Molecular and cellular mechanisms in the viral exacerbation of asthma

Abstract

The aetiology of asthma associated with viral infection is complex. The dynamics that contribute to disease pathogenesis are multifactorial and involve overlapping molecular and cellular mechanisms, particularly the immune response to respiratory virus infection or allergen sensitization. This review summarizes the evidence associated with factors that may contribute to the development or exacerbation of asthma including age, host factors, genetic polymorphisms, altered immune responses, and aspects of viral antigen expression. This review also provides an important perspective of key events linked to the development of asthmatic disease and related pulmonary inflammation from human and animal studies, and discusses their relationship as targets for disease intervention strategies.

Fig. 1

Immune responses triggered by viral infection and allergens. (A) During the early stages of a viral infection, antigen presenting cells (APCs: macrophages, DCs) become activated and secrete IL-12. Viral peptide is presented by APCs to naïve T cells in association with MHC class I and co-stimulatory signals (B7 and CD28). The production of IL-12 and the binding of antigen-MHC molecules commit the differentiation of naïve T cells to the Th1 cell subset that secretes Th1 cytokines including IFN-γ. The cytokine contributes to the activation of macrophage (make more IL-12), B cells (make IgG2a) and cytotoxic T cell (kill infected cells). An IFN-γ dominated microenvironment inhibits the development of a Th2 cell subset. Together, these responses result in the resolution of the infection in the airways. (B) In the early phase of allergen exposure, cross linking of antigen-specific IgE on the surface of mast cells results in the activation and release of mediators that cause bronchoconstriction and inflammation. Activated mast cells also produce IL-4 that commits naïve T cells to the Th2 subset as well as B cell isotype class switching to IgE production. In addition, antigenic peptide is presented to naïve T cells by APCs in the context of MHC class II and co-stimulatory signals. In an IL-4 dominated microenvironment, this triggers the differentiation of naïve T cells to Th2 cell subset that generates Th2 cytokines (IL-4, IL-5, IL-10 and IL-13). These cytokines are responsible for orchestrating the late phase of the allergic response. IL-4 and IL-13 contribute to mast cell activation and the synthesis of IgE. IL-5 is implicated in eosinophilia and is known to stimulate these cells, resulting in degranulation and release of toxic basic proteins (e.g. ECP, MBP). IL-10 inhibits APCs, therefore preventing IL-12 from initiating a Th1 immune response.

Fig. 2

Factors known to affect the likelihood of asthma being exacerbated in response to a viral infection. These factors are responsible for skewing the immune response towards a Th2 biased immune response.

Fig. 3

Immunological effects of viral infection in atopic lung. RSV infection of allergic mice (exposed to OVA) mimics viral infection (e.g. RSV, RV) in an atopic individual (young child or elderly). RSV infection in an atopic person results in further amplification of the Th2 immune response. These aberrant immune responses contribute to exacerbated airway pathology with persistent wheezing and asthma symptoms.