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 ~  Abstract
 ~ Introduction
 ~ Cytadherence
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  Table of Contents  
Year : 2016  |  Volume : 34  |  Issue : 1  |  Page : 7-16

Pathogenesis of Mycoplasma pneumoniae: An update

Department of Microbiology, AIIMS, New Delhi, India

Date of Submission30-Sep-2014
Date of Acceptance08-Sep-2015
Date of Web Publication15-Jan-2016

Correspondence Address:
R Chaudhry
Department of Microbiology, AIIMS, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0255-0857.174112

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 ~ Abstract 

Genus Mycoplasma, belonging to the class Mollicutes, encompasses unique lifeforms comprising of a small genome of 8,00,000 base pairs and the inability to produce a cell wall under any circumstances. Mycoplasma pneumoniae is the most common pathogenic species infecting humans. It is an atypical respiratory bacteria causing community acquired pneumonia (CAP) in children and adults of all ages. Although atypical pneumonia caused by M. pneumoniae can be managed in outpatient settings, complications affecting multiple organ systems can lead to hospitalization in vulnerable population. M. pneumoniae infection has also been associated with chronic lung disease and bronchial asthma. With the advent of molecular methods of diagnosis and genetic, immunological and ultrastructural assays that study infectious disease pathogenesis at subcellular level, newer virulence factors of M. pneumoniae have been recognized by researchers. Structure of the attachment organelle of the organism, that mediates the crucial initial step of cytadherence to respiratory tract epithelium through complex interaction between different adhesins and accessory adhesion proteins, has been decoded. Several subsequent virulence mechanisms like intracellular localization, direct cytotoxicity and activation of the inflammatory cascade through toll-like receptors (TLRs) leading to inflammatory cytokine mediated tissue injury, have also been demonstrated to play an essential role in pathogenesis. The most significant update in the knowledge of pathogenesis has been the discovery of Community-Acquired Respiratory Distress Syndrome toxin (CARDS toxin) of M. pneumoniae and its ability of adenosine diphosphate (ADP) ribosylation and inflammosome activation, thus initiating airway inflammation. Advances have also been made in terms of the different pathways behind the genesis of extrapulmonary complications. This article aims to comprehensively review the recent advances in the knowledge of pathogenesis of this organism, that had remained elusive during the era of serological diagnosis. Elucidation of virulence mechanisms of M. pneumoniae will help researchers to design effective vaccine candidates and newer therapeutic targets against this agent.

Keywords: Epidemiology, Mycoplasma pneumoniae, pathogenesis

How to cite this article:
Chaudhry R, Ghosh A, Chandolia A. Pathogenesis of Mycoplasma pneumoniae: An update. Indian J Med Microbiol 2016;34:7-16

How to cite this URL:
Chaudhry R, Ghosh A, Chandolia A. Pathogenesis of Mycoplasma pneumoniae: An update. Indian J Med Microbiol [serial online] 2016 [cited 2021 Jan 22];34:7-16. Available from:

 ~ Introduction Top

Community-acquired pneumonia (CAP) continues to be a significant cause of mortality and morbidity worldwide, particularly in the elderly population and under five children.[1],[2] The mortality rate of CAP can rise to 10% in hospital ward admitted patients and can exceed 30% in Intensive Care Unit patients requiring mechanical ventilation and prolonged hospitalisation.[3] Of all aetiological agents of CAP, atypical respiratory bacteria viz., Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella spp. are increasingly being recognised as emerging pathogens.[4] Studies have demonstrated that the atypical bacteria rank as the third or fourth leading organisms causing CAP, being present in about 22–40% of all CAP patients, often as co-pathogens with other bacteria.[5],[6],[7] In a multi-centric study involving 12 medical centres across Asia, atypical respiratory bacteria were noted in more than 23% of CAP cases. M. pneumoniae was detected in approximately 12% of all CAP cases and was the most common atypical bacteria isolated.[8] In paediatric population, M. pneumoniae account for approximately 10–40% of all lower respiratory tract infections.[8],[9]

Infection with M. pneumoniae is mostly encountered in outpatient setting. However, it is a significant cause of hospitalisation also due to pneumonia, especially in elderly population and immunocompromised patients.[10] Manifestations of M. pneumoniae infection can range from self-limiting upper respiratory illness to severe pneumonia. Children <5 years of age usually suffer from mild upper respiratory symptoms while older children and adolescents develop bronchopneumonia, requiring hospitalisation.[11],[12]M. pneumonia e has been detected in higher proportions in respiratory samples of adults and children with asthmatic attacks or exacerbation, as compared to healthy controls.[13] High rates of carriage of M. pneumoniae in the airways of chronic stable asthmatics also point towards the association of M. pneumoniae with asthma.[14] In a study from our centre too, there was statistically significant association between M. pneumoniae infection and children with severe persistent asthma and acute exacerbation of asthma in previously diagnosed asthmatic children.[15] However, it is only in the recent studies, significant progress has been made in establishing the mechanism by which this organism can cause or exacerbate asthma, an issue that had remained debatable over the years.[16]

Mycoplasmas, which belong to the bacterial class Mollicutes, are cell-wall deficient smallest self-replicating organisms capable of cell free survival.[17] The genome of M. pneumoniae is small (approximately 816 kilo base-pairs) which accounts for its limited biosynthetic capabilities and slow replication rate.[18] Thus, a major obstacle in understanding the pathogenic role of this organism has been the lack of knowledge of its biological properties due to difficulties associated with cultivation of this organism.

Early researches that have counted the role of M. pneumoniae in the pathogenesis of different clinical entities depended only on serological assays which were less specific and could not provide a definite association with disease pathogenesis.[12] Since, IgM antibodies may not be present early in the course of infection, diagnosis based only on serology may not be accurate. In fact, seroprevalence of M. pneumoniae in adults with pneumoniae has been found to be highly variable ranging from 1.9% to over 30%.[19] Moreover, simultaneous detection of co-pathogens, which included respiratory viruses and other bacteria, often considered M. pneumoniae as an innocent bystander organism.[20],[21] Advances in molecular diagnosis such as nucleic-acid amplification tests (NAATs), sequencing and proteomic studies have helped us to gain knowledge about the pathogenesis of this organism that had remained elusive.[22],[23] In the past few years, potential pathogenic factors associated with this organism have been studied in details using molecular methods by researchers who had looked into different aspects of pathogenesis such as complex adherence mechanism of M. pneumoniae, the community-acquired respiratory distress syndrome toxin (CARDS toxin) that activate the inflammasomes and the genesis of extrapulmonary complications. The inflammatory pathways leading to tissue injury following M. pneumoniae infection have been elucidated using highly sensitive cytokine assays and mRNA expression systems. In this article, we try to comprehensively review the pathogenesis of M. pneumoniae highlighting the recent advances in terms of cytadherence, cytotoxic and inflammatory potential and the pathogenic role of CARDS toxin. We also discuss about the updates in molecular pathogenesis of extrapulmonary manifestations of M. pneumoniae infection.

 ~ Cytadherence Top

The initial step of M. pneumoniae respiratory tract infection involves cytadherence of the organism to the ciliated columnar epithelium of the respiratory tract, which protects the organism from mucociliary clearance and local cytotoxic effects.[12] Cellular adherence to sialoglycoproteins and sulphated glycolipids is mediated by a specialised organelle, the structure of which has been delineated by electron microscopy. It consists of a central core composed of dense filaments and a tip-like structure composed of adhesins and accessory proteins.[24],[25] The major proteins, that have been experimentally proven directly involved in receptor binding, are the 170 kilodalton P1-adhesin and the P30-adhesin. High molecular weight protein-1 (HMW-1), HMW-2, HMW-3 and proteins A, B and C act as accessory proteins, interacting with P1 and P30 and assisting in cytadherence.[26],[27] A schematic representation of M. pneumoniae adherence organelle is provided in [Figure 1].
Figure 1: Mycoplasma pneumoniae cytadherence organelle with adherence proteins (Reproduced from Frontiers in Bioscience 2007; 12: 690-699 by R Chaudhry et al.)

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The P1-adhesin is a transmembrane protein, concentrated primarily at the tip of the attachment organelle of M. pneumoniae. Mutant strains lacking P1-adhesin fail to adhere to animal cells and are avirulent.[28],[29]In vitro studies have demonstrated that P1-adhesin is also involved in gliding motility of the organism that may help in cell to cell transfer. Repeated gliding motility allows the organism to bind and release itself from the attaching surface which eventually increases the infective surface area. Anti-P1 monoclonal antibody had inhibitory effects on gliding motility and adherence to tracheal rings by M. pneumoniae.[30]

Studies by Kenri et al. and Su et al. have shown that there are variable regions on the P1-adhesin protein attributed to the repetitive sequences of this cytadhesin gene.[31],[32] According to Jacobs, the adherence mediating domains of P1-adhesin are highly conserved while the immunodominant epitopes are variable. Thus, antibodies which are predominantly against the immunodominant epitopes, fail to block the antigenically distinct cytadherent protein, allowing the organism to evade antibody response.[33] In a recent study from our centre, we have shown that immunodominant regions are actually distributed throughout the length of P1-protein. Only the amino and carboxy-terminals of P1-protein are surface exposed and antibodies directed to these regions blocked adherence of M. pneumoniae to Hep-2 cell line. Antibodies to the middle part failed to block cytadhesion.[34]


The other important protein involved in adherence of M. pneumoniae is the P30-adhesin. It is a transmembrane protein present in cluster at the attachment organelle tip. Additional function of P30 includes gliding motility and co-ordination of cell division with biogenesis of the attachment organelle.[35],[36]

Accessory adhesion proteins

Interactions of major adhesin proteins with the accessory proteins such as HMW-1, HMW-2, HMW-3 and protein-A, protein-B and protein-C help in establishing the complete attachment organelle structure. Mutations in genes encoding the accessory proteins lead to cytadherence defects.[36],[37] Two other proteins viz., P65 and P116 have recently been shown to be present at the distal end of the terminal organelle, which probably act by interacting with P1 and P30 adhesins thus assisting in attachment.[38],[39] However, further role of these accessory proteins in pathogenesis of M. pneumoniae needs to be studied for better understanding of interactions between host cells and the organism. The adhesion proteins may serve as potential targets for therapeutic and vaccine strategies against M. pneumoniae.

To summarise, the adhesins of M. pneumoniae through their complex interactions allow close association of the organism with host cells which is followed by cytotoxicity and inflammation. Intracellular localisation may occur in M. pneumoniae before it induces cytotoxicity. However, the extent of intracellular localisation is not known in vivo. The fusion of Mycoplasma cell membrane with the host cell enabling intracellular location may help in establishing latent or chronic states, avoiding immune response and impairing drug therapy.

 ~ Cytotoxicity and Inflammation Top

Free radical mediated cellular damage is one of the pathways by which M. pneumoniae affects respiratory epithelium. Oxidative stress as an important step in pathogenesis of M. pneumoniae results from the hydrogen peroxide and superoxide radicals generated by the organisms as well as by the host immune system.[40] Superoxide radicals also inhibit host cell catalase, thereby augmenting the effect of free radical damage.[41] Sun et al. in 2008 demonstrated that M. pneumoniae infection of A549 human lung carcinoma cell line led to generation of reactive oxygen species (ROS). Generation of ROS induced changes in proteomic profile of the cell line in terms of exposure of host oxidative stress response enzymes such as glucose-6-phosphate dehydrogenase, nicotinamide adenine dinucleotide (NAD) dehydrogenase and also caused DNA double-stranded breaks.[42] Similar role of ROS in mediating lung injury by M. pneumoniae has been demonstrated in mice. Mycoplasma infection in mice caused impairment of alveolar ion transport leading to decreased alveolar fluid clearance due to ROS-mediated damage to epithelial sodium channels.[43]

Pulmonary injury due to M. pneumoniae infection has also been attributed to the host inflammatory response. M. pneumoniae infection is characterised by peribronchiolar alveolar infiltration with neutrophils, lymphocytes and plasma cells.[44]In vitro studies in human lung epithelial carcinoma cells have shown increased levels of proinflammatory cytokines-like interleukin-8 (IL-8) and tumour necrosis factor α (TNF-α) in culture media and cellular expression of IL-1β mRNA. These cytokines act as potent chemoattractants for inflammatory cells. Increased levels of these proinflammatory cytokines result from the activation of pattern recognition receptors (PRRs) namely toll-like receptor-1 (TLR-1), TLR-2 and TLR-6 by M. pneumoniae membrane proteins.[45] Lipid-associated membrane protein or a dipalmitoylated lipoprotein of M. pneumoniae activates TLR-1, TLR-2 and TLR-6 leading to activation of monocytic nuclear factor-κβ (NF-κβ), a key regulator of proinflammatory cytokine release.[45],[46] In mice models it was demonstrated that a previous challenge with M. pneumoniae extracts actually upregulated TLR-2 expression in alveolar macrophages which resulted in a magnified inflammatory response to subsequent challenges by the same extract.[45]

Thus, a major pathway of M. pneumoniae pathogenesis is induction of inflammation via the TLR-mediated cytokine release and generation of free radicals. In addition an exaggerated innate immune response in M. pneumoniae infection can be due to a positive feedback effect of previous M. pneumoniae colonisation or asymptomatic infection. This recent update in the concept of immunopathogenesis of M. pneumoniae will help researchers to target potential molecules such as the membrane lipoproteins and other TLR ligands for modulating high levels of airway inflammation and prevent lung injury due to M. pneumoniae.

 ~ Community-Acquired Respiratory Distress Syndrome Toxin Top

Community-acquired respiratory distress syndrome toxin: Background

Early studies in the 1970s and 1980s had tried to describe the pathology of M. pneumoniae infection using organ culture and cell culture systems.[47],[48] Infection of hamster tracheal culture was characterised by ciliostasis and cytoplasmic vacuolisation followed by aggregation of intracellular vacuoles leading to cytoplasmic distortion and cell damage.[48] Based on the cytotoxic effects of M. pneumoniae infection, researchers hypothesised that a Mycoplasma membrane associated toxic factor could be responsible for pathogenesis.[49] Toxic effects of free radical generation could only partially explain such effects of M. pneumoniae virulence.[40],[50] In 1975, Hu et al. demonstrated the inhibition of RNA and protein synthesis along with decreased uptake of metabolic substrates in M. pneumoniae infected host cells which could not be explained by cytadherence process of the organism and effects of generation of ROS. Hu et al. thus, suggested that the primary detrimental effect on the host cell was at the transcriptional or translational level. The fact that cytopathic effects of M. pneumoniae infection could only be reversed by early addition of erythromycin to the organ culture (within 24 h of infection) pointed to the conclusion that the organism required to synthesise a certain protein or toxin to mediate host cell injury.[48]

Subsequently, Kannan et al. in their attempt to characterise the virulence factors of M. pneumoniae observed calcium dependent, trypsin sensitive binding M. pneumoniae to human surfactant protein-A. Surfactant protein-A binding of M. pneumoniae was found to be a crucial factor in the colonisation of the respiratory tract by the organism.[51] This protein of M. pneumoniae, required for binding, was identified by affinity chromatography followed by purification and sequencing. The 68-kDa protein, which was different from adhesin, cytadherence-associated proteins or fibronectin binding proteins, was initially termed as MPN 372. It shared amino acid homology at the catalytic site with that of the S1 subunit of Bordetella pertussis toxin. The MPN 372 protein was found to catalyse adenosine diphosphate ribosylation (ADP-ribosylation), similar to Bordetella pertussis toxin S1 subunit, and possess vacuolating function in infected cells.[51] Using mammalian cell lines and baboon tracheal organ culture, Kannan and Baseman confirmed the virulent properties of the protein and gave it the name CARDS toxin.[52]

Recombinant CARDS toxin was synthesised by expression in  Escherichia More Details coli to overcome the problem of isolating the toxin in minute or insufficient quantities in the broth culture of inherently slow growing mycoplasmas.[53] Treatment of Chinese hamster ovary cells or HEp-2 cells with the recombinant toxin showed its ability to transfer ADP-ribosyl group from nicotinamide adenine diphosphate (NAD +) to amino acids of cellular protein. The ribosylating property of CARDS toxin resulted in alteration of the protein targets including enzymes of host cell metabolic pathways which lead to cellular toxicity. Cytopathic effects in the form of vacuolisation, cellular rounding and cellular distortion were also exhibited.[53] In organ culture of baboon tracheal rings, recombinant CARDS toxin caused loss of ciliary function of respiratory epithelium, intensive cytoplasmic vacuolisation, karyopyknosis and disruption of epithelial integrity.[54] These toxin-mediated progressive cytotoxic changes in tracheal rings were partly explanatory for the mechanism of pathogenesis of airway disease of M. pneumoniae which had remained elusive over the years.

CARDS toxin: Role in pathogenesis

Effect of the recombinant toxin on the respiratory tract has also been studied in mice and primate models. Intranasal inoculation in BALB/c mice induced airway mucous production with extensive peribronchiolar and perivascular inflammation. Along with transient neutrophilia followed by significant increase in eosinophils at day 7 of exposure in the broncho-alveolar lavage fluid (BALF).[55] Hardy et al. demonstrated that the early cytokine response in mice was predominantly proinflammatory which included IL-1, IL-6, IL-12 and TNF-α. In baboons toxin inoculation led to increase in chemokines such as regulated on activation, normal T cell expressed and secreted, IL-8, interferon-γ (IFN-γ) and granulocyte-colony stimulating factor in addition to proinflammatory cytokines, closely resembling human M. pneumoniae infection.[56] Significant increases in expression of TH2 cytokines viz., IL-4 and IL-13 and chemokines, chemokine (C-C motif) ligand-7 (CCL-7) and CCL-32, were also demonstrated using quantitative reverse transcriptase-polymerase chain reaction (PCR) of M. pneumoniae infected mice BALF by Medina et al.[57] Recombinant CARDS toxin exposure resulted in exaggerated TH2 inflammatory response in the respiratory tract of mice, previously sensitised with ovalbumin. Invasive pulmonary measurements in infected mice recorded increased airway resistance and decreased lung compliance due to increased airway reactivity.[57] Thus, in animal models CARDS toxin exposure induced a proinflammatory response in the respiratory tract.

Chemoattractant activities of CCL-17 and CCL-22 leading to lymphocyte and eosinophil recruitment and increased expression of IL-4 and IL-13, eosinophil mediated pulmonary inflammation and increased airway reactivity are determining factors in the pathogenesis of asthma in humans. A similar cytokine and cellular profile of the respiratory tract secretions are induced by CARDS toxin in mice as well as primates such as baboons. These findings point towards a role of this toxin in asthmatic exacerbation and further confirm the association between M. pneumonia infection and asthma.

Community-acquired respiratory distress syndrome toxin and inflammasome

A recent discovery about M. pneumoniae pathogenesis has been the elucidation of the pathway, by which CARDS toxin induces inflammation through regulation of inflammasome activity [Figure 2]. A component of the innate immune response system in mammals, the inflammasome comprises of a multiprotein complex present in the cell cytoplasm and acts by activation of the enzyme caspase-1 which in turn cleaves pro-IL-1β to active IL-1β.[58] The IL-1β is an inflammatory cytokine, which through activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) dependent pathways amplifies inflammatory responses against infectious agents.[59] However, over-activaion of inflammasomes after infection can cause tissue injury due to 'hyperinflammation'.[58],[60] Allergen induced inflammasome activation also leading to lung injury and lung remodelling, which has been implicated in the pathogenesis asthma and chronic obstructive pulmonary disease.[61]
Figure 2: Schematic representation of the pathway for M. pneumoniae CARDS toxin mediated inflammation

Click here to view

Nucleotide-binding oligomerization domain leucine-rich repeats containing receptors (NLRs) are intracellular PRRs, present in a wide variety of cells viz., lymphocytes, macrophages and dendritic cells. The NLRs act as sensors for pathogen associated molecular patterns (PAMPs). The most well-characterised NLR that is, NLRP-3, which is expressed in myeloid cells, complexes with inflammasome after being upregulated in response to PAMPs. This NLRP-3-inflammososme complex can activate caspase-1 which in turn leads to IL-1β release.[60] The CARDS toxin co-localizes with NLRP-3-inflammasome within mice bone-marrow derived macrophages in vitro and by its ADP-ribosylating property of NLRP-3 activates the inflammasome followed by release of IL-1β.[62],[63] The M. pneumoniae CARDS toxin has been shown to be internalised into mammalian cells via clathrin-mediated endocytosis.[64] Hence, following cellular entry CARDS toxin mediated activation of inflammasomes in alveolar macrophages can a potent mechanism of release of IL-1β, a pro-inflammatory cytokine, into the airways. In fact, higher levels of IL-1β has been detected in respiratory samples of symptomatic asthmatic patients compared to healthy controls.[65] Thus, CARDS toxin of M. pneumoniae by its ability to activate inflammasome can act as a trigger in initiating airway inflammation recapitulating the events the occurs in asthma However, the hypothesis of M. pneumoniae CARDS toxin being a causative agent or a triggering factor of asthma still remains to be tested in human models.

 ~ Pathogenesis of Extrapulmonary Manifestations Top

Respiratory infections with M. pneumoniae is often complicated in as many as 25% of cases by the involvement of various extrapulmonary systems such as nervous system, cardiovascular system, bones and joints, kidney, skin and mucosa. However, extrapulmonary manifestations can occur even in the absence of pneumonia.[66],[67] A retrospective study by Pönkä had shown that neurological complications, in absence of any respiratory symptoms, can occur in up to 18% of M. pneumoniae infected cases.[68] Pathogenic mechanisms of extrapulmonary complications have been partly elucidated and further studies are for complete understanding of these processes. Complications of central and peripheral nervous systems rank as the most common of all extrapulmonary complications and can occur in approximately 1–7% of serologically confirmed M. pneumoniae hospitalised for respiratory illnesses.[69],[70] Initial studies on central nervous system (CNS) complications were primarily based on serological diagnosis of M. pneumoniae infection and neural tissue damage was thought to be due to autoimmune mechanisms or due to other pathogens in presence of a false positive Mycoplasma serology.[66],[71] However, detection of Mycoplasma nucleic-acid by NAATs in neurological specimen has changed the perspective. M. pneumoniae associated neurological complications are now hypothesised to be caused by direct inflammatory injury due to cytokines induced by the organism, generation of antibodies cross-reactive with host tissue components and vascular occlusion due to vasculitis and/or thrombosis.[72] Interplay between these mechanisms lead to generation of neurological symptoms.

The most common form neurological complication is encephalitis, more common in children <10 years of age than in adults.[72] Up to 60% of paediatric encephalitis patients end up with neurological sequelae.[73] Other neurological manifestations include aseptic meningitis, meningoencephalitis, acute transverse myelitis, acute disseminating encephalomyelitis (ADEM), Guillain–Barré syndrome (GBS) and stroke.[74] As proposed by Narita, encephalitis due to M. pneumoniae can be classified into early-onset (onset of neurological symptoms within 7 days of onset of fever) and late-onset (onset of neurological symptoms at 8 days or after onset of fever) varieties.[75] Bitnun et al. and Socan et al. have also supported such a classification in their studies.[76],[77] It has been hypothesised that early-onset encephalitis is the result of cytokine mediated direct neural tissue injury while late-onset encephalitis is due to autoimmune mechanisms.[75]

M. pneumoniae was isolated from the autopsied brain specimen of a 30-year-old woman with encephalitis, as early as 1980. Isolation of this organism from lung, kidney and trachea of this patient was the evidence of dissemination of this organism.[66],[78] Subsequently, M. pneumoniae nucleic-acid was detected by PCR and nucleic-acid hybridisation from brain tissues of patients with early-onset encephalitis following pneumonia.[79] In a case series of patients with features of encephalitis, meningoencephalitis and ADEM, antibodies against M. pneumoniae were detected in 74% of cases in the cerebrospinal fluid (CSF) PCR.[80] Even M. pneumoniae antigen has been detected by immunohistochemistry in macrophages from perivascular infiltrates of cerebral hemispheres, medulla oblongata and spinal cord in patients positive for M. pneumoniae DNA in tracheobronchial secretions.[81] Since, M. pneumoniae positive serology or culture or PCR of respiratory tract samples cannot differentiate between colonisation and infection, demonstration of the organism by PCR or culture or antigen detection from CSF samples or detection of intrathecal antibodies have been the key factor behind the hypothesis of dissemination and direct tissue injury by the organism. In fact, other Mycoplasma species have the ability to infect brain tissue of animals such as Mycoplasma galliseptica in birds, Mycoplasma pulmonis in rodents and Mycoplasma hyopneumoniae in pigs.[12]

Dissemination to distant tissues is the earliest step in the pathogenesis of neurological complications due to M. pneumoniae. It has been shown that M. pneumoniae gets passively transferred through gaps between injured respiratory epithelial cells and probably reaches by circulating in blood in a cell-free form.[72],[82] Tissue injury is mediated by local production of cytokine by the interaction of M. pneumoniae glycolipid antigen and TLR-1, TLR-2 and TLR-6 of inflammatory cells leading to activation of cytokine cascade. The two major cytokine that have been found to be elevated intrathecally in early-onset encephalitis has been IL-6 and IL-8, of which IL-8 is a potent neutrophil chemoattractant. Neural tissue injury is probably due to inflammatory cell-mediated damage. In contrast to bacterial meningoencephalitis due to other organisms, elevated levels of IFN-γ and TNF-α were not observed. Another cytokine, IL-18 has been found to be elevated in CSF in patients with late-onset encephalitis due to M. pneumoniae.[75],[83]

Autoimmunity is the proposed mechanism of pathogenesis for M. pneumoniae associated late-onset encephalitis along with acute transverse myelitis, GBS, polyradiculopathies and optic neuritis. Both GM1 ganglioside and galactocerebroside epitopes have been detected on M. pneumoniae cell surface that cross-reacts with host myelin glycolipid moieties expressed in neuronal tissues. Cross-reacting antibodies are either intrathecally produced or cross the blood-brain barrier that become permeable during cytokine-mediated inflammation by direct effect of the organism.[84],[85]

Autoantibodies to lipid-associated neural antigens in patients with Mycoplasma induced CNS disease were first described by Biberfield in 1971.[86] Subsequently, anti-galactocerebroside and anti-GM1 ganglioside antibodies were demonstrated in CSF of patients with post M. pneumoniae CNS dysfunction. In these cases CNS manifestations were preceded by respiratory symptoms by 8 days or more which coincides with the generation of these antibodies.[87],[88] Approximately 5–15% GBS cases are associated with a preceding M. pneumoniae infection and (GBS) patients with evidence of recent M. pneumoniae infection have been shown to be more likely positive for anti-galactocerebroside and anti-GM1 ganglioside antibodies than other GBS patients.[89],[90],[91] The antigen-antibody complexes activates the complement cascade and formation of membrane-attack complex leading to demyelination. Since most of the GBS cases have been diagnosed by serological testing for M. pneumoniae following respiratory illness, establishing a definite causal relationship is difficult in absence of a positive culture or a PCR result.

Anti-galactocerebroside C and antiganglioside antibodies such as anti-GQ1B have also been detected in serum and CSF of patients with acute meningoencephalitis and Bickerstaff's brain-stem encephalitis following M. pneumoniae infection.[92] However, association of M. pneumoniae infection and pathogenesis of these disorders remains unclear and further studies are required. Role of these antibodies in CNS complications has been questioned in a study by Biberfeld et al. in which 80% of M. pneumoniae infected individuals without CNS manifestations had these circulating antibodies.[93] However, further evidence of molecular mimicry of M. pneumoniae has been provided by in vitro studies, where anti-P1-adhesion antibodies cross-reacted with intracellular enzymes viz., glyceralde-3-phosphate dehydrogenase and 2-phospho D-glycerate hydrolase in eukaryotic cell lines.[86]

The third mechanism for CNS manifestations has been proposed to be vascular occlusion. Vascular occlusion is caused by local vascular injury due to cytokines and chemokines due to M. pneumoniae infection.[72],[75] This form of ischaemic injury to CNS occurs in absence of thrombotic mechanism and is the main pathophysiology for bilateral striatal necrosis following M. pneumoniae infection. However, considering stroke in children and adults in whom M. pneumoniae DNA has been detected in CSF, the cause still remains to be elucidated.

M. pneumoniae infection has also been associated with dermatological complications in 1–5% cases, manifested by erythema multiforme and Mycoplasma induced rash and mucositis (MIRM), which includes mild erythematous maculo-papular rash, vesicular eruptions, toxic epidermal necrolysis and rarely Steven–Johnson syndrome.[94] Systematic corticosteroid therapy and/or intravenous immunoglobin may be required in some cases. Cause of MIRM has been attributed to the molecular mimicry between Mycoplasma P1-adhesin molecule and keratinocyte antigen leading to generation of cross-reacting antibodies, immune-complex formation and complement activation. Erythema multiforme following M. pneumoniae infection is hypothesised to be a type-IV hypersensitivity reaction or a cytotoxic damage through a Fas Ligand and granulysin mediated perforin-granzyme pathway.[95] Haematologic manifestations of M. pneumoniae infection include haemolytic anaemia due to autoimmune cold agglutinins and thrombotic thrombocytopenic purpura due to cross-reactive antibodies inactivating plasma von Willebrand factor-cleaving protease.[12],[96] For other systemic complications, additional studies are required to elucidate the pathological pathways.

 ~ Drug Resistance: an Emerging Problem Top

Effective treatment includes macrolides, the antimicrobial of choice and tetracycyclines and fluoroquinolones. However, high rates of macrolide resistance have been reported from Asian countries such as China and Japan. More than 90% of Chinese and approximately 87% of Japanese isolates have been shown to be macrolide resistant.[97],[98] Macrolide resistance strains are also emerging from other parts of the world including USA and European countries such as Germany and France.[99],[100] Macrolide resistance in M. pnuemoniae has been attributed to nucleotide mutations in the 23S rRNA genes which have led to increased minimal inhibitory concentrations to erythromycin, azithromycin and clarithromycin. Although resistance to quinolones or tetracyclines among clinical isolates of M. pneumoniae has not been reported, considering the side effects of tetracycline therapy and fluoroquinolones not being recommended for use in children, an effective vaccine against M. pneumoniae is desirable. Developments of a successful vaccine will not only enable us to prevent the serious complications of M. pneumoniae infection but also act as a preventive strategy against outbreaks, particularly in closed community settings. Inactivated vaccines have been tested in clinical trials and the summarised efficacy was only 40% approximately against M. pneumoniae associated pneumonia.[101] Hence, further efforts for developing a more efficacious, yet safe, vaccine against M. pneumoniae should continue based on the recent advances in knowledge regarding the virulence properties of this organism.

 ~ Conclusion Top

Although majority of patients with M. pneumoniae infection can be treated in outpatient or ambulatory setting, severe infections in susceptible population may require hospitalisation. Moreover, extrapulmonary manifestations, particularly the neurological complications, can lead to poor outcome in infected patients.

Our knowledge regarding the pathogenesis of this organism has improved ever since the introduction of highly sensitive molecular assays. Newer cytadherence proteins have been discovered, immunological pathways leading to tissue injury have been elucidated and researchers have also characterised the novel CARDS toxin molecule. There have been significant advances in the knowledge of immunopathogenesis in terms of the role of TLRs and inflammasomes, which can be used as potential therapeutic targets in modulation of the disease process eg. inhibitors or antibodies against relevant peptides. However, most of the studies have been performed in cell lines or in animal models. Hence, the authors feel that for designing a vaccine which will produce high levels of protective immunity in susceptible population, larger studies regarding the pathogenesis at subcellular levels need to be undertaken in humans. Such studies will further improve our understanding about the disease process, particularly in terms of association of the organism with chronic lung diseases and debilitating extrapulmonary complications. A holistic approach of studying the molecular virulence properties of the organism will not only help in designing an effective vaccine but can also lead to development of newer therapeutic modalities and better diagnostic assays enabling us in comprehensive management of infections due to M. pneumoniae.

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Conflicts of interest

There are no conflicts of interest.

 ~ References Top

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Nair GB, Niederman MS. Community-acquired pneumonia: An unfinished battle. Med Clin North Am 2011;95:1143-61.  Back to cited text no. 3
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