Associate editor: P.D. Foster
Role of atypical bacterial infection of the lung in predisposition/protection of asthma

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Abstract

Asthma is a common inflammatory disease of the airways that results in airway narrowing and wheezing. Allergic asthma is characterised by a T-helper cell-type (Th) 2 response, immunoglobulin (Ig) E production, and eosinophilic influx into the airways. Recently, many clinical studies have implicated Mycoplasma pneumoniae and Chlamydia pneumoniae in the development and exacerbation of both chronic and acute asthma. It is widely accepted that M. pneumoniae and C. pneumoniae infections require Th1 immunity for clearance; therefore, according to the hygiene hypothesis, these infections should be protective against asthma. Here, we review the clinical evidence for the association and mechanisms of predisposition to and protection against asthma by these infections. We will examine the following question: Is it the absence of infection or the age of the individual on infection that confers susceptibility or resistance to asthma and does this vary between normal and predisposed individuals? We put forward a hypothesis of the effects of these infections on the development and prevention of asthma and how novel preventative and treatment strategies involving these microbes may be targeted against asthma.

Introduction

Asthma is an increasingly common condition that affects people of all ages. In spite of the advent of effective therapeutic agents, asthma continues to increase in prevalence particularly in the developed world (Bousquet et al., 2000). In children, asthma is the most common chronic illness that causes loss of time from school. In many areas, the prevalence of asthma has doubled in the past decade (Peat et al., 1994). Asthma now affects 1 in 10 adults and 1 in 4 children in Australia with similar figures reported from the UK and USA. It is accepted that because of the large and increasing burden of illness caused by asthma, there is a recognised potential to achieve major health gains through improved control of asthma. There is a marked variation in the worldwide incidence of asthma, which over the last 20 years has become a major, predominantly First World problem. The prevalence in Australia, for example, is one of the highest in the world at around 25–30% and contrasts with that in Third World countries of around 3–5% (ISAAC, 1998). Changes in risk factors commonly associated with the development of asthma cannot explain these increases; therefore, it has been proposed that a rise in the numbers of people that respond to antigens with a T-helper lymphocyte (Th)2-type immune response may be responsible (Holt et al., 2000). The hygiene hypothesis is the most widely accepted explanation and states that a more hygienic environment results in less childhood infections Strachan, 1989, Strachan, 2000, Shirakawa et al., 1997, Farooqi & Hopkin, 1998, Martinez & Holt, 1999, leading to the inappropriate development of the immature immune system and the maintenance of the neonatal Th2 phenotype (Holt et al., 2000). However, the situation is complex and unlikely to be wholly explained by this relatively simple theory (Umetsu et al., 2002). Many authors point to observations that autoimmune diseases (Eg type 1 diabetes) that are promoted by Th1 immune responses are also increasing in the industrial world at a similar rate to asthma (Stene & Nafstad, 2001). Therefore, the question is whether the absence of infection, the type of infection, the timing of infection, or a combination of these factors cause the increases in asthma. Many different bacterial infections have been associated with predisposition to or protection against asthma. Chronic infections such as Mycoplasma and Chlamydia have been widely implicated in generation of disease; however, infection with these agents later in childhood may be beneficial to the balanced maturation of the immune system. Here, we will use these bacterial infections as examples to review mechanisms of predisposition/protection of asthma and to highlight novel treatments.

Asthma is recognised by episodes of wheezing, which represent expiratory airway narrowing due to airway smooth muscle spasm and airway inflammation. A key feature of airway obstruction in asthma is its variability in both timing and severity. This is associated with the phenomenon termed airway hyperresponsiveness, which results in the airways demonstrating an exaggerated constrictive response to a variety of stimuli, both immunologic and nonimmunologic. The asthmatic response to immunologic stimuli is generally associated with airway inflammation and is best characterised by the response to inhaled allergens. In this setting, the individual is sensitised by genetic susceptibility and environmental exposure to respond to allergen exposure with a Th2-type immune response that is characterised by immunoglobulin (Ig) E-mediated mast cell degranulation and interleukin (IL)-5-mediated eosinophil influx (Larche et al., 2003). Following sensitisation, B-cells switch from an IgG to IgE antibody production under the influence of Th2 cytokines such as IL-4 Gould et al., 2000, Vercelli, 2002. Reexposure to allergen cross-links mast cell-bound IgE, leading to mast cell degranulation and release of preformed mediators such as histamine and newly formed mediators such as prostaglandin D2 (Bradding, 2003). These mediators are potent airway spasmogens and cause airway smooth muscle contraction that occurs within minutes of allergen exposure. This immediate allergic response is followed several hours later by a delayed allergic response that is characterised by prolonged airway narrowing that is poorly responsive to bronchodilators. In this late phase response, there is augmentation of airway inflammation with an influx of eosinophils into the airway. Once activated, eosinophils release preformed granular mediators and newly synthesised lipid mediators such as leukotriene C4. Eosinophil granule mediators cause epithelial desquamation, mucus secretion, and vascular leakage and thus potentiate the inflammatory response (Gleich, 2000).

Interestingly, some eosinophil granule mediators such as eosinophil cationic protein antagonise the cholinergic neural control of resting airway calibre by a direct action at muscarinic receptors. The consequences of this are an increase in the responsiveness of the airways to a variety of nonimmunologic constrictive stimuli (Jacoby et al., 2001). These stimuli are many and varied and include exercise, temperature change, irritants, laughter, pollutants including tobacco smoke, and others. It is this exaggerated constrictive airway response that characterises the clinical manifestations of asthma in an individual, and underpinning this response is a Th2-type immune response in the airway to immunologic stimuli.

In asthma, there is an exaggerated repair response in the airway termed airway wall remodelling (Holgate et al., 1999). The features of this response include deposition of fibrous connective tissue below the epithelial basement membrane (subepithelial fibrosis), goblet cell and mucus gland hyperplasia, smooth muscle hypertrophy/hyperplasia, and increased blood vessel formation in the lamina propria (Stewart, 2001). Apart from the functional consequences of this response, the mechanical effects are an increase in airway wall thickness, which uncouples the airway wall from the surrounding parenchyma, removing the “brake” on airway narrowing, and predisposes the individual to severe airway obstruction. Indeed, it is the ability to progress to complete (terminal) airway obstruction that also differentiates the asthmatic airway from that in normals. The mechanisms and T-cell dependence of airway wall remodelling in asthma are a matter of intense investigation (Foster et al., 2002). Now, it is the Th2-type response that serves to explain many of the pathophysiological features of asthma (Chung & Barnes, 1999). The reasons why an individual responds in a Th2 dominant way to antigenic challenge and develops allergy and asthma is thought to include genetic predisposition and age of first exposure to infections.

Asthma susceptibility genes have begun to be identified that may predispose to atopy and asthma. For example, genetic variants of Tim1 and ADAM33 genes have been implicated to directly affect susceptibility to allergy by inducing aberrant Th2 immunity or epithelial repair processes (reviewed in Umetsu et al., 2002). The genetic background of an individual may also have a more indirect but even more significant role in susceptibility to allergy and asthma. For example, it has long been known that BALB/c mice will mount a Th2 response to immune challenges and are thus more susceptible to allergic inflammation whilst C57BL/6 mice will mount a Th1 response to the same stimuli Heinzel et al., 1991, Kropf et al., 2002. These inherent differences explain why BALB/c mice are less able to clear either chlamydial (Yang et al., 1996) or leishmanial (Heinzel et al., 1991) infections. In addition, it has been shown that some individuals fail to produce antibody responses to some bacterial infections Block et al., 1995, Kutlin et al., 1998 probably as a result of genetic factors. A full assessment of genetic predisposition is beyond the scope of this review.

It is becoming increasingly apparent that the age of first infection is heavily involved in moulding immune responses that dominate later in life and that it is the timing of exposure to antigens or infections of neonates that is of primary importance in determining the phenotype of Th cell responses and the character and gravity of adult respiratory diseases Culley et al., 2002, Holt & Sly, 2002. There is growing evidence to suggest that the neonatal immune system is strongly polarised toward responding in a Th2 fashion Garcia et al., 2000, Rowe et al., 2000, Adkins et al., 2001. The hygiene hypothesis (Strachan, 2000) states that the Th2-biased immune system of pregnancy and the newborn must encounter childhood Th1-inducing stimuli to develop the ability to mount a Th1 response. The absence of exposure to Th1-inducing infections is thought to promote the persistence of a Th2 phenotype and permits the development of allergic disease and asthma. This hypothesis suggests that, in Western societies, the increased use of antibiotics and vaccination, decreased family size resulting in less exposure to infection from older siblings, and generalised increases in hygiene levels may inhibit the development of the neonatal immune system or promote Th2-type immune responses, thereby predisposing to allergy.

We (Jones et al., 2000) and others (von Mutius et al., 2000) have observed that the clinical prevalence of asthma varies inversely with the incidence of certain infections such as tuberculosis and typhoid. These infections elicit a Th1 immune response, which, in the early years of life, may cause immune deviation from the neonatal Th2 response to a mature and balanced Th1/Th2 response. Recent evidence has demonstrated that adult mice, which have been infected with Mycobacterium bovis (Walzl et al., 2003) or Chlamydia trachomatis (Bilenki et al., 2002) or treated with killed Mycobacterium vaccae (Wang & Rook, 1998), M. bovis (Major et al., 2002), or Listeria (Hansen et al., 2000), exhibit a reduced asthma phenotype and altered cytokine pattern (Walzl et al., 2001). However, whether an infection in early life drives beneficial Th1 responses depends on the nature of the infectious agent. It has recently been shown that T-cell memory responses to respiratory viral infections, which induce Th2 responses, reinforce neonatal Th2 immunity Chen et al., 2001, Walzl et al., 2001, Culley et al., 2002, which may predispose to asthma. In addition, early exposure to fungi (Pneumocystis carinii) reduced interferon (IFN)-γ release in the neonatal lung (Qureshi & Garvy, 2001). These types of infections may have protracted effects on predominating immune responses later in life (Culley et al., 2002). Thus, the timing and the nature of infection may be important in the maturation of a balanced immune response or the persistence of the Th2 phenotype that results in asthma.

Primary lung challenge in neonates follows the same activation kinetics as adults; however, neonates express predominantly Th2 memory responses, and Th1 memory is unstable Kovarik & Siegrist, 1998, Adkins, 1999, Culley et al., 2002, Marodi, 2002, Troye-Blomberg, 2002. Reinfection or infection with unrelated agents may reinforce aberrant Th2 responses and alter responses to allergens resulting in inflammation and allergy through differential expression of cytokines and CD4+ and CD8+ T-cells Chen et al., 2001, Walzl et al., 2001, Culley et al., 2002. This indicates that allergy in adults may result from the release of Th2 cytokines from Th2 cells, which were induced by infection at an early age Culley et al., 2002, Holt & Sly, 2002.

The largest Th2 responses are observed with priming at the earliest age, and in unaffected mice, Th2 responses decrease with age (Culley et al., 2002). It has been shown, however, that the fixing of Th2 immune responses in adulthood may be partially reversed by strong Th1 stimulation (Barrios et al., 1996). It is unknown if the neonatal Th2 skewed responses result from the types of T-cells present, a deficiency in neonatal memory T-cells, the types of dendritic cells that predominate in neonates, a lack of IL-12 release by neonatal dendritic cells and macrophages, or a combination of these effects Taylor & Bryson, 1985, Lewis et al., 1986, Lewis et al., 1991, Nelson et al., 1994, Goriely et al., 2001, Culley et al., 2002, White et al., 2002.

The idea that Th1- or Th2-inducing infections can modulate immune development in such a simplistic manner is naı̈ve. Other factors such as regulatory T-cells are probably involved (Umetsu et al., 2002) and further experimental studies designed to elucidate the mechanisms underlying the phenomena of immune deviation are essential. Specifically, temporal studies are needed to investigate the effect of differences in developmental stage on immune modulation to bacterial infection and the subsequent precipitation of asthma.

The relative effects of host and environmental factors, alone or in combination, in the development of asthma are the subject of much debate and study, and the effect of M. pneumoniae and C. pneumoniae infection, the age of infection, and some aspects of genetic predisposition related to infection will be reviewed here.

Section snippets

Mycoplasma pneumoniae and Chlamydia pneumoniae

M. pneumoniae and C. pneumoniae are atypical bacteria that have very different life cycles but both require Th1 responses for clearance. M. pneumoniae is an extracellular bacteria and C. pneumoniae is an obligate intracellular parasite. Both species can commonly cause acute and chronic diseases of the respiratory tract, but subclinical infection is common and a large percentage of the human population have antibodies to M. pneumoniae and C. pneumoniae Grayston, 1992, Foy, 1993, Cunningham et

Clinical evidence for the association

The clinical association between M. pneumoniae infection and asthma has been proposed for 2 decades; however, the nature of the correlation is still far from clear. Several recent studies have implicated M. pneumoniae infection in the pathophysiology of asthma in subsets of patients. In 2 of the most influential studies, Kraft et al. (1998) and Martin et al. (2001b) detected M. pneumoniae in the lungs of 25 out of 55 (45%) adult patients with chronic stable asthma predominantly in the lower

Clinical evidence for the association

Chlamydiae are among the most common of human pathogens in all age groups (Hammerschlag, 2000a) frequently causing trachoma, sexually transmitted diseases, pneumonia, and possibly coronary artery disease (Stephens, 2003), which may be acute or chronic and subclinical Hammerschlag et al., 1992, Beatty et al., 1994. Of chlamydiae, C. pneumoniae is a common respiratory pathogen and an intracellular parasite that exists in 2 forms: an infectious form (elementary bodies) and a metabolic form

Therapeutic strategies for the treatment of atypical bacterial-induced asthma

Observations that M. pneumoniae and C. pneumoniae play an important role in the induction and exacerbation of asthma have opened up the possibility of novel treatment strategies for asthma using therapeutics against causative bacterial infections.

Hypothesis and novel treatment strategies

Considering as a whole the information presented throughout this review, it is our opinion that it is the timing of the infection relative to allergen exposure, the age of first infection, and/or the underlying immune phenotype of the individual that predispose to M. pneumoniae- and C. pneumoniae-induced allergy and asthma rather than the nature of the infection per se and that such Th1 infections do protect against allergy and asthma if they occur at an appropriate age (Fig. 1).

Given the

Conclusions

M. pneumoniae and C. pneumoniae infections have been commonly associated with asthma. However, it is unknown whether these associations predominantly result from (1) infection fixing Th2 responses and facilitating the subsequent development of inflammation and asthma or (2) immune responses that lead to inflammation and asthma also predisposing to atypical bacterial infection. Furthermore, it is not known whether these effects differ among neonates, infants, and adults. Despite recent advances

References (157)

  • G.J. Gleich

    Mechanisms of eosinophil-associated inflammation

    J Allergy Clin Immunol

    (2000)
  • D.L. Hahn et al.

    Can acute Chlamydia pneumoniae respiratory tract infection initiate chronic asthma?

    Ann Allergy Asthma Immunol

    (1998)
  • K.L. Hoek et al.

    Mycoplasma pneumoniae-induced activation and cytokine production in rodent mast cells

    J Allergy Clin Immunol

    (2002)
  • D.B. Jacoby et al.

    Eosinophil recruitment to the airway nerves

    J Allergy Clin Immunol

    (2001)
  • P.D. Jones et al.

    The prevalence of asthma appears to be inversely related to the incidence of typhoid and tuberculosis: hypothesis to explain the variation in asthma prevalence around the world

    Med Hypotheses

    (2000)
  • S. Kondo et al.

    Progressive bronchial obstruction during the acute stage of respiratory tract infection in asthmatic children

    Chest

    (1994)
  • J. Kovarik et al.

    Immunity in early life

    Immunol Today

    (1998)
  • M. Kraft

    The role of bacterial infections in asthma

    Clin Chest Med

    (2000)
  • M. Kraft et al.

    Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin

    Chest

    (2002)
  • M. Larche et al.

    The role of T lymphocytes in the pathogenesis of asthma

    J Allergy Clin Immunol

    (2003)
  • B. Adkins et al.

    Freshly isolated, murine neonatal T cells produce IL-4 in response to anti-CD3 stimulation

    J Immunol

    (1992)
  • B. Adkins et al.

    Developmental regulation of IL-4, IL-2, and IFN-gamma production by murine peripheral T lymphocytes

    J Immunol

    (1993)
  • B. Adkins et al.

    The generation of Th memory in neonates versus adults: prolonged primary Th2 effector function and impaired development of Th1 memory effector function in murine neonates

    J Immunol

    (2001)
  • P. Apfalter et al.

    Reliability of nested PCR for detection of Chlamydia pneumoniae DNA in atheromas: results from a multicenter study applying standardized protocols

    J Clin Microbiol

    (2002)
  • P. Apfalter et al.

    Comparison of a new quantitative ompA-based real-time PCR TaqMan assay for detection of Chlamydia pneumoniae DNA in respiratory specimens with four conventional PCR assays

    J Clin Microbiol

    (2003)
  • R.L. Bailey et al.

    Subjects recovering from human ocular chlamydial infection have enhanced lymphoproliferative responses to chlamydial antigens compared with those of persistently diseased controls

    Infect Immun

    (1995)
  • T.M. Ball et al.

    Siblings, day-care attendance, and the risk of asthma and wheezing during childhood

    N Engl J Med

    (2000)
  • C. Barrios et al.

    Partial correction of the TH2/TH1 imbalance in neonatal murine responses to vaccine antigens through selective adjuvant effects

    Eur J Immunol

    (1996)
  • W.L. Beatty et al.

    Persistent chlamydiae: from cell culture to a paradigm for chlamydial pathogenesis

    Microbiol Rev

    (1994)
  • Berry, L. J., Hickey, D. K., Skelding, K. A., Bao, S., Rendina, A. M., Hansbro, P. M., Gockel, C. M., & Beagley, K. W....
  • P.N. Black et al.

    Serological evidence of infection with Chlamydia pneumoniae is related to the severity of asthma

    Eur Respir J

    (2000)
  • P.N. Black et al.

    Trial of roxithromycin in subjects with asthma and serological evidence of infection with Chlamydia pneumoniae

    Am J Respir Crit Care Med

    (2001)
  • F. Blasi et al.

    Chlamydia pneumoniae respiratory infections

    Curr Opin Infect Dis

    (2000)
  • S. Block et al.

    Mycoplasma pneumoniae and Chlamydia pneumoniae in pediatric community-acquired pneumonia: comparative efficacy and safety of clarithromycin vs. erythromycin ethylsuccinate

    Pediatr Infect Dis J

    (1995)
  • M.H. Blotta et al.

    Corticosteroids inhibit IL-12 production in human monocytes and enhance their capacity to induce IL-4 synthesis in CD4+ lymphocytes

    J Immunol

    (1997)
  • A. Bot et al.

    Immune response of neonates elicited by somatic transgene vaccination with naked DNA

    Front Biosci

    (1997)
  • J. Bousquet et al.

    Asthma. From bronchoconstriction to airways inflammation and remodeling

    Am J Respir Crit Care Med

    (2000)
  • J.J. Bowden et al.

    Dexamethasone and oxytetracycline reverse the potentiation of neurogenic inflammation in airways of rats with Mycoplasma pulmonis infection

    Am J Respir Crit Care Med

    (1994)
  • P. Bradding

    The role of the mast cell in asthma: a reassessment

    Curr Opin Allergy Clin Immunol

    (2003)
  • H.D. Chen et al.

    Memory CD8+ T cells in heterologous antiviral immunity and immunopathology in the lung

    Nat Immunol

    (2001)
  • H.W. Chu et al.

    Effects of respiratory Mycoplasma pneumoniae infection on allergen-induced bronchial hyperresponsiveness and lung inflammation in mice

    Infect Immun

    (2003)
  • K.F. Chung et al.

    Cytokines in asthma

    Thorax

    (1999)
  • P. Clementsen et al.

    Chlamydia pneumoniae infection and its role in asthma and chronic obstructive pulmonary disease

    J Investig Allergol Clin Immunol

    (2002)
  • W.A. Clyde

    Mycoplasma pneumoniae respiratory disease symposium: summation and significance

    Yale J Biol Med

    (1983)
  • P.J. Cook et al.

    Chlamydia pneumoniae and asthma

    Thorax

    (1998)
  • B.K. Coombes et al.

    Strategic targeting of essential host-pathogen interactions in chlamydial disease

    Curr Drug Targets Infect Disord

    (2002)
  • T.W. Cotter et al.

    Reactivation of chlamydial genital tract infection in mice

    Infect Immun

    (1997)
  • F.J. Culley et al.

    Age at first viral infection determines the pattern of T cell-mediated disease during reinfection in adulthood

    J Exp Med

    (2002)
  • A.F. Cunningham et al.

    Chronic Chlamydia pneumoniae infection and asthma exacerbations in children

    Eur Respir J

    (1998)
  • A. Dakhama et al.

    Induction of RANTES and TGF-{beta}1 in airway epithelial cells by Mycoplasma pneumoniae

    Am J Respir Cell Mol Biol

    (2003)
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