MYCOPLASMAS
“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.” (Baseman, 1997)Members of the genus Mycoplasma [NCBI TAXONOMY] include over 100 documented human, animal and plant species and are the smallest organisms lacking cell walls that are capable of self-replication and cause various diseases in humans, animals, and plants.
Seven different species of mycoplasma have been associated with various infections in humans to date. The earliest reports of mycoplasma infectious agents in humans appeared in the 1930s, 1940s and finally, in the early 1960s when the definite relationship between Mycoplasma pneumoniae as the primary cause of atypical pneumoniae was established.
Many strains of mycoplasma have been thought of in the past as benign bacteria commonly found in the gut and mucous and just a part of the “friendly” bacteria of the body which comprise the commensal microbial flora of healthy persons. However, recent advances in genome research and testing methodologies demonstrate that these mycoplasma may be implicated in the pathogenisis of many chronic diseases when they invade host cells and move out of the microbial flora and into other tissues, organs and the blood supply.
A good example of this is that a common mycoplasma found in the urogenital tract, Mycoplasma genitalium, was recently found in the lung and upper repiratory tract of patients suffering from a range of upper respiratory diseases including chronic asthma. (Baseman, 1997) Conversely, Mycoplasma pneumoniae, normally only found in respiratory mucous, was isolated living in the human urogenital tract led researchers to suggest “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.”(Goulet 1995)
A review of the clinical documentation being performed around the world on mycoplasmas indicate that scientists are hypothesizing them to be cofactors or actual causes of many human diseases, including: chronic fatigue immune dysfunction syndrome, auto-immune disorders (lupus, multiple sclerosis and Lou Gehrig’s Disease/ALS), arthritis, fibromyalgia, acquired immune deficiency syndrome, “idiopathic” cd4 positive t-lymphocytopenia (aka HIV-negative AIDS), psoriasis, scleroderma, Crohn’s disease, cancers, lymphoma, leukemia, pelvic inflammatory disease, asthma, atypical pneumonia, Sjogren’s syndrome, interstitial cytitis, and Alzheimer’s disease.
To understand how mycoplasmas can cause chronic disease, we must first look at the species’ unique properties and interactions with host cells. Unlike viruses and bacteria, mycoplasmas are the smallest free-living and self-duplicating micro-organisms, as they don’t require living cells to replicate their DNA and growth.
More complex than viruses, mycoplasmas utilize RNA for replication, which in turn makes them susceptible only to the nucelophylic growth and/or protein synthesis inhibiting antibiotics. This antibiotic sensitivity was a clue used in the identification of the filtrable viral-like “Eaton Agent” as Mycoplasma pneumoniae, the cause of atypical pneumonia. This respiratory strain is now also suspected as a cause of arthritis, neurological and other localized disorders.
Mycoplasma’s tiny viral-like size and pleomorphism (The variation in the appearance of the nuclei of the same cell type.) facilitates their cell penetration but limits their synthetic capacity, thus requiring preformed maco moleules from another host cell for growth and reproduction. These include basic peptides or protein fragments from enzyme digested tissues and constant cell replacement.
Also required are nuecleotides, neucleic acid fragments, cholesterol and fatty acids in the form of nucleoproteins and lipoproteins. To survive and replicate, mycoplasmas can live intra and extracellularly as saprophytes utilizing the fragments from living, dead or dying cells.
Their double layer lioprotein membrane controls the intracellular flow of nutrients and provides a highly unstable osmolar microbe, difficult to isolate and visualize. Interestingly, when scientists tried to culture strains of mycoplasmas, they were seen to actually mimic their culture media, leading reseearchers to conclude that their composition and properties would also mimic and vary among the in-vivo cultures of host tissues and fluids.
For example, the cholesterol concentration in the host’s mycoplasmas would depend on the host’s cholesterol levels in blood and tissues. The wide variation in mycoplasma’s composition of lipid, neucleic acid, and protein produced in a test tube culture may be even more variable in the hosts. Therefore, depending on which host cells the mycoplasma invade or attach to, it can actually morph into or mimic the host cells and begin competing for certain cellular nutrients like proteins, amino acids and lipids causing a deregulation of the cell without actually killing it.
Based on new advances in genome research pertaining to mycoplasmas and host cell interaction indicates the following: “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.” (Nicolson, GL 1999)
Clearly, multiple pathways of interactions with host/target cells appears to be the modus operandi of the Mycoplasma species. This can result in a variety of diseases and chronic syndromes depending on which host cells are targeted and used. Documented interactions with host cells by mycoplasmas in the below referenced clinical documentation includes the following:
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.
Mycoplasmas can target the host white blood cells (lymphocytes/WBC) for intracellular infection, and these cells have the unique ability to cross the blood-brain barrier over into the spinal fluid and d into the host central nervous system (CNS).
Once inside the host CNS, certain pathogenic mycoplasmas have been reported to activate the CNS hypothalamus/pituitary/adrenal axis and neuroendocrine system. The hypothalamus and pituitary glands form part of the human endocrine system which produces hormones that regulate nearly every bodily function. This involvement is hypothesized to contribute to diseases such as fibromyalgia, chronic fatigue, and some AIDS-related symptoms.[Yirmiya R, 1999]
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. 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.
Mycoplasmas can escape 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 directly suppress host immune responses by initiating or enhancing apoptosis. For example, M. fermentans, a recently discovered mycoplasma found in the urine of HIV and AIDS positive patients, can initiate or enhance concanavalin A-induced apoptosis (programmed cell death) 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.
Hydrogen peroxide and superoxide radicals are generated by adhering mycoplasmas, which induces oxidative stress, including host cell membrane damage.
Competition for and depletion of nutrients or biosynthetic precursors by mycoplasmas, which disrupts host cell maintenance and function.
Existence of capsule-like material and electron-dense surface layers or structures, which provides increased integrity to the mycoplasma surface and confers immunoregulatory activities
High-frequency phase and antigenic variation, which results in surface diversity and possible avoidance of protective host immune defenses
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 tumor formation.
Intracellular residence, which sequesters mycoplasmas, establishes latent or chronic states, and circumvents mycoplasmicidal immune mechanisms and selective drug therapies
“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.” (Baseman, 1997)Members of the genus Mycoplasma [NCBI TAXONOMY] include over 100 documented human, animal and plant species and are the smallest organisms lacking cell walls that are capable of self-replication and cause various diseases in humans, animals, and plants.
Seven different species of mycoplasma have been associated with various infections in humans to date. The earliest reports of mycoplasma infectious agents in humans appeared in the 1930s, 1940s and finally, in the early 1960s when the definite relationship between Mycoplasma pneumoniae as the primary cause of atypical pneumoniae was established.
Many strains of mycoplasma have been thought of in the past as benign bacteria commonly found in the gut and mucous and just a part of the “friendly” bacteria of the body which comprise the commensal microbial flora of healthy persons. However, recent advances in genome research and testing methodologies demonstrate that these mycoplasma may be implicated in the pathogenisis of many chronic diseases when they invade host cells and move out of the microbial flora and into other tissues, organs and the blood supply.
A good example of this is that a common mycoplasma found in the urogenital tract, Mycoplasma genitalium, was recently found in the lung and upper repiratory tract of patients suffering from a range of upper respiratory diseases including chronic asthma. (Baseman, 1997) Conversely, Mycoplasma pneumoniae, normally only found in respiratory mucous, was isolated living in the human urogenital tract led researchers to suggest “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.”(Goulet 1995)
A review of the clinical documentation being performed around the world on mycoplasmas indicate that scientists are hypothesizing them to be cofactors or actual causes of many human diseases, including: chronic fatigue immune dysfunction syndrome, auto-immune disorders (lupus, multiple sclerosis and Lou Gehrig’s Disease/ALS), arthritis, fibromyalgia, acquired immune deficiency syndrome, “idiopathic” cd4 positive t-lymphocytopenia (aka HIV-negative AIDS), psoriasis, scleroderma, Crohn’s disease, cancers, lymphoma, leukemia, pelvic inflammatory disease, asthma, atypical pneumonia, Sjogren’s syndrome, interstitial cytitis, and Alzheimer’s disease.
To understand how mycoplasmas can cause chronic disease, we must first look at the species’ unique properties and interactions with host cells. Unlike viruses and bacteria, mycoplasmas are the smallest free-living and self-duplicating micro-organisms, as they don’t require living cells to replicate their DNA and growth.
More complex than viruses, mycoplasmas utilize RNA for replication, which in turn makes them susceptible only to the nucelophylic growth and/or protein synthesis inhibiting antibiotics. This antibiotic sensitivity was a clue used in the identification of the filtrable viral-like “Eaton Agent” as Mycoplasma pneumoniae, the cause of atypical pneumonia. This respiratory strain is now also suspected as a cause of arthritis, neurological and other localized disorders.
Mycoplasma’s tiny viral-like size and pleomorphism (The variation in the appearance of the nuclei of the same cell type.) facilitates their cell penetration but limits their synthetic capacity, thus requiring preformed maco moleules from another host cell for growth and reproduction. These include basic peptides or protein fragments from enzyme digested tissues and constant cell replacement.
Also required are nuecleotides, neucleic acid fragments, cholesterol and fatty acids in the form of nucleoproteins and lipoproteins. To survive and replicate, mycoplasmas can live intra and extracellularly as saprophytes utilizing the fragments from living, dead or dying cells.
Their double layer lioprotein membrane controls the intracellular flow of nutrients and provides a highly unstable osmolar microbe, difficult to isolate and visualize. Interestingly, when scientists tried to culture strains of mycoplasmas, they were seen to actually mimic their culture media, leading reseearchers to conclude that their composition and properties would also mimic and vary among the in-vivo cultures of host tissues and fluids.
For example, the cholesterol concentration in the host’s mycoplasmas would depend on the host’s cholesterol levels in blood and tissues. The wide variation in mycoplasma’s composition of lipid, neucleic acid, and protein produced in a test tube culture may be even more variable in the hosts. Therefore, depending on which host cells the mycoplasma invade or attach to, it can actually morph into or mimic the host cells and begin competing for certain cellular nutrients like proteins, amino acids and lipids causing a deregulation of the cell without actually killing it.
Based on new advances in genome research pertaining to mycoplasmas and host cell interaction indicates the following: “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.” (Nicolson, GL 1999)
Clearly, multiple pathways of interactions with host/target cells appears to be the modus operandi of the Mycoplasma species. This can result in a variety of diseases and chronic syndromes depending on which host cells are targeted and used. Documented interactions with host cells by mycoplasmas in the below referenced clinical documentation includes the following:
