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.