Neuroimmune regulation of viral respiratory infection in infancy
Respiratory viruses, predominated RSV, are the leading cause of acute lower respiratory tract infections in infancy and the prime cause of hospitalization in this age population in developed countries21,22. Primary infection at a young age plays a pivotal role in the severity of acute disease and in subsequent recurrent wheezing, peaking in infants aged <3 months21,23,24. The interplay RSV-host is complex and involves cells of the innate and adaptive immune systems, whose excessive activation may induce significant cytopathic effects to the airways24,25. RSV infection-induced injury leads to bronchoconstriction, airway inflammation and edema. The multifaceted mechanisms provoking RSV-induced airway inflammation and hyperreactivity are still only partially understood but there is evidence that dysregulation of the NANC system is involved, favoring the bronchoconstrictive and pro-inflammatory effects of tachykinin peptides, exemplified by Sub P, against the bronchorelaxant effect of vasoactive intestinal peptide (VIP) 2. RSV upregulates the expression of nerve growth factor (NGF) and of its p75 neurotrophin receptors in target cells 25. NGF acts as promoter of acetylcholine release and as signaling molecule to induce the production of Sub P, that persists after RSV clears from the lungs2,14,25 (figure 2A). Hence, the decreased threshold of excitatory NANC activation results from the upregulated Sub P/NK1 axis and likely underlies long-term airway dysfunction and recurrent inflammation and hyperresponsiveness 25,26. The long-lasting sequelae of the early-life RSV infection can also be explained by the observation that the upregulated NGF also leads to short- and long-term changes in the distribution and reactivity of sensory nerves across the respiratory tract, enhancing the exaggerated functional and inflammatory reactions to infections14,24,25. The possible role of neuropeptides in induction of early childhood disorders characterized by recurrent wheeze in other early viral infections, such as Rhinovirus, has not been evaluated or reported.