Respiratory Viral Infections and Asthma: Is There a Link?

Erwin W. Gelfand, MD

In This Article

Viral-Induced Effectors of the Inflammatory Response

The complexity of the effects of respiratory infection on airway function are underscored by the many cell-mediated immune responses to viruses (Figure). Increased expression of a number of important adhesion molecules can be detected in response to infection. These proteins regulate inflammatory cell migration, enhancing airway inflammatory responses. One example is intercellular adhesion molecule 1 (ICAM-1), a molecule in which expression is increased during and following viral infection. ICAM-1 is expressed on a wide variety of cells, including epithelial cells, endothelial cells, fibroblasts, lymphocytes, and monocytes. Expression of ICAM-1 is increased by the pro-inflammatory mediators (cytokines) interferon-gamma, interleukin (IL)-1, and tumor necrosis factor (TNF).

ICAM-1 is the major human rhinovirus receptor. Upregulation of ICAM-1 has been detected following experimental rhinovirus infection. Binding of the virus to ICAM-1 on different cell types triggers the release of a number of cytokines and further increases in ICAM-1 expression on adjacent cells, thereby enhancing adhesion and spread of the virus. With increased expression of ICAM-1, eosinophil and neutrophil migration, adhesion and attraction are augmented; this leads to enhanced inflammation, which increases AHR. Support for this pathway in the pathogenesis of disease is provided by studies in different animal models where blockade of ICAM-1 reduces inflammatory cell accumulation.

Host-virus interactions.

Many of the respiratory viruses, but especially RSV, can affect the respiratory epithelium, triggering the release of both eosinophil chemoattractants (eg, Rantes) and IL-6, IL-8, GM-CSF, and macrophage inflammatory protein (MIP-1alpha). In a recent study of RSV-stimulated neutrophils, the release of IL-8 and MIP-1beta and neutrophil degranulation were demonstrated.[9] Rantes is a potent chemoattractant for eosinophils, while GM-CSF is important for eosinophilopoiesis. IL-8 will lead to the influx of neutrophils, which, in turn, can further contribute to inflammation by the release of their stored/de novo synthesized chemokines and granular enzymes.

MIP-1alpha stimulates eosinophil and basophil chemotaxis and degranulation, which leads to further recruitment of these cells and the subsequent release of eosinophil cationic proteins (ECP) and histamine into the airways.

MIP-1beta is a member of the c-c chemokine family. Its function is not fully defined, but it appears capable of stimulating antigen-specific Th2 lymphocyte proliferation and upregulating the costimulatory molecule CD80 on antigen-presenting cells. Of note, ECP, eosinophil neurotoxin, and histamine have been identified in the respiratory secretions of bronchoalveolar lavage fluid of infants with RSV bronchiolitis. Neutrophils, IL-8, and neutrophil myeloperoxidase have also been found in the respiratory secretions of children with viral-induced asthma.

Another inflammatory mechanism possibly involved in the development of asthmatic symptoms may be the increase in production of IL-11 by epithelial cells following viral infection. In children with viral upper RTI and in those with wheezing, IL-11 levels are elevated in nasal secretions. Administration of recombinant IL-11 into the lungs of mice results in increased airway responsiveness to methacholine. The role IL-11 plays in virus-induced lung disease remains to be determined.

The inflammatory response elicited by viral RTI and particularly the accumulation of eosinophils most likely play essential roles in the development of wheezing during acute infection. The study authors have recently reported in a murine model[10,11] that the eosinophilic component of the inflammatory response to acute RSV infection and the associated development of AHR to methacholine provocation are dependent on the presence of IL-5. Blockade of the eosinophil adhesion molecule VLA-4 prevented both eosinophil migration into the airways and the associated development of AHR. These data extend some of the clinical observations that development of RSV-induced AHR is associated with the presence of eosinophils and may be dependent on this eosinophilic response.

Dependence of virus-induced AHR on IL-5 has also been reported in a guinea pig model of parainfluenza infection. Studies in guinea pigs revealed a mechanism by which eosinophils could influence airway tone and reactivity. Cationic proteins released by eosinophils are capable of binding to presynaptic M2 muscarinic receptors on postganglionic parasympathic airway nerves. The resulting blockade interrupts an inhibitory feedback mechanism, resulting in increased release of acetylcholine and in increased airway muscle tone and reactivity. This mechanism has been demonstrated both in models of allergic sensitization and following acute viral infection. Parainfluenza neuraminidase can also bind to M2 muscarinic receptors directly and may be responsible for effects described in the absence of eosinophilic inflammation. In addition, viral infection and interferon-gamma downregulate M2 receptor gene expression.


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