The cell biology of acute childhood respiratory disease: therapeutic implications

Abstract

Respiratory syncytial virus (RSV), the recently identified human metapneumovirus (HMPV), and the human parainfluenza viruses (HPIVs), cause most cases of childhood croup, bronchiolitis, and pneumonia. Influenza virus also causes a significant burden of disease in young children, although its significance in children was not fully recognized until recently. This article discusses pathogens that have been studied for several decades, including RSV and HPIVs, and also explores the newly identified viral pathogens HMPV and human coronavirus NL63. The escalating rate of emergence of new infectious agents, fortunately meeting with equally rapid advancements in molecular methods of surveillance and pathogen discovery, means that new organisms will soon be added to the list. A section on therapies for bronchiolitis addresses the final common pathways that can result from infection with diverse pathogens, highlighting the mechanisms that may be amenable to therapeutic approaches. The article concludes with a discussion of the overarching impact of new diagnostic strategies.

Fig. 1

Model of paramyxovirus fusion protein–mediated membrane fusion. The trimeric F protein (A) contains two hydrophobic domains: the fusion peptide and the transmembrane-spanning domain. Each is adjacent to one of two heptad repeat (HR) regions, HR-N and HR-C. The F protein binds to a receptor on the host cell membrane, and a conformational change leads to insertion of the hydrophobic fusion peptide into the host cell membrane (B). Multiple trimers of F mediate the fusion process (C). Protein refolding occurs as host and viral cell membranes bend toward each other (D) and the lipids on the outer part of the membranes begin to interact (E). As protein refolding finishes (F), the fusion peptide and the transmembrane domain are antiparallel in the same membrane. (From Moscona A. Entry of parainfluenza virus into cells as a target for interrupting childhood respiratory disease. J Clin Invest 2005;115:1688–98; with permission.)

Fig. 2

Steps of the paramyxovirus lifecycle that offer targets for antiviral molecules (with HPIV as the model virus). (A) Agents that block HN's recruitment of inflammatory cells to the lung and resultant cytokine expression may reduce the inflammatory response to infection and lessen disease severity. (B) Molecules that fit into the binding pocket on HN's head region may inhibit HN-receptor binding and thereby inhibit the F-triggering mediated by HN's stalk. The diagram on the left shows HN with an inhibitor bound, precluding the next step shown on the right, in which HN's receptor-binding has led to F-activation. (C) F peptides may prevent the refolding of F that is necessary for fusion during virus entry into the host cell. In addition, the F protein may be triggered too early and thus be put out of action before it reaches the target host cell membrane. (D) HN's neuraminidase activity cleaves sialic acid moieties of the cellular receptors, allowing release of new virions from the host cell. Specific inhibition of neuraminidase may prevent virion entry into additional uninfected cells. (From Moscona A. Entry of parainfluenza virus into cells as a target for interrupting childhood respiratory disease. J Clin Invest 2005;115:1688–98; with permission.)