Mycoplasma pneumoniae

In 1898, Nocard and Roux isolated an agent assumed to be the cause of cattle pneumonia and named it microbe de la peripneumonie Microorganisms from other sources, having properties similar to the pleuropneumonia organism (PPO) of cattle, soon came to be known as pleuropneumonia-like organisms (PPLO), but their true nature remained unknown. In 1944, Monroe Eaton used embryonated chicken eggs to cultivate an agent thought to be the cause of human primary atypical pneumonia (PAP), commonly known as "walking pneumonia." This unknown organism became known as the "Eaton agent". At that time, Eaton's use of embryonated eggs, then used for cultivating viruses, supported the idea that the Eaton agent was a virus. Yet it was known that PAP was amenable to treatment with broad-spectrum antibiotics, making a viral etiology suspect. Robert Chanock, a researcher from the NIH who was studying the Eaton agent as a virus, visited the Wistar Institute in Philadelphia in 1961 to obtain a cell culture of a normal human cell strain developed by Leonard Hayflick. This cell strain was known to be exquisitely sensitive to isolate and grow human viruses. Chanock told Hayflick of his research on the Eaton agent, and his belief that its viral nature was questionable. Although Hayflick knew little about the current research on this agent, his doctoral dissertation had been done on animal diseases caused by PPLO. Hayflick knew that many lower animals suffered from pneumonias caused by PPLOs (later to be termed mycoplasmas). Hayflick reasoned that the Eaton agent might be a mycoplasma, and not a virus. Chanock had never heard of mycoplasmas, and at Hayflick's request sent him egg yolk containing the Eaton agent. Using a novel agar and fluid medium formulation he had devised, When this discovery became known to Emmy Klieneberger-Nobel of the Lister Institute in London, the world's leading authority on these organisms, she suggested that the organism be named Mycoplasma hayflickiae. Hayflick demurred in favor of Mycoplasma pneumoniae. This smallest free-living microorganism was the first to be isolated and proven to be the cause of a human disease. For his discovery, Hayflick was presented with the Presidential Award by the International Organization of Mycoplasmology. The inverted microscope under which Hayflick discovered Mycoplasma pneumoniae is kept by the Smithsonian Institution. ==Taxonomy and classification==

The term mycoplasma ( meaning fungus, and , meaning formed) is derived from the fungal-like growth of some mycoplasma species. Mycoplasmas, which are among the smallest self-replicating organisms, are parasitic species that lack a cell wall and periplasmic space, have reduced genomes, and limited metabolic activity. Mycoplasmas are further classified by the sequence composition of 16s rRNA. All mycoplasmas of the pneumoniae group possess similar 16s rRNA variations unique to the group, of which M. pneumoniae has a 6.3% variation in the conserved regions, that suggest mycoplasmas formed by degenerative evolution from the gram-positive eubacterial group that includes bacilli, streptococci, and lactobacilli. M. pneumoniae is a member of the family Mycoplasmataceae and order Mycoplasmatales. ==Cell biology==

Mycoplasma pneumoniae cells have an elongated shape that is approximately 0.1–0.2 μm (100–200 nm) in width and 1–2 μm (1000-2000 nm) in length. The extremely small cell size means they are incapable of being examined by light microscopy; a stereomicroscope is required for viewing the morphology of M. pneumoniae colonies, which are usually less than 100 μm in length. M. pneumoniae is consequently very susceptible to loss of enzymatic function by gene mutations, as the only buffering systems against functional loss by point mutations are for maintenance of the pentose phosphate pathway and nucleotide metabolism.  This means that the pathogen has fewer metabolic reactions in comparison to other bacterial species such as B.subtilis and Escherichia coli. Since Mycoplasma pneumoniae has a reduced genome, it has a smaller number of overall paths and metabolic enzymes, which contributes to its more linear metabolome. Extensive study of the metabolic network of this organism has led to the identification of biomarkers that can potentially reveal the presence of the extensive complications the bacteria can cause. Metabolomics is increasingly being used as a useful tool for the verification of biomarkers of infectious pathogens. ==Pathogenicity==

Mycoplasma pneumoniae parasitizes the respiratory tract epithelium of humans. This network of proteins participates not only in the initiation of attachment organelle formation and adhesion but also in motility. Both the presence of P1 and its concentration on the cell surface are required for the attachment of M. pneumoniae to the host cell. M. pneumoniae cells treated with monoclonal antibodies specific to the immunogenic C-terminus of the P1 adhesin have been shown to be inhibited in their ability to attach to the host cell surface by approximately 75%, suggesting P1 is a major component in adherence. Lectins on the surface of the bacterial cells are capable of binding oligosaccharide chains on glycolipids and glycoproteins to facilitate attachment, in addition to the proteins TU and pyruvate dehydrogenase E1 β, which bind to fibronectin. In addition to the close physical proximity of M. pneumoniae and host cells, the lack of cell wall and peculiar cell membrane components, like cholesterol, may facilitate fusion. Internal localization may produce chronic or latent infections as M. pneumoniae is capable of persisting, synthesizing DNA, and replicating within the host cell even after treatment with antibiotics. The CARDS toxin most likely aids in the colonization and pathogenic pathways of M. pneumoniae, leading to inflammation and airway dysfunction. The third virulence factor is the formation of hydrogen peroxide in M. pneumoniae infections. The cytotoxic effects of M. pneumoniae infections translate into common symptoms like coughing and lung irritation that may persist for months after infection has subsided. Local inflammation and hyperresponsiveness by infection induced cytokine production has been associated with chronic conditions such as bronchial asthma and has also been linked to progression of symptoms in individuals with cystic fibrosis and COPD. ==Antimicrobial activity==

Infections can be treated with oral antibiotics from the macrolide family, which work by inhibiting the Mycoplasma protein biosynthesis. Historically, erythromycin is the oldest drug. As first choice, azithromycin or clarithromycin are used, as they have more convenient pharmacokinetics than erythromycin: they only need to be taken once or twice and not four times a day and they have fewer side effects. Alternatively, tetracyclines (eg, doxycycline), and respiratory fluoroquinolones (eg, levofloxacin or moxifloxacin) can be used; they have an undesirable side effect profile in children. Beta-lactams such as penicillin are completely ineffective, because they target the cell wall synthesis. Resistance Resistance to macrolides has been reported as early as 1967. Increased antibiotic usage has been followed by an increase in resistance since 2000. Resistance in the 2020s has been highest in Asia, as high as 100%, while rates in the United States have varied from 3.5% to 13%. A single base mutation in the V region of 23S rRNA, like A2063/2064G is responsible for more than 90% of the macrolide-resistant infections. Since routine culture and susceptibility testing is not performed, as M. pneumoniae is difficult to grow, clinicians will select an antibiotic based on an estimate of local resistance, on treatment response and on other factors. ==See also==