The microbiology of asthma

Abstract

Asthma remains an important human disease that is responsible for substantial worldwide morbidity and mortality. The causes of asthma are multifactorial and include a complex mix of environmental, immunological and host genetic factors. In addition, epidemiological studies show strong associations between asthma and infection with respiratory pathogens, including common respiratory viruses such as rhinoviruses, human respiratory syncytial virus, adenoviruses, coronaviruses and influenza viruses, as well as bacteria (including atypical bacteria) and fungi. In this Review, we describe the many roles of microorganisms in the risk of developing asthma and in the pathogenesis of and protection against the disease, and we discuss the mechanisms by which infections affect the severity and prevalence of asthma.

Figure 1. The microbiome is influenced by and may determine factors affecting asthma.

The microbiome is regulated by diet, environmental factors (such as smoking and pollution), treatment, host genetics, and previous infections and host immunity. The diversity of the microbiome may in turn affect asthma development, as suggested by the hygiene hypothesis, and may influence the pathogenic species that contribute to stable and severe asthma and asthma exacerbations.

Figure 2. Viruses and bacteria associated with asthma exacerbations.

The prevalence of viruses and bacteria in young children (<2 years old), older children (6–17 years old) and adults, presented as median percentages from several studies (data were obtained from a recent review). Enterovirus estimations in adults and bocavirus estimations in 6–17 year olds and in adults may be under-represented owing to that data not being available in published studies.

Figure 3. Microorganisms involved in asthma and their niches.

A cross-section of the human lower respiratory tract, showing sites of infection for different microorganisms and the effects that they have on airway function.

Figure 4. Viruses and bacteria induce airway inflammation.

Bacterial and viral infections of the airways activate immune and structural cells, promoting inflammation and influencing responses to other pathogens, allergens and pollution. Infection of airway epithelium by both viruses and bacteria induces neutrophil chemokines (CXC-chemokine ligand 1 (CXCL1; also known as GROα), CXCL5 (also known as ENA78) and CXCL8 (also known as IL-8)), and T helper 1 (T_H1) type chemokines (CC-chemokine ligand 5 (CCL5; also known as RANTES), CXCL10 (also known as IP10) and CXCL11 (also known as ITAC)), and increases epithelial permeability. Neutrophils secrete several mediators that can contribute to inflammation and the integrity of the airway, including matrix metalloproteinases (MMPs), elastase and reactive oxygen species (ROS). Epithelial cells normally express luminal CD200, which, when bound to its receptor, CD200R, on lumen macrophages, prevents the macrophage response to inflammatory stimuli. Lumen macrophages are normally inhibitory, as they produce transforming growth factor-β (TGFβ), which inhibits inflammatory airway dendritic cells (DCs). A higher epithelial permeability or epithelial damage as a result of infection allows the unrestrained submucosal macrophages access to the allergen and to other stimuli, and this can promote overzealous inflammation. Submucosal macrophages and epithelial cells are triggered by exposure to bacteria or viruses (and their products) to produce interleukin-1β (IL-1β), IL-6 and tumour necrosis factor (TNF), which promote inflammation. ASM, airway smooth muscle; GM-CSF, granulocyte–macrophage colony-stimulating factor; IFNγ, interferon-γ; MHC, major histocompatibility complex; T_H1, T helper 1.

Figure 5. Respiratory viruses interact with allergens in an additive or synergistic manner, promoting asthma.

Following sensitization, allergen presentation by airway dendritic cells (DCs) facilitates the promotion of T helper 2 (T_H2) cells. Viruses infect epithelial cells, stimulating the release of T_H2 cell-promoting chemokines CC-chemokine ligand 17 (CCL17) and CCL22, and cytokines thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25) and IL-33. The T_H2 type chemokines attract T_H2 cells into the airway, and these in turn secrete IL-4, IL-5 and IL-13. IL-5 promotes eosinophilia, and the resultant eosinophils release the inflammatory mediators major basic protein (MBP), eosinophil cationic protein (ECP) and transforming growth factor-β (TGFβ), inducing inflammation in the airway smooth muscle (ASM). IL-4 and IL-13 cause antibody class switching to immunoglobulin E in B cells, so that B cells secrete allergen-specific IgE. This antibody then binds mast cells, and crosslinking of the allergen on mast cell-bound IgE causes mast cell degranulation and release of preformed mediators, including histamine, prostaglandin (PGD₂) and leukotrienes (LTC₄, LTD₄ and LTE₄). These mediators cause bronchoconstriction and further airway inflammation. Mast cells also produce the T_H2 cytokines IL-4 and IL-13, as well as other cytokines, including TGFβ and tumour necrosis factor (TNF), promoting further T_H2 type immune responses and inflammation.