Asthma-related microbes

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Chronic Mycoplasma pneumonia and Chlamydia pneumonia infections are associated with the onset and exacerbation of asthma. [1] These microbial infections result in chronic lower airway inflammation, impaired mucociliary clearance, an increase in mucous production and eventually asthma. Furthermore, children who experience severe viral respiratory infections early in life have a high possibility of having asthma later in their childhood. These viral respiratory infections are mostly caused by respiratory syncytial virus (RSV) and human rhinovirus (HRV). Although RSV infections increase the risk of asthma in early childhood, the association between asthma and RSV decreases with increasing age. HRV on the other hand is an important cause of bronchiolitis and is strongly associated with asthma development. In children and adults with established asthma, viral upper respiratory tract infections (URIs), especially HRVs infections, can produce acute exacerbations of asthma. Thus, Chlamydia pneumoniae , Mycoplasma pneumoniae and human rhinoviruses are microbes that play a major role in non-atopic asthma. [1]

Contents

Asthma

According to Hertzen (2002), a common characteristic of asthmatic patients is to have epithelial cells that respond to injury by enhancing the capability of producing proinflammatory and profibrogenic cytokines, instead of repairing the injured epithelial layer. [2] As a result, inflammation and associated healing process leads to scar formation and tissue remodelling, which are symptoms that can be found in almost all asthmatics patients. Thus, asthma is a chronic inflammatory disorder of the airways. Asthma is divided into two subgroups: atopic (extrinsic) and non-atopic (intrinsic). The atopic subgroup is closely associated with family history of the disease, whereas the non-atopic subgroup has its onset in adulthood and it is not caused by inheritance. It is known that non-atopic asthma has a more severe clinical course than atopic asthma. Non-atopic asthma may be caused by chronic viral, bacterial infections, or colonization with pathogenic bacteria. [2]

The distinction between atopic and non-atopic asthma is nuanced. "Atopic" is defined as having one or more positive skin tests to a battery of common aeroallergens, however, compared to people without asthma both atopic and non-atopic asthmatics have elevated levels of serum IgE (the "allergic" antibody) that is believed to be more directly responsible for asthma symptoms. [3] [4] A recent meta-analysis reported that the overall population attributable risk for C. pneumoniae-specific IgE in chronic asthma was 47% and was strongly and positively associated with disease severity. [5] Population-attributable risk is the proportion of disease that is potentially attributable to the risk factor under investigation, indicating the potential for infection with this "stealth pathogen" as a significant contributor to asthma incidence and prevalence.

Associated microorganisms

Chlamydia pneumoniae

General descriptions

Chlamydia pneumoniae.jpg

Chlamydia pneumoniae, formerly known as Chlamydophila pneumoniae, is a bacterium that belongs to the phylum Chlamydiae, order Chlamydiales, and genus Chlamydia. [6] It is rod-shaped and Gram-negative. [6] It has a characteristic pear-shaped elementary body (EB) that is surrounded by a periplasmic space, which makes it morphologically distinct from the round EBs of C. trachomatis and C. psittaci. [7] C. pneumoniae is non-motile and utilizes aerobic respiration. As an obligate intracellular bacterium, C. pneumoniae is both parasitic and mesophilic. [7]

Biological interactions with host

C. pneumoniae is able to grow in monocytes, macrophages, endothelial and smooth muscle cells. [2] It replicates within the host cell cytoplasm. Due to the fact that it does not have the ability to synthesize its own ATP, it is entirely dependent on energy produced by their host. [2] [8] Reinfection of the host with C. pneumoniae is common because the memory immunity elicited by C. pneumoniae is short-lived and partial. [2] In addition, C. pneumoniae infection tends to be persistence due to IFN-γ, penicillin and nutrient deficiencies. [9] These deficiencies prevent C. pneumoniae from completing their normal developmental cycle, leading to the formation of aberrant, noninfectious C. pneumoniae that persist in the human host. [9] C. pneumoniae infection may not only be persistent and chronic, but it also has irreversible tissue injury and scarring processes, [2] which are symptoms in asthma patients. Infection with C. pneumoniae induces both humoral and cell-mediated immune responses. [2] Among the two immune responses, cell-mediated immune response that involves CD8+ T cells in particular is crucial to eradicate C. pneumoniae, whereas the humoral immune response appears to be rather ineffective in protection against C. pneumoniae infection. [2] In fact, CD8+ T cells are so important that if it is absent in the host, the C. pneumoniae infection would progress rapidly. Although cell-mediated immune response is responsible for the clearance of C. pneumoniae, this response can be harmful to the host because it favours the development of inflammation that can lead to asthma. [2]

Roles in asthma

There is a strong association of C. pneumoniae with long-standing asthma among the non-atopic asthma in comparison to atopic asthma. [2] In fact, the severity of asthma can be determined by the elevated titres to C. pneumoniae, but not to other potential pathogens such as Mycoplasma pneumoniae, adenovirus, influenza A and B or parainfluenza virus. [2] It is hypothesized that C. pneumoniae is associated with asthma because C. pneumoniae has been found to cause ciliostasis in bronchial epithelial cells. [2] Meanwhile, sero-epidemiological data also provide evidences to support that C. pneumoniae plays a role in asthma by amplifying inflammation and inciting the disease process. [2] The association of C. pneumoniae and asthma begins with C. pneumoniae producing 60-kDa heat shock proteins that provide a prolonged antigenic stimulation. [2] This particular heat shock protein is known as a member of hsp60 family of stress proteins, which can be found in both eukaryotes and prokaryotes. The production of hsp60 remains unaltered even when C. pneumoniae is dormant and does not replicate, since that hsp60 serves as a protective antigen. [2] Its antigenic stimulation strongly amplifies chronic inflammation by increasing the production of proinflammatory cytokines, tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IFN-γ by infected cells, which ultimately leads to immunopathological tissue damage and scarring in the asthmatic lungs. [2] Furthermore, infection with C. pneumoniae also induces serum immunoglobulin IgA, and IgG responses, which are associated with chronic asthma. [7] Most strikingly, a recent systematic review and meta-analysis found that C. pneumoniae-specific IgE was associated with almost half of the asthma cases studied. [5] Lastly, a growing body of evidence from animal model studies finds that C. pneumoniae infection not only creates the "asthma phenotype" but also induces previously non-allergic animals to display allergic responses to exogenous (i.e., non-chlamydial) allergens. [10]

Mycoplasma pneumoniae

General descriptions

Mycoplasma pneumoniae is a bacterium that belongs to the phylum Firmicutes, class Mollicutes, order Mycoplasmatales and family Mycoplasmataceae. [11] It is either filamentous or spherical. Individual spindle-shaped cells of M. pneumoniae are 1 to 2 μm long and 0.1 to 0.2 μm wide. [11] M. pneumoniae is a motile, mesophilic bacterium that exhibits obligate aerobic respiration. It is an extracellular, host-associated bacterium that lacks a cell wall [12] and is unable to survive outside of a host due to osmotic instability in the environment.

Biological interactions with host

M. pneumoniae can cause infections in humans, animals, plants, and cell cultures. It is a parasitic bacterium that invades the mucosal membranes of the upper and lower respiratory tract, including nasopharynx, throat, trachea, bronchi, bronchioles, and alveoli. [12] In order to survive, M. pneumoniae needs essential nutrients and compounds such as amino acids, cholesterol, precursors to nucleic acid synthesis, and fatty acids obtained from the mucosal epithelial cells of the host. [11] Its adhesion proteins attach to tracheal epithelial cells by sialoglycoproteins or sialoglycolipid receptors, which are located on its cell surface. [11] It may cause injury to the respiratory epithelial cell after its attachment. The injury of host epithelial cells caused by M. pneumoniae adhesion is thought to be due to the production of highly reactive species: hydrogen peroxide (H2O2) and superoxide radicals (O2–). [11] M. pneumoniae has the potential for intracellular localization. The intracellular existence of M. pneumoniae could facilitate the establishment of latent or chronic states, circumvent mycoplasmacidal immune mechanisms, its ability to cross mucosal barriers and gain access to internal tissues. Besides, fusion of the mycoplasmal cell membrane with that of the host not only results in the release of various hydrolytic enzymes produced by the mycoplasma, but also leads to the insertion of mycoplasmal membrane components into the host cell membrane, a process that could potentially alter receptor recognition sites and affect cytokine induction and expression. [12] As stated by Nisar et al. (2007), M. pneumoniae can persist in the respiratory tract up to several months after recovery from acute pneumonia. [13] In fact, M. pneumoniae can be cultured from respiratory secretions even after the pneumonia patients are treated with effective antibiotics. [13] Thus, M. pneumoniae infection is chronic and persistent. Besides, Nisar et al. (2007) also adds that M. pneumoniae infection causes pulmonary structural abnormalities, resulting in a decrease in expiratory flow rates and an increase in airways hyper-responsiveness in non-asthmatic individuals. [13]

Roles in asthma

M. pneumoniae infection is responsible for triggering exacerbation of asthma in 3.3 to 50% in such cases. [13] Furthermore, M. pneumoniae may also precede the onset of asthma, because patients with an acute infection by M. pneumoniae, followed by the development of asthma, have significant improvement in lung function and asthma symptoms after they are given antimicrobial treatment against M. pneumoniae. The release of proinflammatory cytokines in response to M. pneumoniae infection has been indicated as a possible mechanism leading to bronchial asthma. [12] This is because the increase of cytokine production results in a continuing inflammatory response in the airway, followed by negative effects such as immunopathological tissue damage and scarring as described in the C. pneumoniae's role in asthma section. Furthermore, patients with asthma are found to have an increased release of type II cytokines, especially IL4 and IL5, but a normal or low level of type I cytokine production. Similarly, M. pneumoniae infection promotes a T helper type 2 response, which is why M. pneumoniae-positive patients with asthma have increased airways expression of tumour necrosis factor a, IL4 and IL5. The T helper type 2 predominant airways disease caused by M. pneumoniae infection may lead to IgE-related hyper-responsiveness and eosinophil function, resulting in an onset of asthma. [13] There is also a possibility that M. pneumoniae infection may destroy respiratory mucosal cells and facilitate the penetration of antigens into the mucosa. [13] A study done by Laitinen et al. (1976) suggests that M. pneumoniae infection denude the epithelial surface and expose irritant receptors. [14] On top of that, M. pneumoniae induces the activation of mast cells by releasing serotonin and hexosaminidase. [12] By producing antigen, M. pneumoniae is capable of initiating an antibody response. Its antigen interacts with IgE that attaches to mast cells, leading to the stimulation of histamine release followed by airway obstruction. [13]

Human rhinoviruses (HRVs)

General descriptions

Human rhinovirus.jpg

Rhinoviruses are known to be the most important common cold viruses. [15] They are ssRNA positive-strand viruses with no DNA stage, and are classified within the family Picornaviridae. [15] Rhinoviruses are small, with the length of approximately 30 nm, and do not contain an envelope. [15] Their icosahedral capsids contain 4 proteins: VP1, VP2, VP3 and VP4. VP1, VP2, and VP3 are located on the surface of the capsid and are responsible for the antigenic diversity of Rhinoviruses. [15] In contrast, VP4 is located inside the virus and its function is to anchor the RNA core to the viral capsid. [16] While sharing basic properties with enteroviruses, such as size, shape, nucleic acid composition, and ether-resistance, rhinoviruses are distinguished from enteroviruses by having a greater buoyant density and a susceptibility to inactivation if they are exposed to an acidic environment. [15] Nevertheless, they share a common ancestor with enteroviruses. [15]

Biological interactions with host

The optimal temperature for rhinovirus replication is 33-35 °C, which corresponds to the temperature of nasal mucosa. At 37 °C virus replication rate falls to 10% to 50% of optimum. [15] This may be the major reason why rhinoviruses can replicate better in the nasal passages and upper tracheobronchial tree than in the lower respiratory tract. [17] Most of the rhinovirus serotypes bind to intercellular adhesion molecule (ICAM), whereas approximately 10% of the serotypes bind to the low-density lipoprotein receptor. [17] Normally, rhinoviruses would infect small clusters of cells in the epithelial layer with little cellular cytotoxicity. [17] Although an increase in polymorphonuclear neutrophils are shown in infected nasal epithelium, little or no mucosal damage occurs from the infection. [16] Nevertheless, rhinovirus infection leads to symptoms of the common cold, which is primarily an upper airway illness. [16] Rhinovirus receptors are insensitive to neuraminidase but are sensitive to proteolytic enzymes. [15]

Roles in asthma

Asthmatic subjects in 9 to 11 years old, 80% to 85% of asthma exacerbations that were associated with reduced peak expiratory flow rates and wheezing were due to viral upper respiratory tract infections (URIs). High rates of asthma attacks due to rhinovirus infection are also found in adults. [16] It turns out that rhinovirus are capable of inducing epithelial cells to produce proinflammatory cytokines that result in airway hyperresponsiveness, neurogenic inflammatory responses, mucous secretion, inflammatory cell recruitment and activation, and plasma leakage. To support this statement, asthmatic subjects that are infected with rhinovirus have demonstrated an increase in airway hyperresponsiveness, airway obstruction, and inflammation. Similarly, rhinovirus infection has caused subjects with allergic rhinitis but no history of asthma to have a significantly increased airway hyperreactivity as well as a significantly increased incidence of late asthmatic reactions. This shows that in addition to causing airway hyperreactivity, rhinovirus also promotes the onset of non-atopic asthma. [16] Furthermore, rhinovirus infection also promotes eosinophil recruitment to airway segments after antigen challenges, and thus intensifies airway inflammatory response to antigens, leading to the development of asthma.

Related Research Articles

<span class="mw-page-title-main">Rhinovirus</span> Genus of viruses (Enterovirus)

The rhinovirus is a positive-sense, single-stranded RNA virus belonging to the genus Enterovirus in the family Picornaviridae. Rhinovirus is the most common viral infectious agent in humans and is the predominant cause of the common cold.

<span class="mw-page-title-main">Sputum</span> Mucus that is coughed up from the lower airways

Sputum is mucus that is coughed up from the lower airways. In medicine, sputum samples are usually used for a naked eye examination, microbiological investigation of respiratory infections and cytological investigations of respiratory systems. It is crucial that the specimen does not include any mucoid material from the nose or oral cavity.

Mycoplasma pneumoniae is a species of very small cell bacteria that lack a cell wall, in the class Mollicutes. M. pneumoniae is a human pathogen that causes the disease Mycoplasma pneumonia, a form of atypical bacterial pneumonia related to cold agglutinin disease. M. pneumoniae is characterized by the absence of a peptidoglycan cell wall and resulting resistance to many cell wall active antibacterial agents.

<i>Chlamydia pneumoniae</i> Species of bacterium

Chlamydia pneumoniae is a species of Chlamydia, an obligate intracellular bacterium that infects humans and is a major cause of pneumonia. It was known as the Taiwan acute respiratory agent (TWAR) from the names of the two original isolates – Taiwan (TW-183) and an acute respiratory isolate designated AR-39. Briefly, it was known as Chlamydophila pneumoniae, and that name is used as an alternate in some sources. In some cases, to avoid confusion, both names are given.

Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut.

Acute severe asthma, also known as status asthmaticus, is an acute exacerbation of asthma that does not respond to standard treatments of bronchodilators (inhalers) and corticosteroids. Asthma is caused by multiple genes, some having protective effect, with each gene having its own tendency to be influenced by the environment although a genetic link leading to acute severe asthma is still unknown. Symptoms include chest tightness, rapidly progressive dyspnea, dry cough, use of accessory respiratory muscles, fast and/or labored breathing, and extreme wheezing. It is a life-threatening episode of airway obstruction and is considered a medical emergency. Complications include cardiac and/or respiratory arrest. The increasing prevalence of atopy and asthma remains unexplained but may be due to infection with respiratory viruses.

Pneumococcal pneumonia is a type of bacterial pneumonia that is caused by Streptococcus pneumoniae (pneumococcus). It is the most common bacterial pneumonia found in adults, the most common type of community-acquired pneumonia, and one of the common types of pneumococcal infection. The estimated number of Americans with pneumococcal pneumonia is 900,000 annually, with almost 400,000 cases hospitalized and fatalities accounting for 5-7% of these cases.

<span class="mw-page-title-main">Interleukin 13</span> Protein and coding gene in humans

Interleukin 13 (IL-13) is a protein that in humans is encoded by the IL13 gene. IL-13 was first cloned in 1993 and is located on chromosome 5q31.1 with a length of 1.4kb. It has a mass of 13 kDa and folds into 4 alpha helical bundles. The secondary structural features of IL-13 are similar to that of Interleukin 4 (IL-4); however it only has 25% sequence identity to IL-4 and is capable of IL-4 independent signaling. IL-13 is a cytokine secreted by T helper type 2 (Th2) cells, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils and nuocytes. Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation. It is a mediator of allergic inflammation and different diseases including asthma., and atopic dermatitis.

<span class="mw-page-title-main">Allergic bronchopulmonary aspergillosis</span> Medical condition

Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterised by an exaggerated response of the immune system to the fungus Aspergillus. It occurs most often in people with asthma or cystic fibrosis. Aspergillus spores are ubiquitous in soil and are commonly found in the sputum of healthy individuals. A. fumigatus is responsible for a spectrum of lung diseases known as aspergilloses.

Pitrakinra is a 15-kDa human recombinant protein of wild-type human interleukin-4 (IL-4). It is an IL-4 and IL-13 antagonist that has been studied in a phase IIb clinical trial for the treatment of asthma. Two point mutations on pitrakinra confer its ability to block signaling of IL-4 and interleukin-13 (IL-13) by preventing assembly of IL-4 receptor alpha (IL-4Rα) with either IL-2Rγ or IL-13Rα. Upregulation of Th2 cytokines, including IL-4 and IL-13, is thought to be critical for the allergic inflammation associated with atopic diseases such as asthma and eczema. The targets of pitrakinra action are inflammatory cells and structural cells that express IL-4Rα. The drug has been applied both as a subcutaneous injection and as an inhalation, but the latter formulation proved to be more effective.

<span class="mw-page-title-main">Thymic stromal lymphopoietin</span> Cytokine, alarmin, and growth factor.

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-2-like cytokine, alarmin, and growth factor involved in numerous physiological and pathological processes, primarily those of the immune system. It shares a common ancestor with IL-7.

<span class="mw-page-title-main">Interleukin-17A</span> Protein-coding gene in the species Homo sapiens

Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.

<span class="mw-page-title-main">Mucosal immunology</span> Field of study

Mucosal immunology is the study of immune system responses that occur at mucosal membranes of the intestines, the urogenital tract, and the respiratory system. The mucous membranes are in constant contact with microorganisms, food, and inhaled antigens. In healthy states, the mucosal immune system protects the organism against infectious pathogens and maintains a tolerance towards non-harmful commensal microbes and benign environmental substances. Disruption of this balance between tolerance and deprivation of pathogens can lead to pathological conditions such as food allergies, irritable bowel syndrome, susceptibility to infections, and more.

<span class="mw-page-title-main">Pathophysiology of asthma</span> Medical condition

Asthma is a common pulmonary condition defined by chronic inflammation of respiratory tubes, tightening of respiratory smooth muscle, and episodes of bronchoconstriction. The Centers for Disease Control and Prevention estimate that 1 in 11 children and 1 in 12 adults have asthma in the United States of America. According to the World Health Organization, asthma affects 235 million people worldwide. There are two major categories of asthma: allergic and non-allergic. The focus of this article will be allergic asthma. In both cases, bronchoconstriction is prominent.

The lung microbiota is the pulmonary microbial community consisting of a complex variety of microorganisms found in the lower respiratory tract particularly on the mucous layer and the epithelial surfaces. These microorganisms include bacteria, fungi, viruses and bacteriophages. The bacterial part of the microbiota has been more closely studied. It consists of a core of nine genera: Prevotella, Sphingomonas, Pseudomonas, Acinetobacter, Fusobacterium, Megasphaera, Veillonella, Staphylococcus, and Streptococcus. They are aerobes as well as anaerobes and aerotolerant bacteria. The microbial communities are highly variable in particular individuals and compose of about 140 distinct families. The bronchial tree for instance contains a mean of 2000 bacterial genomes per cm2 surface. The harmful or potentially harmful bacteria are also detected routinely in respiratory specimens. The most significant are Moraxella catarrhalis, Haemophilus influenzae, and Streptococcus pneumoniae. They are known to cause respiratory disorders under particular conditions namely if the human immune system is impaired. The mechanism by which they persist in the lower airways in healthy individuals is unknown.

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.

Sir Stephen Townley Holgate is a British physician who specializes in immunopharmacology, respiratory medicine and allergies, and asthma and air pollution, based at the University of Southampton and University Hospital Southampton NHS Foundation Trust, UK.

Donna Elizabeth Davies is a British biochemist and professor of respiratory cell and molecular biology at the University of Southampton. In 2003, Davies was the co-founder of Synairgen, an interferon-beta drug designed to treat patients with asthma and chronic obstructive pulmonary disease.

Type 2 inflammation is a pattern of immune response. Its physiological function is to defend the body against helminths, but a dysregulation of the type 2 inflammatory response has been implicated in the pathophysiology of several diseases.

<span class="mw-page-title-main">Asthma trigger</span> Factor that provokes symptoms of asthma

Asthma triggers are factors or stimuli that provoke the exacerbation of asthma symptoms or increase the degree of airflow disruption, which can lead to an asthma attack. An asthma attack is characterized by an obstruction of the airway, hypersecretion of mucus and bronchoconstriction due to the contraction of smooth muscles around the respiratory tract. Its symptoms include a wide range of manifestations such as breathlessness, coughing, a tight chest and wheezing.

References

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  14. ↑ Laitinen, LA; Elkin, RB.; Jacobs, L.; et al. (1976). "Changes in bronchial reactivity after administration of live attenuated influenza virus". Am. Rev. Respir. Dis.: 194–198.
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