Mycoplasma pneumoniae is a species of very small-cell bacteria that lack a cell wall, in the class Mollicutes. M. pneumoniae is a human pathogen that causes the disease Mycoplasma pneumonia, a form of atypical bacterial pneumonia related to cold agglutinin disease.

It is one of the smallest self-replicating organisms and its discovery traces back to 1898 when Nocard and Roux isolated a microorganism linked to cattle pneumonia. This microbe shared characteristics with pleuropneumonia-like organisms (PPLOs), which were soon linked to pneumonias and arthritis in several animals. A significant development occurred in 1944 when Monroe Eaton cultivated an agent thought responsible for human pneumonia in embryonated chicken eggs, referred to as the "Eaton agent." This agent was classified as a bacteria due to its cultivation method and because antibiotics were effective in treating the infection, questioning its viral nature. In 1961, a researcher named Robert Chanock, collaborating with Leonard Hayflick, revisited the Eaton agent and posited it could be a mycoplasma, a hypothesis confirmed by Hayflick's isolation of a unique mycoplasma, later named Mycoplasma pneumoniae. Hayflick's discovery proved M. pneumoniae was responsible for causing human pneumonia.

Taxonomically, Mycoplasma pneumoniae is part of the Mollicutes class, characterized by their lack of a peptidoglycan cell wall, making them inherently resistant to antibiotics targeting cell wall synthesis, such as beta-lactams. With a reduced genome and metabolic simplicity, mycoplasmas are obligate parasites with limited metabolic pathways, relying heavily on host resources. This bacterium uses a specialized attachment organelle to adhere to respiratory tract cells, facilitating motility and cell invasion. The persistence of M. pneumoniae infections even after treatment is associated with its ability to mimic host cell surface composition.

Pathogenic mechanisms of M. pneumoniae involve host cell adhesion and cytotoxic effects, including cilia loss and hydrogen peroxide release, which lead to respiratory symptoms and complications such as bronchial asthma and chronic obstructive pulmonary disease. Additionally, the bacterium produces a unique CARDS toxin, contributing to inflammation and respiratory distress. Treatment of M. pneumoniae infections typically involves macrolides or tetracyclines, as these antibiotics inhibit protein synthesis, though resistance has been increasing, particularly in Asia. This resistance predominantly arises from mutations in the 23S rRNA gene, which interfere with macrolide binding, complicating management and necessitating alternative treatment strategies.

Discovery and history

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.

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 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.

thumb|Metabolic pathway map depicting the enzymes of glycolysis in Mycoplasma pneumoniae.Green boxes signify enzymes that are present in the pathway. The white boxes symbolize missing enzymes. Enzymes of the TCA cycle are missing in M. pneumoniae. The complete pathway can be found at KEGG.

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. 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.

Macrolide antibiotics work by inhibiting Mycoplasma protein biosynthesis. The Chinese Journal of Pediatrics recommends macrolides for mild infections in children, with azithromycin as the first choice, followed by erythromycin or clarithromycin.

Alternatively, tetracyclines (eg, doxycycline), and respiratory fluoroquinolones (eg, levofloxacin or moxifloxacin) can be used, but the United States CDC does not recommend them as a first line treatment for children. 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.

  • Bacterial pneumonia

References

This article incorporates public domain text from the CDC as cited.

Further reading

  • See also Hayflick's comments on Meredith Wadman's book, "The Vaccine Race: Science, Politics and the Human Costs of Defeating Disease", 2017 Errors in "The Vaccine Race" book
  • Mycoplasma pneumoniae genome
  • Type strain of Mycoplasma pneumoniae at BacDive – the Bacterial Diversity Metadatabase
  • Mycoplasmoides pneumoniae at VetBact