Rhinoviruses, allergic inflammation, and asthma

Abstract

Viral infections affect wheezing and asthma in children and adults of all ages. In infancy, wheezing illnesses are usually viral in origin, and children with more severe wheezing episodes are more likely to develop recurrent episodes of asthma and to develop asthma later in childhood. Children who develop allergen-specific immunoglobulin E (allergic sensitization) and those who wheeze with human rhinoviruses (HRV) are at especially high risk for asthma. In older children and adults, HRV infections generally cause relatively mild respiratory illnesses and yet contribute to acute and potentially severe exacerbations in patients with asthma. These findings underline the importance of understanding the synergistic nature of allergic sensitization and infections with HRV in infants relative to the onset of asthma and in children and adults with respect to exacerbations of asthma. This review discusses clinical and experimental evidence of virus-allergen interactions and evaluates theories which relate immunologic responses to respiratory viruses and allergens to the pathogenesis and disease activity of asthma. Greater understanding of the relationship between viral respiratory infections, allergic inflammation, and asthma is likely to suggest new strategies for the prevention and treatment of asthma.

Figure 1

Role of viral infections in the inception and exacerbation of asthma.

Figure 2

HRV‐induced signaling pathways in epithelial and monocytic cells. Major group HRV binds to ICAM‐1 and minor group HRV binds to LDLR receptors on the surface of cells, such as epithelial cells and leukocytes that would be abundant in the airway, to induce downstream signaling. The receptor and signaling pathways induced by HRVC serotypes has yet to be elucidated. (A) Upon ligation of HRV to surface receptors on epithelial cells, direct uncoating of viral RNA or clathrin‐mediated endocytosis leads to the release/replication of HRV RNA into the cytoplasm. This viral RNA is detected by endosomal receptors, such as TLR3, to propagate downstream signaling and induction of gene expression, including the production of interferons that can exert an autocrine/paracrine effect by binding to interferon receptors and triggering a JAK/STAT signaling cascade. Replication‐independent signaling is also induced upon HRV infection, and includes the activation of Src, Syk, and MAPK signaling cascades. Yellow solid lines: data to support link; Dashed lines: indirectly connected (may have signaling molecules in between); Red lines: signaling induced by product of HRV‐induced gene transcription; Green lines: replication‐dependent signaling. (B) Unlike epithelial cells, HRV‐signaling in monocytic cells is thought to be replication independent, as viral replication in these cells is inefficient. In monocytic cells, such as alveolar macrophages and peripheral blood monocytes, HRV induces the activation of both NF‐κB and the stress‐activated protein kinases (SAPK) cascades. Transcriptional activation after HRV binding leads to the induction of gene expression, including IFNs that bind to IFN receptors on the surface of both monocytic and epithelial cells, to induce downstream JAK/STAT signaling and further gene expression. Blue solid lines: data to support link; Dashed lines: indirectly connected (may have signaling molecules in between). It has yet to be determined whether HRV‐induced JNK and CREB activation are essential for the expression of cytokines.

Figure 3

Mechanisms of virus–allergen interactions.