Respiratory syncytial virus (RSV) is a common respiratory tract infection seen in children. Virtually all children contract it by the age of three presenting the leading cause of pneumonia and bronchiolitis in infants, and possibly a key contributor to the pathogenesis of asthma and chronic obstructive pulmonary disease. Disease severity varies widely and aggressive treatment of severe infection could present both significant long-term advantages and also improved prognosis for at risk children.

RSV G glycoprotein has been shown to be associated with a number of proinflammatory effects and may contribute to the pathogenesis of RSV disease in several ways. Studies of mice have shown that RSV G glycoprotein modifies chemokine and cytokine expression, alters pulmonary leukocyte recruitment, and sensitizes for pulmonary eosinophilia. BALB/c mice immunized with vaccinia virus expressing G glycoprotein, purified G glycoprotein, or formalin-treated RSV produce an exaggerated CD4 T-cell response with increased Th2-type cytokine expression and pulmonary eosinophilia when challenged with RSV.

Structurally, the RSV G glycoprotein is of particular interest as it contains a CX3C motif at amino acid positions 182 to 186 in the central conserved region and has the ability to functionally mimic the CX3C chemokine fractalkine (FKN). FKN has been shown previously to bind to neurons and microglia expressing its receptor, CX3CR1, and induces an excitatory effect that mediates the release of neuronal products such as SP. Accordingly, CX3C chemokine mimicry by the RSV G glycoprotein may alter signal transduction between the immune system and the nervous system, alter immune responses, and modulate disease pathogenesis associated with RSV infection.

Researchers from the Centers for Disease Control and Prevention and the National Jewish Medical and Research Center in Denver have recently investigated the possibility that RSV infection might alter respiratory tract performance as a result of RSV G glycoprotein. This group found that the RSV G glycoprotein depressed the respiratory rate in mice through a mechanism involving CX3C interaction with CX3CR1 and subsequent induction of SP.

The molecular mimicry described in this study may contribute to a key effect of RSV infection since apnea is frequently observed in infected infants and young children; indeed in one study of 274 infants under 6 months of 20.4% infants had apnea with RSV infection. Since anti-SP antibody treatment decreases pulmonary inflammation associated with primary RSV, the ability of RSV G glycoprotein to activate CX3CR1 and increase SP release might contribute to the pathophysiological effects of RSV infection more generally including the development of bronchiolitis and bronchial hypersensitivity.

Clinically this study is important since it suggests that vaccines that incorporate positions 182 to 186 of the RSV G glycoprotein may provoke symptoms of RSV infection. On the other hand, the development of antibodies, drugs, or agents that inhibit the interaction between G glycoprotein and CX3CR1 or the actions of SP may be beneficial in treating some aspects of RSV disease.

Entry date Tuesday, June 03, 2003

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk