NEUROIMMUNE MECHANISMS LEADING TO PERSISTENT WHEEZE:
RSV AND OTHER INFECTIONS
GIOVANNI PIEDIMONTE, M.D.
___________________________________________________________________
Department of Pediatrics and Pediatric Research Institute
West Virginia University School of Medicine, Morgantown, WV, U.S.A.
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CORRESPONDENCE
Giovanni Piedimonte, M.D.,
Department of Pediatrics,
Robert C. Byrd Health Sciences Center,
West Virginia University School of Medicine,
1 Medical Center Drive, P.O. Box 9214,
Morgantown, WV 26506-9214,
Telephone: (304) 293-4451, Fax: (304) 293-4454.
Email: gpiedimonte@hsc.wvu.edu 1
Introduction - A number of environmental factors can impact the development and
severity of allergy and asthma; however, it can be argued that the most significant
inhaled agents which modulate the development of these conditions are biologics. In
particular, many pathogens, especially viruses, target airway epithelial cells and
impact the host immune and inflammatory responses to those pathogens. This
review examines some new aspects of the neurobiology of the response against
respiratory syncytial virus (RSV), which is the most common respiratory pathogen in
early life, in the context of the subsequent development of allergy and asthma. Also,
new experimental evidence suggests that other viral (e.g., rhinovirus) and bacterial
(e.g., Pseudomonas aeruginosa) can affect neural development and neuro-immune
interactions in the respiratory tract with modality that are significantly different from
those previously reported for RSV.
Viral infection and neuro-immune interactions - Although RSV infection is usually
self-limited and the virus is cleared from the respiratory tract of immune-competent
children within several weeks, there is growing evidence to suggest that RSV
infection may have long-term sequelae in the developing respiratory system (1). In
fact, epidemiological evidence from several retrospective studies, as well as more
recent well-controlled prospective studies, supports the association between early life
RSV lower respiratory tract illness and recurrent episodes of wheezing and the
development of asthma during the first decade of life. Indeed, RSV bronchiolitis and
asthma share several clinical features (wheezing, increased work of breathing,
tachypnea, and reversible changes in pulmonary function), but they also differ
substantially in terms of response to bronchodilator and anti-inflammatory therapies.
Despite extensive research, the precise molecular mechanisms and pathways by
which RSV infection causes airway inflammation and affects long-term control of
airway function subsequent to the initial insult remain unclear.
Compromised epithelial integrity, the elaboration of local proinflammatory mediators,
and
dysfunction
of neural pathways
may influence
airway responses to
environmental stimuli. Some investigators postulate that infection with RSV or other
viral pathogens can precipitate an imbalance in local cell-mediated immune
responses. Others hypothesize that infant bronchiolitis may result in alterations to
neuronal pathways that influence airway smooth muscle tone and airway patency via
the release of neurotransmitters. We have proposed that combined neuro-immune
interactions primed by the virus can initiate and propagate a cascade of events
leading to recurrent cycles of airway inflammation and obstruction (1).
In the airways, a dense network of sensory nerve fibers is strategically placed just
below the epithelial surface so that any change in the bronchial environment may
stimulate the release of the proinflammatory neuropeptide substance P. During RSV
infection, stimulation of these nerves causes a marked increase in airway vascular
permeability and results in an increase in overall inflammatory status. Our work has
revealed that these changes are mediated by the high affinity receptor for substance
P (NK1 receptor), whose expression is greatly increased by RSV. This up-regulation
presumably occurs at the pre-translational level, as NK1 receptor mRNA levels
increase substantially during RSV infection. We have also shown that T-lymphocyte
subpopulations, predominantly CD4+ cells, within the bronchial-associated lymphoid
tissue (BALT) of RSV-infected lungs, express high levels of the NK1 receptor. As a
consequence, stimulation of the sensory nerves by airborne irritants has the potential
of causing a new inflammatory cycle mediated by NK1 receptor-expressing T-helper
lymphocytes and monocytes attracted into the airways and activated by substance P.
This mechanism may establish important neuro-immune interactions, which undergo
long-term dysregulation following RSV infection and predispose to airway
inflammation and hyperreactivity.
Viral infection, nerve growth factor and neurotrophins - Our recent studies show
that RSV infection promotes a large increase in the expression of nerve growth factor
(NGF) and neurotrophin receptors both in animal models and in humans (2). NGF
activation of the receptor tyrosine kinase pathway is critical for the neurogenicmediated lymphocytic and monocytic response in RSV-infected airways, suggesting
that neuro-immune interactions driven by neurotrophic pathways play an important
role in the pathophysiology of local and systemic inflammation against viral
respiratory infections. This important inflammatory mechanism is largely resistant to
inhaled corticosteroids (3), which provides a plausible explanation for the poor
therapeutic activity of these drugs in children with virus-induced wheezing.
NGF is the first discovered component of the neurotrophin family, which also includes
the brain-derived neurotrophic factor (BDNF) and the neurotrophins 3 (NT-3) and 4/5
(NT-4/5). Neurotrophins modulate survival, differentiation and apoptosis of peripheral
afferent and efferent neurons, and specifically control the expression of genes that
encode the precursors of substance P and other peptide neurotransmitters. These
effects are mediated by binding to high affinity tyrosine kinase (trk) receptors
(generally promoting neuron survival and differentiation) or to the low affinity panneurotrophin receptor p75 (generally mediating apoptosis and death). The high
affinity receptor for NGF is the trkA subtype. Neurotrophins exert changes in the
functional activity of peripheral neurons in a number of ways that collectively define
“neuronal plasticity”. Examples from studies in vitro and in vivo include increased
production of neurotransmitters, increased number of nerves that produce specific
neuropeptides, and increased neurotransmitter release from nerve terminals
mediated by increased expression and function of the vanilloid receptor TRPV1 (the
capsaicin receptor). NGF is also synthesized in several non-neuronal cell types
including epithelial and inflammatory cells (e.g., mast cells and CD4+ T cells) that
also express trk receptors. This function may target the innervation of specific
tissues, but there is growing evidence that NGF functions as a potent and eclectic
neuro-immunomodulator, which releases and is released by a variety of inflammatory
mediators. In particular, patients with bronchial asthma and allergic rhinoconjunctivitis
display high serum levels of NGF, suggesting an important pathogenetic role of
neurotrophins in allergic disorders.
Because NGF is released from airway epithelial cells, increases the production and
release of substance P and other tachykinins from adult sensory neurons, and
induces sensory hyper-innervation in the airways of transgenic mice, it represents an
ideal link between virus-infected respiratory epithelium and the dense sub-epithelial
network of unmyelinated sensory fibers. RSV-induced release of NGF may lead to
short- and long-term changes in the distribution and reactivity of sensory nerves
across the respiratory tract, participating in exaggerated inflammatory reactions
during and after the infection. NGF and its receptors may also amplify other
immunologic and neuronal pathways contributing to airway inflammation and
hyperreactivity. Based on these observations, we postulate that changes of
neurotrophin expression in the respiratory tract may coordinate a variety of
interactions between sensory afferent nerves and multiple components of the
immune system and inflammatory pathways, thus generating a pathophysiological
link between early-life viral infections and childhood asthma.
Neurotrophins and other infections – New experimental evidence suggests that
other viral (e.g., rhinovirus) and bacterial (e.g., Pseudomonas aeruginosa) infections
can affect neural development and neuro-immune interactions in the respiratory tract,
but they do so with modality that are significantly different from those previously
reported for RSV. In particular, differently from the exclusive tropism of RSV for the
bronchiolar epithelium, rhinovirus exhibits temperature-dependent tropism for
different sections of the respiratory tract (4). In the case of P. aeruginosa, the effect
of the infection on neurotrophin expression and neurogenic inflammation is maximal
during a specific developmental window in early-life (5), confirming the importance of
early and aggressive antibiotic therapy in children with diseases like cystic fibrosis.
Thus, much more investigative work is necessary to explore the complex interactions
between airborne biological agents (alone or in combination), airways neural
development, and neuro-immune interactions.
References
1. Piedimonte, G. 2001. Neural mechanisms of respiratory syncytial virus-induced
inflammation and prevention of respiratory syncytial virus sequelae. Am J Respir Crit
Care Med 163:S18-S21.
2. Tortorolo, L., Langer, A., Polidori, G., Vento, G., Stampachiacchere, B., Aloe, L.,
and Piedimonte, G. 2005. Neurotrophins overexpression in lower airways of infants
with respiratory syncytial virus infection. Am J Respir Crit Care Med 172:233-237.
3. Mothasham, L., Auais, A., and Piedimonte, G. 2007. Nerve growth factor mediates
steroid-resistant inflammation in respiratory syncytial virus infection. Pediatr Pulmonol
42:496-504.
4. Othumpangat, S., Walton, C., Samsell, L., and Piedimonte, G. 2010. NGF
regulates the expression of ICAM-1 in human airway epithelial cells during
Rhinovirus-16 infection. Am J Respir Crit Care Med in press.
5. Cardenas, S., Scuri, M., Samsell, L., Ducatman, B., Bejarano, P., Auais, A., Doud,
M., Mathee, K., and Piedimonte, G. 2010. Neuroimmune responses to early-life
Pseudomonas aeruginosa infection in rat lungs. Am J Respir Crit Care Med in press.