities to evade host immune
responses.
For example, some mycoplasmas can inhibit or
stimulate the proliferation of normal lymphocyte subsets, induce B-cell differentiation
and trigger the secretion of cytokines, including interleukin-1 (IL-1), IL-2, IL-4, IL-6,
tumor necrosis factor-a (TNFa), interferons, and granulocyte macrophage-colony stimulating
factor (GM-CSF) from B-cells as well as other cell types. Moreover, it was also found that
M. fermentans-derived lipids can interfere with the interferon (IFN)-g-dependent
expression of MHC class II molecules on macrophages. This suppression results in impaired
antigen presentation to helper T-cells in an experimental animal model. Also, mycoplasmas
are able to secret soluble factors that can stimulate proliferation or inhibit the growth
and differentiation of immune competent cells.
Mycoplasma species are known to secrete
immune-modulating substances.
For example, immune cells are affected by spiralin, a
well-characterized mycoplasmal lipoprotein that can stimulate the in vitro proliferation
of human peripheral blood mononuclear cells and murine splenocytes. This stimulation of
immune cells results in secretion of proinflammatory cytokines (TNFa, IL-1 or -6).
Spiralin can also induce the maturation of murine B-cells.
As described above, mycoplasmas can evade immune
recognition by undergoing surface antigenic variations thus rapidly altering their cell
surface structures. Such antigenic variability, the ability to suppress host immune
responses, slow growth rates and intracellular locations may explain the chronic nature of
mycoplasmal infections and the common inability of a host to suppress mycoplasmal
infections with host immune and nonimmune responses.
Rapid adaptation to host microenvironments by
mycoplasmas is usually accompanied by rapid changes in cell surface adhesion receptors for
more successful cell binding and entry as well as rapid structural protein changes to
mimic host antigenic structures (antigen mimicry). For example, during chronic, active
arthritis the size and antigenic diversity of the surface lipoprotein Vaa antigen changes
in structure and expression in vivo.
Antigenic divergence of Vaa can affect the adherence
properties of M. hominis and enhance evasion of host-mediated immunity. Variations in the
Vaa genes reveal a distinct pattern of mutations that generate mycoplasma surface
variations and thus avoid host immune responses.
Mycoplasmas Can Induce Programmed Cell Death and
Necrosis Mycoplasmas can directly suppress host immune responses by initiating or
enhancing apoptosis. For example, M. fermentans, an AIDS-associated mycoplasma, can
initiate or enhance concanavalin A-induced apoptosis of T-cells. Relatively large amounts
of nucleases are also expressed by Mycoplasma species, and these can be released
intracellularly to cause degradation of host DNA. Mycoplasmal nucleases may also be
involved in secondary necrosis seen in advanced mycoplasmal infections, as indicated by
the occurrence of morphological characteristics of apoptosis (chromatin condensation) and
necrosis (loss of membrane integrity and organelle swelling). Although mycoplasmas can
release activated oxygen species that may be involved in initiating apoptosis, some
Mycoplasma species, such as M. fermentans, express a novel cytolytic activity in a
nonlipid protein fraction that has a cytocidal effect not mediated by the known
mycoplasmal cytokines like TNFa.
In addition to apoptosis, mycoplasmas can also
release growth inhibitory molecules into their surroundings, such as arginine deaminase.
This enzyme can act as a growth-inhibitory substance that suppresses IL-2 production and
receptor expression in T-cells stimulated by non-specific mitogens, and it can induce the
morphologic features of dying cells and DNA fragmentation indicative of apoptosis.
Clinical Testing for Mycoplasmal Infections
Until recently one of the most difficult problems in
detecting mycoplasmal infections was that the available techniques, seriological and
culturing procedures, were relatively insensitive for detecting intracellular infections.
Mycoplasma culture techniques can be highly specific for detection of some mycoplasmal
infections, but they are relatively insensitive because of difficulty culturing various
Mycoplasma species.
Conventional serological detection of mycoplasmal
infections is quite difficult due to the lack of humoral immune responses in most
patients. Also, detection methods that use antibodies against mycoplasma antigens are not
very reliable, because mycoplasmas are able to hide inside cells. This can result in
rather normal antibody titers during active mycoplasmal infections.
The most reliable clinical testing for mycoplasmal
infections uses whole blood, blood leukocytes or tissue biopsies and polymerase chain
reaction (PCR). Even with this approach it is necessary to insure that intracellular
Mycoplasma species are being detected at high sensitivity. Another research technique that
has been used for intracellular infections is nucleoprotein gene tracking. This approach
detects mycoplasmal genes directly in nucleoprotein complexes isolated directly from cell
nuclear fractions. Although highly specific, it is not as sensitive as PCR.
Persistence of Mycoplasmal Infections and Various
Clinical Conditions
Mycoplasmas have been found at significantly higher
incidence in blood and tissue specimens obtained from patients with various chronic
illnesses compared to healthy controls. Since little is known about the involvement of
mycoplasmas in the pathogenesis of chronic illnesses, it remains uncertain whether these
findings indicate that some Mycoplasma species are causal agents, cofactors, or
opportunistic (superinfections) in patients with immundisturbances. Since mycoplasmas can
be found at superficial sites, such as normal flora in the genitourinary tract, oral
cavity and gut where they are thought to be nonpathogenic. The distinguishing
characteristic in pathogenic infections may be the penetration of
Mycoplasma species into the blood circulation and
especially into cells in various tissues. This may explain the finding of pathogenic
Mycoplasma species in genitourinary tract, oral cavity, gut and the blood in a few percent
of asymptomatic subjects. Unless mycoplasmas penetrate into tissues and cells, it is
unlikely that they can exert their pathogenic effects, but in some individuals the
presence of mycoplasmas is not associated with any clinical condition. In such cases it is
not apparent whether this represents a superficial infection, an early nonsymptomatic or
dormant phase of the illness process or a carrier phenomenon.
The persistence of mycoplasmal infections has many
similarities with Chlamydial persistence. Certain Chlamydia species infections can remain
dormant and do not always progress to replication and host cell lysis, and similarly
certain Mycoplasma species can remain inside cells for long periods without initiating
apoptosis and eventual cell lysis. Unlike Chlamydia species where much is known about the
dormant or cryptic intracellular phase of their life cycles, little is known about the
mechanism of persistence of mycoplasmal infections. Both of these bacteria (at least their
pathogenic strains) are considered obligatory intracellular parasites because they are
dependent on host cell intermediary metabolites and biosynthetic precursors, and they are
thought to cause much of their pathogenic effects during their intracellular persistence
phase.
Alternatively, when intracellular pathogens, such as
certain Mycoplasma species, are released from cells without cell lysis, they can carry
host cell surface antigens with them, eventually resulting in autoimmune host responses
against the infected tissues.
Mycoplasmal Infections and Respiratory Illnesses
Various respiratory illnesses, such as chronic
asthma, airway inflammation, chronic pneumonia and other respiratory diseases, are known
to be associated with mycoplasmal infections. For example, M. pneumoniae is a common cause
of upper respiratory infections, and severe asthma is commonly associated with mycoplasmal
infections. Recent evidence has shown that certain mycoplasmas, such as M. fermentans
(incognitus strain), are unusually invasive and found within respiratory epithelial cells.
Similar to certain
Chlamydia species, pulmonary macrophages appear
unable to kill pathogenic Mycoplasma species.
Although mycoplasmal infections are often associated
with chronic asthma, the exact role of mycoplasmas in the pathogenesis of asthma remains
unclear.
Certain Mycoplasma species are involved in
respiratory tract infections associated with airway inflammations, induction of bronchial
hyperresponsiveness (BHR) and asthmatic attacks. At a minimum, M. pneumoniae infections
can cause worsening of conditions in asthmatic patients, whose attacks are associated with
significant and specific IgA and IgE responses. Specific antibodies of these subclasses
for M. pneumoniae protein antigens were found in a majority of patients with M. pneumoniae
infections. Mycoplasmas are only one of many agents that can trigger BHR, and other
infectious or chemical agents may contribute to the complex disease process.
Mycoplasmal Infections in Urogenital Diseases
Mycoplasma species are commonly found in urogenital
infections. For example, M. hominis was detected in more than 12% of females who presented
at gynecological services, and M. genitalium has been associated with acute and
nonspecific non-gonococcal urethritis in males but not in asymptomatic controls. This
organism is also a common cause of genital infections in women, and it was detectable in
7% of women with sexually transmitted diseases. M. hominis and U. urealyticum have been
implicated in a wide variety of urogenital diseases, such as pelvic inflammatory disease,
infertility, non-gonococcal urethritis (NGU) and other genital infections, pyelonephritis,
Reiter's syndrome, and peritonitis. The appearance of various bacterial species in
bacterial vaginosis may be a result of pathophysiological alterations of the vaginal
ecosystem, and mycoplasmas appear to play an important role in this process. Mycoplasmas
are also known to interfere in pregnancy, For example, U. urealyticum was found to be
involved in 11% of patients with fertility problems.
Mycoplasmal Infections in Immunosuppressive Diseases
Some Mycoplasma species, M. fermentans, M. penetrans,
and M. pirum, have been implicated as infectious cofactors in HIV-AIDS. Using relatively
insensitive techniques all three mycoplasmas have been detected in up to 20% of patients
with HIV infections, and serological studies have suggested that the presence of M.
penetrans is also associated with HIV infection. Moreover, the incidence of systemic
mycoplasmal infections in HIV-AIDS patients could be much higher than previously thought.
Most of the analyses were performed using relatively insensitive techniques, such as
serological analysis. Pathogenic Mycoplasma species may influence HIV pathogenesis by
specific and direct activation or suppression of the immune system, the production of
superantigens with subsequent alterations in immune responses, or their contribution to
the oxidative stress observed in HIV-positive patients. Also, the development of AIDS may
increase the susceptibility of HIV-infected patients for coinfection with various
Mycoplasma species, such as M. fermentans. This species is able to bind HIV capsid protein
gp120 permitting adhesion of HIV virions to the mycoplasma surface.
Subsequently the HIV viruses could be transported
directly to cells expressing CD4 receptors. After binding to target cells, mycoplasmas can
stimulate host cell activation by IL-1 and TNFa, which are known effectors for virus
reproduction. In addition, oligosaccharides of the mycoplasmal glycocalyx may protect
bound HIV-1 virons from host immune responses.
Antigen similarities between the surface components
of mycoplasmas and HIV-1 have led to speculation that they use similar mechanisms for cell
entry. For example, the HIV-1 gp120 envelope glycoprotein and M. genitalium adhesion
proteins share sequence homology and also have significant similarity with the CD4-binding
site of the class II major histocompatibility complex (MHC) proteins. The interactions of
microorganisms with MHC-related antigens on host cells could contribute to a number of
possible outcomes, including T-cell dysfunction, T-cell depletion, T-cell shift, B-cell
proliferation, hyperglobulinemia and antigen-presenting cell dysfunction. Interestingly,
all of these have been observed during the development of HIV-AIDS.
Mycoplasmal Infections in Rheumatic Diseases
Although the underlying causes of rheumatic diseases
are not known, rheumatoid arthritis (RA) and other rheumatic illnesses may involve, at
least in part, infectious agents. In addition, the progression of rheumatic diseases may
also be related to infectious processes. The remarkable clinical and pathological
similarities between certain infectious diseases in some animal species and those of some
human rheumatic illnesses, such as RA, have encouraged the search for microbial etiologies
for these syndromes.
A long list of microorganisms, including aerobic and
anaerobic intestinal bacteria, several viruses and Mycoplasma species have been proposed
as important in these illnesses. We recently found multiple mycoplasma species in about
one-half of the blood samples from RA patients using PCR. All multiple infections occurred
as combinations of M. fermentans with other species.
Mycoplasma species are known to be able to induce
immundysfunction and autoimmune reactions that could be related to the development of RA.
In animal models of RA, M. arthritidis-related superantigens were found to compromise
T-cells, and they can trigger and exacerbate autoimmune arthritis. Furthermore, M.
arthritidis can release substances that can act n polymorphonuclear granulocytes, such as
oxygen radicals and chemotactic and aggregating substances. Also, the isolated membranes
of M. arthritidis possessed toxic effects when injected into various animals.
Mycoplasmal Infections in Cardiac Diseases
Mycoplasmal infections of the heart have been
reported in patients with different types of carditis. The most common association was
with M. pneumoniae infection. Endocarditis and myocarditis associated with M. pneumoniae
infections appear to be an important cause of death in M. pneumoniae infections. Direct
bacterial invasion of M. pneumoniae into pericardial tissue appears to be more likely to
cause pericarditis than autoimmune phenomena. Viral and bacterial (Mycoplasma, Chlamydia
and Mycobacterium tuberculosis) infections appear to be common causes of myocarditis
and/or pericarditis, and this is just beginning to be appreciated by infectious disease
specialists.
Mycoplasmal Infections in Autoimmune Diseases
Although pathogenic mechanisms have not been
established in autoimmune diseases, mycoplasmal infections seem to play an important but
not well understood role in these diseases. Several characteristics of mycoplasmas make
them attractive as agents that may be responsible for triggering autoimmune responses.
First, during their intracellular replication and release from host cells mycoplasmas can
capture antigens from the host cell surface and incorporate them into their cell
membranes. This can lead to immune responses against these antigens and possibly
autoimmune reactions.
Second, mycoplasmal antigens can mimic host antigens
and trigger immune responses against these antigens with resulting cross reactivity
against host antigens. Third, mycoplasmas can cause apoptosis of host cells with
subsequent release of normal host antigens.
Superantigens are potent immunomodulators derived
from microorganisms, such as bacteria, viruses and mycoplasmas. Their effects on immune
systems are the result of their binding both to MHC-binding sites on antigen presenting
cells and binding to structures within hypervariable regions of T-cell antigen receptors.
The contributions of microbial superantigens to the pathogenesis of autoimmune diseases
have been investigated in experimental animal models where a superantigen, the mycoplasma
arthritis T-cell
mitogen, was arthritogenic in mice. When injected
into mice, M. arthritidis causes a chronic arthritis that resembles RA in its pathology
and pathogenesis.
Mycoplasmal infections have also been implicated in
the progression of Kawasaki disease, Graves¹ disease, Hashimoto¹s disease, Sjögren¹s
syndrome, systemic lupus erythematosis (SLE) and multiple sclerosis (MS).
Mycoplasmal Infections in Fatigue Illnesses
Chronic fatigue is the most commonly reported medical
complaint of all patients seeking medical care. However, the fatigue syndromes, such as
chronic fatigue syndrome (CFS, sometimes called myalgic encephalomyelitis), fibromyalgia
syndrome (FMS) and Gulf War illnesses (GWI) are distinguishable as separate syndromes that
have muscle and overall fatigue as major characteristics, among many other multiorgan
signs and symptoms, including immune system abnormalities. Because of the complex nature
of these illnesses, many patients are often diagnosed with multiple syndromes. We and
others have examined the presence of mycoplasmal blood infections in CFS, FMS and GWI
patients and have found that the majority of patients have blood mycoplasmal infections.
Patients with CFS or FMS often have multiple
mycoplasmal infections and probably other chronic infections as well. When we examined
CFS/FMS patients for the presence of M. fermentans, M. pneumoniae, M. penetrans, M.
hominis infections, multiple infections were found in over one-half of 93 patients.
CFS/FMS patients had double (>30%) or triple (>20%) mycoplasmal infections, but only
when one of the species was M. fermentans or M. pneumoniae (17). We also found higher
score values for increases in the severity of signs and symptoms in CFS/FMS patients with
multiple infections.
CFS/FMS patients with multiple mycoplasmal infections
generally had a longer history of illness, suggesting that patients may have contracted
additional infections during their chronic illnesses.
Antimicrobial Therapy for Mycoplasmal Infections
Once mycoplasmal infections have been identified in
subsets of chronic illness patients, they can be successfully treated, if the therapy
continues for some time to eliminate or suppress dormant forms of the microorganism. Using
this strategy appropriate treatment with antibiotics can result in patient improvement and
even recovery. The recommended treatments for diagnosed mycoplasmal blood infections
require long-term antibiotic therapy, usually multiple 6-week cycles of doxycycline
(200-300 mg/day), ciprofloxacin (1,500 mg/day), azithromycin (500 mg/day) or
clarithromycin (750-1,000 mg/day). Multiple cycles are required, because few patients
recover after only a few cycles, possibly because of the intracellular locations of
mycoplasmas like M. fermentans and M. penetrans, the slow-growing nature of these
microorganisms and their ability to exhibit persistence as dormant forms and their
relative drug sensitivities. For example, of 87 GWI patients that tested positive for
mycoplasmal infections, all patients relapsed after the first 6-week cycle of antibiotic
therapy, but after up to 6 cycles of therapy 69/87 patients recovered and returned to
active duty. The clinical responses that were seen were not due to placebo effects,
because administration of some antibiotics, such as penicillins, resulted in patients
becoming more not less symptomatic, and they were not due to immunosuppressive effects
that can occur with some of the recommended antibiotics.
Chronic illness patients often have nutritional and
vitamin deficiencies that must be corrected. These patients are often depleted in vitamins
B, C and E and certain minerals. Unfortunately, patients with these chronic] illnesses
often have poor absorption. Therefore, high doses of some vitamins must be used, and
others, such as vitamin B complex, must be given sublingual. Antibiotics that deplete
normal gut bacteria can result in over-growth of less desirable flora, so Lactobacillus
acidophillus supplementation is recommended. In addition, a number of natural remedies
that boost the immune system are available and are potentially useful, especially during
antibiotic therapy or after therapy has been completed.
They appear to be useful during therapy to boost the
immune system or after antibiotic therapy in a maintenance program to prevent relapses.
Conclusions
Why aren¹t physicians successfully treating
mycoplasmal, chlamydial and other chronic infections? In many cases they are treating
these infections, but they are often not taking into account the intracellular persistent
phases of these infections. And it has been only recently that such infections have been
found in so many unexplained chronic illnesses.
These infections cannot be successfully treated with
the usual short courses of antibiotics due to their intracellular locations, slow
proliferation rates, persistence and inherent insensitivity to most antibiotics. In
addition, a fully functional immune system may be essential to overcoming these
infections, and this is why vitamin and nutritional supplements are important in the
therapy. Finally, chronic illness patients must be weaned off antidepressants and other
potentially immune suppressing drugs before they can fully recover from their illnesses.
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