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Pathogenesis of Mycoplasma pneumoniae: An update

Article  in  Indian Journal of Medical Microbiology · January 2016

DOI: 10.4103/0255-0857.174112

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Indian Journal of Medical Microbiology, (2016) 34(1): 7-16 1

Review Article

Pathogenesis of Mycoplasma pneumoniae: An update

*R Chaudhry, A Ghosh, A Chandolia

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.

Key words: Epidemiology, Mycoplasma pneumoniae, pathogenesis

Introduction emerging pathogens.[4] Studies have demonstrated that

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
*Corresponding author (email: <drramach@gmail.com>)
Department of Microbiology (RC, AG, AC), AIIMS,
New Delhi, India
Received: 30-09-2014
Accepted: 08-09-2015
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.[5-7] 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.

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How to cite this article: Chaudhry R, Ghosh A, Chandolia A.
DOI: Pathogenesis of Mycoplasma pneumoniae: An update. Indian J Med
10.4103/0255-0857.174112 Microbiol 2016;34:7-16.

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8 Indian Journal of Medical Microbiology
Children <5 years of age usually suffer from mild upper
respiratory symptoms while older children and adolescents
develop bronchopneumonia, requiring hospitalisation.[11,12]
M. pneumoniae 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
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vol. 34, No. 1
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
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.
P1-adhesin
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
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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January-March 2016 Chaudhry, et al.: M. pneumoniae pathogenesis update
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]
P30-adhesin
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
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9
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
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10 Indian Journal of Medical Microbiology
modulating high levels of airway inflammation and prevent
lung injury due to M. pneumoniae.
Community-acquired Respiratory Distress Syndrome
Toxin
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 coli to overcome the problem of
isolating the toxin in minute or insufficient quantities in the
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vol. 34, No. 1
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
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January-March 2016 Chaudhry, et al.: M. pneumoniae pathogenesis update
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]
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
Figure 2: Schematic representation of the pathway for M. pneumoniae
CARDS toxin mediated inflammation
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11
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
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
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12 Indian Journal of Medical Microbiology
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,
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vol. 34, No. 1
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
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January-March 2016 Chaudhry, et al.: M. pneumoniae pathogenesis update
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
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
www.ijmm.org
13
organism.
Conclusion
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.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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