Mycoplasma

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Mycoplasma
Scientific classification
Kingdom: Bacteria
Phylum: Tenericutes  or
Firmicutes
Class: Mollicutes
Order: Mycoplasmatales
Family: Mycoplasmataceae
Genus: Mycoplasma
Nowak 1929
Species

M. gallisepticum
M. genitalium
M. haemofelis
M. hominis
M. hyopneumoniae
M. ovipneumoniae
M. pneumoniae
etc.

Mycoplasmosis
Classification and external resources
ICD-10 A49.3
ICD-9 041.81

Mycoplasma refers to a genus of bacteria that lack a cell wall.[1] Without a cell wall, they are unaffected by many common antibiotics such as penicillin or other beta-lactam antibiotics that target cell wall synthesis. They can be parasitic or saprotrophic. Several species are pathogenic in humans, including M. pneumoniae, which is an important cause of atypical pneumonia and other respiratory disorders, and M. genitalium, which is believed to be involved in pelvic inflammatory diseases. Mycoplasma are the smallest living cells yet discovered,[2] can survive without oxygen and are typically about 0.1 µm in diameter.

Origin of the name[edit]

The name Mycoplasma, from the Greek mykes (fungus) and plasma (formed), was first used by Albert Bernhard Frank in 1889. He thought it was a fungus, due to fungus-like characteristics.[3]

An older name for Mycoplasma was Pleuro pneumonia-Like Organisms (PPLO), referring to organisms similar to the causative agent of contagious bovine pleuropneumonia (CBPP).[4] It was later found that the fungus-like growth pattern of M. mycoides is unique to that species and Mycobacteria.

History of Mycoplasma research[edit]

The discovery of mycoplasmas date back to 1898. Initially, due to their unknown nature and relationships with other organisms, while being minute in size and not being qualified as bacteria they were considered viruses for years. However, many years later with further discovery mycoplasmas were confused with the L-forms, which are bacteria that have lost their cell walls either completely or partially. Nevertheless, in 1950s and 1960s this confusion came to end when first genomic analysis data through DNA hybridization were obtained. This analysis ruled out any relationship of mycoplasmas to the L-forms.

Currently, mycoplasmas are considered to have evolved from gram-positive, walled eubacteria by degenerative evolution, meaning their evolutionary history appears to include the loss of cell wall. Further, in 1960s and 1970s knowledge about ultrastructure, cell membrane, genome and metabolic pathways of mycoplasmas resulted in conclusion that they are the smallest and simplest self-replicating organisms.

The lack of cell wall convey some unique properties of mycoplasmas such as sensitivity to osmotic shock and detergents, resistance to penicillin, and formation of odd fried-egg shaped colonies. Sections of mycoplasmas reveal that their cells are essentially built of three organelles, such as: the cell membrane, ribosomes, and circular double stranded DNA tightly packed molecule. Their mode of replication is no different from that of prokaryotes dividing by binary fission. However for binary fission to happen, cytoplasmic division must fully synchronize with genome replication and in mycoplasmas cytoplasmic replication lags behind genome replication, which ultimately results in the formation of multinucleated filaments.

From in vitro cultivation of mycoplasmas it has been discovered that they are "fastidious", i.e. difficult to cultivate. The reasons for these difficulties for species such as Mycoplasma genitalium and Mycoplasma pneumoniae is the lack of all the genes involved in amino acid synthesis, making them dependent on exogenous supply of amino acids.

Dependence on exogenous supplies of fatty acids and cholesterol serves as an advantage to conduct further studies on these organisms. In order to compensate for these deficiencies mycoplasmas are grown on complex media, usually consisting of beef heart infusion, peptone, yeast extract, and serum with various supplements.

Mycoplasmas are known to consist of just plasma membrane which makes them good models for membrane studies. Due to this reason the availability of these membranes in pure state have enabled their chemical, enzymatic and antigenic characterization. The membrane mostly consists of 60% to 70% of proteins and the rest of it being 20% to 30% of lipid.

[5]

Characteristics[edit]

There are over 100 recognized species of the genus Mycoplasma, one of several genera within the bacterial class Mollicutes. Mollicutes are parasites or commensals of humans, other animals (including insects), and plants; the genus Mycoplasma is by definition restricted to vertebrate hosts. Cholesterol is required for the growth of species of the genus Mycoplasma as well as certain other genera of mollicutes. Their optimum growth temperature is often the temperature of their host if warmbodied (e. g. 37° C in humans) or ambient temperature if the host is unable to regulate its own internal temperature. Analysis of 16S ribosomal RNA sequences as well as gene content strongly suggest that the mollicutes, including the mycoplasmas, are closely related to either the Lactobacillus or the Clostridium branch of the phylogenetic tree (Firmicutes sensu stricto).

Cell morphology[edit]

The bacteria of the genus Mycoplasma (trivial name: mycoplasmas) and their close relatives are characterized by lack of a cell wall. Despite this, the cells often present a certain shape, with a characteristic small size, with typically about 10% of the volume of an Escherichia coli cell. These cell shapes presumably contribute to the ability of mycoplasmas to thrive in their respective environments. Most are pseudococcoidal, but there are notable exceptions. Species of the M. fastidiosum cluster are rod-shaped. Species of the M. pneumoniae cluster, including M. pneumoniae, possess a polar extension protruding from the pseudococcoidal cell body. This tip structure, designated an attachment organelle or terminal organelle, is essential for adherence to host cells and for movement along solid surfaces (gliding motility), and is implicated in normal cell division. M. pneumoniae cells are pleomorphic, with an attachment organelle of regular dimensions at one pole and a trailing filament of variable length and uncertain function at the other end, whereas other species in the cluster typically lack the trailing filament. Other species like M. mobile and M. pulmonis have similar structures with similar functions.

Mycoplasmas are unusual among bacteria in that most require sterols for the stability of their cytoplasmic membrane. Sterols are acquired from the environment, usually as cholesterol from the animal host. Mycoplasmas generally possess a relatively small genome of 0.58-1.38 megabases, which results in drastically reduced biosynthetic capabilities and explains their dependence on a host. Additionally they use an alternate genetic code in which the codon UGA encodes the amino acid tryptophan instead of the usual stop codon. They have a low GC-content (23-40 mol %).

First isolation[edit]

In 1898 Nocard and Roux reported the cultivation of the causative agent of CBPP, which was at that time a grave and widespread disease in cattle herds.[6][7] The disease is caused by M. mycoides subsp. mycoides SC (small-colony type), and the work of Nocard and Roux represented the first isolation of a mycoplasma species. Cultivation was, and still is difficult because of the complex growth requirements.

These researchers succeeded by inoculating a semi-permeable pouch of sterile medium with pulmonary fluid from an infected animal and depositing this pouch intraperitoneally into a live rabbit. After fifteen to twenty days, the fluid inside of the recovered pouch was opaque, indicating the growth of a microorganism. Opacity of the fluid was not seen in the control. This turbid broth could then be used to inoculate a second and third round and subsequently introduced into a healthy animal, causing disease. However, this did not work if the material was heated, indicating a biological agent at work. Uninoculated media in the pouch, after removal from the rabbit, could be used to grow the organism in vitro, demonstrating the possibility of cell-free cultivation and ruling out viral causes, although this was not fully appreciated at the time .[6]

Small genome[edit]

Recent advances in molecular biology and genomics have brought the genetically simple mycoplasmas, particularly M. pneumoniae and its close relative M. genitalium, to a larger audience. The second published complete bacterial genome sequence was that of M. genitalium, which has one of the smallest genomes of free-living organisms.[8] The M. pneumoniae genome sequence was published soon afterwards and was the first genome sequence determined by primer walking of a cosmid library instead of the whole-genome shotgun method.[9] Mycoplasma genomics and proteomics continue in efforts to understand the so-called minimal cell,[10] to catalog the entire protein content of a cell,[11] and generally continue to take advantage of the small genome of these organisms to understand broad biological concepts.

Taxonomy[edit]

The medical and agricultural importance of members of the genus Mycoplasma and related genera has led to the extensive cataloging of many of these organisms by culture, serology, and small subunit rRNA gene and whole genome sequencing. A recent focus in the sub-discipline of molecular phylogenetics has both clarified and confused certain aspects of the organization of the class Mollicutes.[12]

Originally the trivial name "mycoplasmas" has commonly denoted all members of the class Mollicutes. The name "Mollicutes" is derived from the Latin mollis (soft) and cutis (skin), and all of these bacteria do lack a cell wall and the genetic capability to synthesize peptidoglycan.

Despite the lack of a cell wall, many taxonomists have classified Mycoplasma and relatives in the phylum Firmicutes, consisting of low G+C Gram-positive bacteria such as Clostridium, Lactobacillus, and Streptococcus based on 16S rRNA gene analysis.

The order Mycoplasmatales contains a single family, Mycoplasmataceae, comprising two genera: Mycoplasma and Ureaplasma. Now Mycoplasma is a genus in Mollicutes.

Historically, the description of a bacterium lacking a cell wall was sufficient to classify it to the genus Mycoplasma and as such it is the oldest and largest genus of the class with about half of the class' species (107 validly described), each usually limited to a specific host and with many hosts harboring more than one species, some pathogenic and some commensal. In later studies, many of these species were found to be phylogenetically distributed among at least three separate orders.

A limiting criterion for inclusion within the genus Mycoplasma is that the organism have a vertebrate host. In fact, the type species, M. mycoides, along with other significant mycoplasma species like M. capricolum, is evolutionarily more closely related to the genus Spiroplasma in the order Entomoplasmatales than to the other members of the Mycoplasma genus. This and other discrepancies will likely remain unresolved because of the extreme confusion that change could engender among the medical and agricultural communities.

The remaining species in the genus Mycoplasma are divided into three non-taxonomic groups, hominis, pneumoniae and fermentans, based on 16S rRNA gene sequences.
The hominis group contains the phylogenetic clusters of M. bovis, M. pulmonis, and M. hominis, among others. M. hyopneumoniae is a primary bacterial agent of the porcine respiratory disease complex.

The pneumoniae group contains the clusters of M. muris, M. fastidiosum, U. urealyticum, the currently unculturable haemotrophic mollicutes, informally referred to as haemoplasmas (recently transferred from the genera Haemobartonella and Eperythrozoon), and the M. pneumoniae cluster. This cluster contains the species (and the usual or likely host) M. alvi (bovine), M. amphoriforme (human), M. gallisepticum (avian), M. genitalium (human), M. imitans (avian), M. pirum (uncertain/human), M. testudinis (tortoises), and M. pneumoniae (human). Most if not all of these species share some otherwise unique characteristics including an attachment organelle, homologs of the M. pneumoniae cytadherence-accessory proteins, and specialized modifications of the cell division apparatus.

A study of 143 genes in 15 species of Mycoplasma suggests that the genus can be grouped into four clades: the M. hyopneumoniae group, the M. mycoides group, the M. pneumoniae group and a Bacillus-Phytoplasma group.[13] The M. hyopneumoniae group is more closely related to the M. pneumoniae group than the M. mycoides group.

Laboratory contaminant[edit]

Mycoplasma species are often found in research laboratories as contaminants in cell culture. Mycoplasmal cell culture contamination occurs due to contamination from individuals or contaminated cell culture medium ingredients[clarification needed][citation needed]. Mycoplasma cells are physically small – less than 1 µm – and they are therefore difficult to detect with a conventional microscope.

Mycoplasmas may induce cellular changes, including chromosome aberrations, changes in metabolism and cell growth. Severe Mycoplasma infections may destroy a cell line. Detection techniques include DNA Probe, enzyme immunoassays, PCR, plating on sensitive agar and staining with a DNA stain including DAPI or Hoechst.

It has been estimated that at least 11 to 15% of U.S. laboratory cell cultures are contaminated with mycoplasma.[14] A Corning study showed that half of U.S. scientists did not test for mycoplasma contamination in their cell cultures. The study also stated that, in former Czechoslovakia, 100% of cell cultures that were not routinely tested were contaminated while only 2% of those routinely tested were contaminated (study page 6). Since the U.S. contamination rate was based on a study of companies that routinely checked for mycoplasma, the actual contamination rate may be higher. European contamination rates are higher and that of other countries are higher still (up to 80% of Japanese cell cultures).[15] About 1% of published Gene Expression Omnibus data may have been compromised.[16][17] Several antibiotic based formulation of anti-mycoplasma reagents have been developed over the years.[18]

Synthetic mycoplasma genome[edit]

A chemically synthesized genome of a mycoplasmal cell based entirely on synthetic DNA which can self-replicate has been referred to as Mycoplasma laboratorium.[19]

Pathogenicity[edit]

Several Mycoplasma species can cause disease, including M. pneumoniae, which is an important cause of atypical pneumonia (formerly known as "walking pneumonia"), and M. genitalium, which has been associated with pelvic inflammatory diseases. Mycoplasma infections in humans are associated with skin eruptions in 17% of cases.[20]:293

Links to cancer[edit]

Several species of mycoplasma are frequently detected in different types of cancer cells.[21][22][23] These species are:

The majority of these mycoplasma have shown a strong correlation to malignant transformation in mammalian cells in vitro.

Mycoplasma infection and host cell transformation[edit]

The presence of mycoplasma was first reported in samples of cancer tissue in the 1960s.[23] Since then there have been several studies trying to find and prove the connection between mycoplasma and cancer, as well as how the bacterium might be involved in the formation of cancer.[22] Several studies have shown that cells that are chronically infected with the bacteria go through a multistep transformation. The changes caused by chronic mycoplasmal infections occur gradually and are both morphological and genetic.[22] The first visual sign of infection is when the cells gradually shift from their normal form to sickle shaped. They also become hyperchromatic due to an increase of DNA in the nucleus of the cells. In later stages, the cells lose the need for a solid support in order to grow and proliferate as well as the normal contact dependent inhibition cells.[23]

Possible intracellular mechanisms of mycoplasmal malignant transformation[edit]

Karyotypic changes related to mycoplasma infections

Cells infected with mycoplasma for an extended period of time show significant chromosomal abnormalities. These include the addition of chromosomes, the loss of entire chromosomes, partial loss of chromosomes and chromosomal translocation. All of these genetic abnormalities may contribute to the process of malignant transformation. Chromosomal translocation and extra chromosomes help create abnormally high activity of certain proto-oncogenes. Proto-oncogenes with increased activity caused by these genetic abnormalities include those encoding c-myc, HRAS,[24] and vav.[22] The activity of proto-oncogenes is not the only cellular function that is affected; tumour suppressor genes are affected by the chromosomal changes induced by mycoplasma as well. Partial or complete loss of chromosomes causes the loss of important genes involved in the regulation of cell proliferation.[23] Two genes whose activities are markedly decreased during chronic infections with mycoplasma are the Rb and the p53 tumour suppressor genes.[22] A major feature that differentiates mycoplasmas from other carcinogenic pathogens is that the mycoplasmas do not cause the cellular changes by insertion of their own genetic material into the host cell.[24] The exact mechanism by which the bacterium causes the changes is not yet known.

Partial reversibility of malignant transformations

The malignant transformation induced by mycoplasma is also different from that caused by other pathogens in that the process is reversible. The state of reversal is, however, only possible up to a certain point during the infection. The window of time that reversibility is possible varies greatly; it depends primarily on the mycoplasma involved. In the case of M. fermentans, the transformation is reversible up until around week 11 of infection and starts to become irreversible between week 11 and 18.[23] If the bacteria are killed using antibiotics [23] (i.e. ciprofloxacin [22] or Clarithromycin [29]) before the irreversible stage, the infected cells should return to normal.

Connections to cancer in vivo and future research[edit]

Though mycoplasmas are confirmed to be carcinogenic in vitro, it is not yet confirmed whether mycoplasma might be an actual cause of cancer in vivo.[citation needed]. However recent epidemiologic, genetic, and molecular studies suggest infection and inflammation initiate certain cancers, including those of the prostate. In a 2009 study, Mycoplasma genitalium and Mycoplasma hyorhinis were found to induce malignant phenotype in benign human prostate cells (BPH-1) that were "non-tumorigenic" after 19 weeks of exposure. This study is described as one of the "first report(s) describing the capacity of M. genitalium or M. hyorhinis infection to lead to the malignant transformation of benign human epithelial cells". [27]

Some uncertainties regarding the bacteria’s potential to cause malignancies may be due to the fact that cells used in studies are often from immortalised cell lines like the BEAS-2B cells. These are essentially cells on the verge of becoming malignant. One problem with using such cells to induce carcinogenesis is that they transform spontaneously after 32 passagess (when a small number of cells are transferred into a new vessel to extend culture duration).[citation needed] This, and the fact that malignant transformation has not been directly detected in non-immortalised “normal” cells that have been infected, might indicate that mycoplasmas accelerates a cell’s progression towards malignancy, rather than actually causing it. No mycoplasma-generated cancer has yet to be documented in vivo cultures.[citation needed] It might, however, be possible that very long, chronic infections of mycoplasma are able to cause cancer in non-immortalised cells. This is not yet known since non-immortalised cells can only divide for a limited number of times, and therefore it has not been possible to keep culturing them long enough to develop cancer. More research is needed to confirm that mycoplasma infections cause cancer or initiate malignancies in human cells. This might be an important step to treat and prevent cancer.[27]

Types of cancer associated with mycoplasma[edit]

Colon cancer: In a study to understand the effects of mycoplasma contamination on the quality of cultured human colon cancer cells, it was found that there is a positive correlation between the amount of M. hyorhinis present in the sample and the percentage of CD133 positive cells (a glycoprotein with an unknown function). Further tests and analysis are required to determine the exact reason for this phenomenon.[30]

Gastric cancer: There are strong indications that the infection of M. hyorhinis contributes to the development of cancer within the stomach and increases the likelihood of malignant cancer cell development.[31]

Lung cancer: Studies on lung cancer have supported the belief that there is more than a coincidental positive correlation between the appearance of Mycoplasma strains in patients and the infection with tumorigenesis. Because this is a such a new area of research, more studies must be performed to further understand the correlation and determine possible preventative steps for lung cancer involving mycoplasma.[32]

Prostate cancer: p37, a protein encoded for by M. hyorhinis, has been found to promote the invasiveness of prostate cancer cells. The protein also causes the growth, morphology, and the gene expression of the cells to change, causing them to become a more aggressive phenotype.[33]

Renal Cancer: Patients with renal cell carcinoma (RCC) exhibited a significantly high amount of Mycoplasma sp. compared with the healthy control group. This suggests that mycoplasma may play a role in the development of RCC.[29]

References[edit]

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External links[edit]