Infectious Disease–Review

Veterinary Pathology
2015, Vol. 52(1) 97-106
The Relationship Between Respiratory ª The Author(s) 2014
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Syncytial Virus and Asthma DOI: 10.1177/0300985814520639
vet.sagepub.com

C. J. Knudson1 and S. M. Varga1,2,3

Abstract
Asthma is a chronic inflammatory disease of the lung that is a leading cause of morbidity and mortality in children worldwide. Most
infants who experience wheezing episodes also exhibit evidence of an ongoing respiratory viral infection. Respiratory syncytial
virus (RSV) is the leading cause of lower respiratory tract infection in children and is a common cause of wheezing in infants and
young children. In the past several decades, a number of studies have demonstrated a relationship between infants with severe
RSV infections and the subsequent development of asthma later during childhood. This review provides an overview of data that
suggests a severe RSV infection early in childhood is linked to development of asthma later in life. In addition, the current and
potential future use of various animal models to gain additional insight into the relationship between RSV and asthma is discussed.

Keywords
asthma, bronchiolitis, respiratory syncytial virus, wheezing, animal models, Th2 cells, Th17 cells, immunoregulation

Asthma is a common chronic inflammatory disease of the respira-
tory tract that is characterized by narrowing of the airways that
recurs throughout an individual’s lifetime. Prevalence rates for
asthma are at historically high levels and remain a significant pub-
lic health problem.2 Asthma attacks are often characterized by
recurring episodes of symptoms such as coughing, wheezing,
shortness of breath, and chest pain. Acute asthma episodes can
be triggered by a number of factors, including allergens, chemical
irritants, drugs, infection, strenuous exercise, or sudden changes
in weather. It is currently unclear what factors lead to the initial
development of asthma. It is likely that asthma inception is due
to a combination of both genetic predisposition and environmen-
tal cues. Virus infection may represent a critical environmental
trigger for the development of asthma. RNA from common
respiratory viral infections can be detected in 90% of nasal lavage
samples from children aged 1 to 3 years experiencing wheezing
episodes.35 Rhinovirus and respiratory syncytial virus (RSV) are
the most common viruses detected in children experiencing
wheezing.35 A study of children with wheezing symptoms
revealed a strong correlation with a concurrent rhinovirus and/
or RSV infection. Children with wheezing episodes who were
infected by either rhinovirus or RSV in the first 3 years of life had
a greater tendency to develop asthma by age 6 years compared
with children not infected by either virus.35 This suggests that
exposure to common respiratory viral infections such as RSV dur-
ing early childhood may increase the risk of developing asthma.
RSV is a negative-sense single-stranded RNA virus of the
Paramyxoviridae family and a common cause of bronchiolitis
in infants. RSV is the leading cause of lower respiratory tract
infections in infants and young children.27,77,93 By the age 2
years, nearly all children have been infected by RSV at least
once.22 While RSV is a significant health care burden, there
is currently no licensed vaccine available. Over the past 20
years, there have been a number of studies demonstrating a pos-
itive correlation between severe RSV infection early in child-
hood and a greater risk of developing asthma.29,53,55,80,81
This review explores the relationship between severe RSV
infection and the subsequent development of asthma. Further-
more, it describes the use of BALB/c mouse models to explore
this relationship and discusses the potential utility of other ani-
mal models of RSV and asthma that could be used to shed fur-
ther light on this important topic.
Relationship Between Severe RSV Infection
and Asthma
Epidemiology
RSV is a seasonal virus in temperate climates with infection
rates peaking during winter months. However, in tropical cli-
mates, RSV infection can occur year-round.8 While virtually
all children eventually become infected with RSV, only 0.5%
to 2% of infants require hospitalization during their initial
1
Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa
City, IA, USA
2
Department of Microbiology, University of Iowa, Iowa City, IA, USA
3
Department of Pathology, University of Iowa, Iowa City, IA, USA
Corresponding Author:
S. M. Varga, University of Iowa, 51 Newton Rd, 3-532 BSB, Iowa City, IA 52242,
USA.
Email: steven-varga@uiowa.edu
98
exposure.76 Hospitalizations during RSV infection are a result
of airway dysfunction caused by inflammation of the bronch-
ioles resulting in bronchiolitis. Reinfection by RSV can occur
throughout one’s lifetime as sterilizing immunity is not gener-
ated following infection.22,25,28 However, subsequent RSV
exposures are believed to be less severe in healthy adults.
Link Between Severe RSV Infection and Development of
Recurrent Wheezing or Asthma
A large number of studies have identified a link between severe
RSV infection and an increased likelihood to develop either
recurrent wheezing or asthma.* The Avon Longitudinal Study
of Parents and Children by Henderson et al29 revealed that chil-
dren admitted to the hospital for RSV-induced bronchiolitis
prior to the age 1 year were at increased risk of developing
recurrent wheezing at 30 to 42 and 69 to 81 months compared
with the control group (28.1% vs 13.1% and 22.6% vs 9.6%,
respectively). Furthermore, 38.4% of the severe RSV group
developed asthma by age 7 years compared with only 20.1%
of the control group. Similar results were observed in a long-
term Swedish study of 140 children by Sigurs et al.80 Children
who experienced a severe RSV infection prior to 1 year of age
were at a much greater risk of developing asthma by age 7.5
years (30% vs 3% of control group). In addition, recurrent
wheezing symptoms were more likely to occur in the children
who experienced RSV-induced bronchiolitis (28%) compared
with the control group (11%). A 5-year and a 10-year follow-
up study of the same cohort revealed similar trends. Children
who had experienced a severe RSV infection during infancy
exhibited a significantly greater incidence of either recurrent
wheezing (30% vs 16.3%) or asthma (37% vs 5.4%) by age
13 years.81 The incidence of recurrent wheezing (30% vs
1%) remained significantly higher in children with an early
severe RSV infection by age 18 years.79 The authors also noted
that children who had experienced an early severe RSV infec-
tion were more likely to develop allergic sensitization to com-
mon inhaled or food allergens at any of the 3 age time points
investigated.79–81 Since allergen sensitization is a major risk
factor associated with asthma inception, severe RSV infection
during early childhood may contribute to the development of
asthma through sensitization to common allergens.60,68,84,86
Overall, these studies suggest that experiencing a severe RSV
infection during early childhood increases the likelihood of
developing asthma later in life.
While numerous studies indicate a link between early severe
RSV infection and an increased risk in developing asthma, the
exact nature of the relationship is unclear. The results from the
Tennessee Asthma Bronchiolitis Study (TABS) of 95 310 chil-
dren by Carroll et al10 and Wu et al98 suggest that a causal rela-
tionship exists between severe RSV infection and the
development of asthma. This study assessed the relationship
between the risk of developing asthma by age 5.5 years and the
*References 18, 29, 37, 39, 47, 53, 55, 80, 81, 87, 98.
Veterinary Pathology 52(1)
time of year at which there was the greatest number of
bronchiolitis-related hospitalizations (BRHs). The number of
BRHs peaks every year during the winter months in temperate
climates. If there was no relationship between the risk of devel-
oping asthma and severe bronchiolitis, then rates of asthma
among children would be expected to be similar year-round
irrespective of patterns of BRH. However, the authors observed
similar patterns between the timing of the peak of BRHs and
the likelihood of infants developing asthma. Children born 4
months prior to the annual peak of BRHs were 29% more likely
to develop asthma compared with infants born 1 year from this
time point. This relationship was similar across the 5-year
study even though the peak of BRHs shifted by up to 6 weeks.
It was not determined if children were infected with a specific
virus such as RSV, although up to 70% of severe bronchiolitis
cases are associated with RSV infection.58 The TABS suggests
that viral infection during childhood directly contributes to an
increased risk of developing asthma.
Influence of Age in Longitudinal RSV and Asthma Studies
Although a number of studies indicate an increased risk of
developing recurrent wheezing later during childhood follow-
ing a severe RSV infection, a few longitudinal studies suggest
these changes are transient. A study by Pullan and Hey65 deter-
mined that children with severe RSV infections prior to 1 year
of age experienced recurrent wheezing symptoms primarily
during the first 4 years of life (38% vs 15% of control group).
However, by age 10 years, there was no longer a significant dif-
ference in rates of wheezing (6.2% vs 4.5%). Similar results
were observed in the Tucson Children’s Respiratory Study of
1246 children.87,91 Infants who experienced a severe RSV
infection in the first 3 years of life were at a significantly
increased risk of exhibiting recurrent wheezing symptoms at
ages 6 and 11 years. However, there was no significant differ-
ence in infrequent or frequent wheezing symptoms by age 13
years. These data are in contrast to the longitudinal study by
Sigurs et al81 that demonstrated a significant increase in chil-
dren with asthma by age 13 years. The differential findings
reported in these studies could be due to many factors, includ-
ing genetic variability among cohorts, parameters used to select
the cohort, how wheezing/asthma is evaluated, and differences
in the relative pathogenicity of circulating RSV strains.
Palivizumab Prophylaxis Treatment and the
Development of Recurrent Wheezing
An alternative approach to determining if RSV contributes to
the development of asthma is to limit RSV-induced disease.
Although there is currently no licensed vaccine, passive immu-
nization has shown some promise.24,69 In the mid-1990s, a
monoclonal antibody specific for the fusion protein of RSV,
palivizumab, was evaluated across the United States, United
Kingdom, and Canada for efficacy in the prophylactic treat-
ment of RSV infection.1 Palivizumab prophylaxis reduced
RSV-associated hospitalization rates by 55% (10.6% placebo
Knudson and Varga
vs 4.8% palivizumab). Due to cost considerations, palivizu-
mab prophylaxis is administered only to children at high risk
of developing severe RSV-induced disease, such as preterm
infants. In a study by Simoes et al,82 preterm infants who
either had received or had never been administered palivizu-
mab prophylaxis were followed for development of wheezing
symptoms.
This study indicated there were long-term benefits to lessen-
ing the severity of RSV infection. The rates of recurrent wheez-
ing were compared between infants with prophylactic treatment
who were not hospitalized for severe RSV infection and children
who were hospitalized for RSV-induced bronchiolitis without
prior palivizumab treatment. Children from the prophylaxis
group were significantly less likely to develop physician-
diagnosed recurrent wheezing (8% vs 16% of no prophylaxis
group) by 3.5 years of age.82 These data further support the
notion that severe RSV infection may contribute to the develop-
ment of asthma.
Lung Function and Immune Response to
RSV Infection
Lung Function
Infants younger than 6 months are highly susceptible to RSV-
induced bronchiolitis.21,59 This is likely due to their reduced
pulmonary function since lung development continues for sev-
eral years.49,100 Length of hospital stay often correlates with the
degree of lung dysfunction, and a significant number of infants
with severe RSV-induced disease require mechanical ventila-
tion.90 If severe RSV infection increases an individual’s risk
of asthma inception, there may be long-term alterations to the
lung environment. In agreement, children evaluated approxi-
mately 6 years after a severe RSV infection exhibited signifi-
cantly reduced respiratory capacity compared with infants
who were not hospitalized for RSV infection.63 A study by
Korppi et al37 also demonstrated reduced lung function in
young adults 20 years after a severe RSV infection. Similar
results were observed in a number of other studies in which
children exhibited reduced lung function 7 or more years after
a severe RSV infection.11,41,50,55,81,85 These studies indicate
that severe RSV infection may alter the lung environment and
lead to prolonged lung dysfunction long after the infection is
resolved.
Immune Response
Infection with RSV results in a significant increase in proin-
flammatory cytokines and chemokines such as interleukin
(IL)–1a, IL-1b, IL-6, IL-8, interferon (IFN)–g, tumor necrosis
factor (TNF)–a, monocyte chemotactic protein 1 (MCP-1),
macrophage inflammatory protein (MIP)–1a, and MIP-1b.
Since asthma is a chronic inflammatory disease, severe RSV
infection may promote a prolonged inflammatory environment
within the lung that leads to the development of asthma. Naso-
pharyngeal aspirates obtained from asthmatic infants infected
99
with RSV by age 2 years revealed significantly elevated IL-6
protein levels compared with controls.56 Furthermore, in mur-
ine models of allergic inflammatory disease, protein levels of
proinflammatory chemokines MIP-1a and CCL5 (RANTES)
were elevated and significantly contributed to allergic airway
inflammation.36,71 Increased levels of RANTES protein also
have been correlated with increased RSV disease severity.
Studies also suggest that an imbalance in the type of CD4
T-cell response further exacerbates allergic responses. Infec-
tion by RSV at an early age tends to induce a type 2 helper
T-cell response (Th2) that produces IL-4, IL-5, and IL-13.6,14
A Th2-biased immune response is known to contribute to dis-
ease in murine models of allergic airway inflammation and is
strongly associated with asthmatic patients.13,17,32,73,78 There-
fore, infection by RSV at an early age may induce a Th2-
biased immune response that promotes asthma inception.
Recent work also suggests a role for IL-17–induced patho-
genesis in a subset of asthmatic patients. IL-17 is secreted by
type 17 helper T cells (Th17) and can induce the chemotaxis
of granulocytes such as neutrophils or directly signal through
cells such as fibroblasts and macrophages to produce proin-
flammatory cytokines IL-1b, IL-6, and TNF-a.51 Levels of
IL-17 are elevated in the sputum and bronchoalveolar lavage
(BAL) of asthmatic human patients.15,51 A Th17-biased immune
response and subsequent neutrophilia is also observed in mice
following allergic sensitization to ovalbumin (OVA).97 Further-
more, both IL-17 secretion and neutrophil influx were necessary
to mediate granulocytic chemotaxis, mucus hypersecretion, and
airway hypersensitivity following allergic sensitization.51,97
These studies indicate that Th17 responses play a critical role
in mediating particular forms of asthma. In addition, levels of
IL-17 are elevated in both humans and mice with severe RSV
infection.52 Neutralization of IL-17 signaling during RSV infec-
tion significantly reduced granulocytic infiltrate, airway resis-
tance, and mucus hypersecretion.52 These data suggest that
elevated Th17 responses following RSV infection may increase
an individual’s susceptibility to developing asthma.
Genetic Predisposition to Asthma and the
Influence of RSV Infection
Two-Hit Hypothesis
It is possible that children who are genetically predisposed to
developing asthma will eventually develop chronic lung
inflammation and are more likely to experience greater mor-
bidity from RSV infection. Children who exhibit bronchiolitis
prior to 1 year of age show signs of reduced lung function at 5
weeks old.100 However, as discussed, a number of studies sug-
gest that severe RSV infection may increase an individual’s
risk of developing asthma later in life. Children younger than
6 months exhibit the greatest risk of severe morbidity from
an RSV infection.21,59 It is unclear how RSV infection would
promote asthma, a chronic lung disease, years after the primary
infection has been resolved.
100
It has been proposed that the development of asthma may
require a ‘‘2-hit’’ scenario as illustrated in Fig. 1.31,42 This
hypothesis suggests that asthma inception depends on the inter-
action of at least 2 genetic, developmental, or environmental fac-
tors. An example may be a polymorphism in a cytokine that
predisposes an individual to develop allergic responses. If an
individual with this polymorphism experiences a severe RSV
infection, he or she is more likely to exhibit either long-term
symptoms or chronic inflammation such as asthma. The 2-hit
hypothesis also predicts that if only one factor is present, then
either disease or allergic responses would be transient. This may
explain why not all children who experience severe RSV-
induced bronchiolitis develop asthma as well as why some chil-
dren with early childhood wheezing exhibit resolution of their
illness by their adolescence.46,65,87,88 A number of gene poly-
morphisms are associated with both asthma and susceptibility
to severe RSV-induced disease, as discussed below.
Cytokines
Cytokines play a significant role in influencing the type of
immune response that develops following infection. Cytokines
such as IL-4 and IL-13 are primarily produced by Th2 CD4 T
cells and play a crucial role in the induction of some allergic
immune responses. Children with gain-of-function polymorph-
isms in both IL4RA and IL13 are almost 5 times as likely to
develop asthma compared to individuals without polymorphisms
in either gene.32 Gain-of-function polymorphisms in IL-4 and
IL-13 cytokine genes have also been reported to be increased
in children hospitalized for RSV infection.30,66 A study by
Ermers et al17 also determined that following a severe RSV
infection, children with the IL13-R130Q polymorphism were
significantly more likely to experience wheezing at age 6 years.
In addition, children with low IFN-g, a type 1 helper CD4 T-cell
(Th1)–associated cytokine, also exhibited an increased risk in
developing recurrent wheezing during infancy.20,89 Taken
together, these studies indicate that an imbalanced immune sys-
tem, Th2 biased over Th1, may contribute to severe RSV infec-
tion and subsequent asthma inception.
Chemokines
Chemokines are critical for the recruitment and adhesion of
leukocytes during infection. Polymorphisms in either chemo-
kines or their receptors may predispose an individual toward
chronic pulmonary inflammation and increase disease severity
following respiratory viral infection. The chemokine CCL5,
also known as RANTES, is an important chemotactic agent for
Th2-associated immune cells, including Th2 cells, eosinophils,
and basophils. Gain-of-function polymorphisms in the promo-
ter region of the CCL5 gene have been associated with asthma
and severe airway dysfunction.40 These promoter region poly-
morphisms have also been correlated with severe cases of
RSV-induced bronchiolitis.3 A study of 320 Chinese children
with RSV-induced bronchiolitis revealed an increased risk of
infants with CCL5 promoter region polymorphisms to exhibit
Veterinary Pathology 52(1)
severe morbidity during RSV infection and an increased likeli-
hood to develop recurrent wheezing.94 Furthermore, children
with elevated CCL5 levels from nasal epithelium at the time
of RSV-induced bronchiolitis exhibit an increased risk of
developing asthma by age 7 years.5
Attachment of the RSV virion to the host epithelial cell is
mediated through the G protein of RSV, which is necessary for
optimal infection.43,92 While the G protein of RSV typically
binds to highly sulfated heparin-like glucosaminoglycans, it
also contains a chemokine motif similar to CX3CL1 or frac-
talkine.19,96 The CX3CL1 mimicry function of RSV likely
allows the virus to alter the host immune response.12,96 A
T280M mutation in CX3CR1, which encodes for the receptor
that binds CX3CL1, has also been associated with increased
morbidity following RSV infection and an increased risk of
developing asthma.4,95 These studies suggest that excessive
CX3CL1-CX3CR1 signaling following RSV infection in chil-
dren with CX3CR1 polymorphisms further predisposes those
infants to asthma inception.
IL-8 is a chemokine secreted by epithelial cells and macro-
phages that recruits primarily neutrophils but also targets
macrophages, mast cells, endothelial cells, and keratinocytes.
Therefore, IL-8 is an important mediator of the innate immune
system to initiate inflammation. Two separate studies by Hull
et al33,34 demonstrate that gain-of-function polymorphisms in
the promoter region of IL8 lead to increased disease severity
in infants following RSV infection. Polymorphisms in IL-8 are
also associated with an increased risk of developing asthma.67
Furthermore, a study of 164 children in the United Kingdom
revealed that children with a IL-8 polymorphism were signifi-
cantly more likely to have episodes of wheezing following
RSV-related bronchiolitis.23 Taken together, these studies sug-
gest that genetic predispositions to allergic illness can alter the
disease severity of RSV infection and the subsequent develop-
ment of asthma.
Immune Tolerance
RSV infection may also increase the susceptibility to develop
allergic immune responses by breaking immune tolerance to
allergens early in life. Regulatory T cells (Tregs) play an essen-
tial role in mediating immune tolerance and prevention of
immune responses to allergens.44 Tregs can regulate the immu-
nogenicity of dendritic cells (DCs) by reducing DC expression
of the costimulatory molecules CD80 and CD86 as well as
expression of major histocompatibility complex (MHC) class
II.44 However, infection of mice with RSV following OVA
sensitization significantly inhibits the suppressive capacity of
Tregs.38 The impaired Treg response correlates with increased
DC expression of the costimulatory molecules CD40 and CD86
as well as MHC class II. This suggests that if immune tolerance
is broken by RSV infection, infants may be more susceptible to
the development of chronic inflammation to allergens and sub-
sequent asthma. Furthermore, RSV infection may differentially
affect the function of various DC subsets. RSV infection of
myeloid DCs, but not plasmacytoid DCs, leads to the
Knudson and Varga 101

Figure 1. Proposed model of severe respiratory syncytial virus (RSV) infection and asthma inception based on the ‘‘2-hit’’ hypothesis. A young
infant must have a combination of 1 or more genetic factor(s) and RSV-related immunological factor(s) to develop asthma as suggested by the
2-hit hypothesis. An infant with a genetic predisposition to allergen sensitization can develop asthma following a severe RSV infection. For exam-
ple, an infant with a gain-of-function gene polymorphism for the cytokine interleukin (IL)–4 may exhibit a Th2-biased immune response following
a severe RSV infection. In the absence of either a genetic factor or a severe RSV infection, thus not fulfilling a 2-hit scenario, the infant will likely
experience either transient pulmonary dysfunction or no disease at all. A child with a gain-of-function CCL5 polymorphism who experiences a
mild RSV infection is an example of this, likely having either short-term pulmonary dysfunction or no long-term disease. Last, an infant who
experiences a mild or asymptomatic RSV infection with no genetic predisposition toward allergic sensitization will exhibit no long-term disease.

upregulation of maturation markers and an increased capacity are important for promoting allergic sensitization, whereas
to induce the proliferation of OVA-specific T cells in vitro.7 plasmacytoid DCs are tolerogenic.57 Together, these studies
Previous work has indicated that immunogenic myeloid DCs suggest that impaired regulation of allergic immune responses
102
Figure 2. Murine models of allergen sensitization and respiratory syn-
cytial virus (RSV) infection. (A) BALB/c mice are sensitized to OVA
following RSV challenge and analyzed on day 21 postinfection (PI).75
(B) BALB/c mice are sensitized to OVA prior to RSV challenge and
assessed on day 15 PI.62 (C) BALB/c mice are infected with RSV prior
to sensitization against cockroach antigen (CRA) and challenged with
methacholine 43 days PI.45 (D) Cotton rats are sensitized to Aspergillus
fumigatus (Af) and infected with RSV 14 days later. Cotton rats are
challenged with Af on day 2 PI and airway hyperreactivity assessed
on day 4 PI.26 i.n., intranasal; i.p., intraperitoneal; i.t., intratracheal.
following RSV infection can contribute to the development of
asthma.
Use of Murine Models to Explore the
Relationship Between RSV and Asthma
While many human studies have indicated a role for RSV-
induced inception of asthma, far less work has been performed
using animal models to explore the underlying immunological
mechanisms that link RSV infection and the induction of
asthma. This is due to the complexity of asthma and the lack
of animal models that reflect the entire disease spectrum
observed in RSV-infected humans.9,16 However, murine mod-
els of allergen sensitization have been used extensively to
investigate the impact of RSV infection in the induction of
Veterinary Pathology 52(1)
asthma.62,75 BALB/c mice can be infected with RSV either
prior to or following allergic sensitization to OVA, as illu-
strated in Fig. 2A and Fig. 2B, respectively. Both models lead
to increased airway resistance in comparison to OVA-
sensitized mice not infected with RSV. Studies using these 2
models have yielded several significant pieces of information.
Using the model of allergic sensitization followed by RSV
infection, Peebles et al62 reported that RSV-infected mice exhi-
bit greater airway resistance for up to 2 weeks following infec-
tion compared with the OVA sensitization alone or acute RSV
infection groups. Interestingly, the elevated airway hyperreac-
tivity did not correlate with an elevated Th2 immune response
since Th2 CD4 T cells and Th2 cytokine protein levels were
similar to the OVA sensitization alone group.61 In contrast, the
Th2-associated cytokines IL-4 and IL-5 play a crucial role in
mediating the elevated airway hyperresponsiveness in the mur-
ine model of RSV infection followed by OVA sensitization.74
Similar results were observed by Lukacs et al45 in BALB/c
mice infected with RSV prior to cockroach antigen (CRA) sen-
sitization, as illustrated in Fig. 2C. Neutralization of the Th2-
associated cytokine IL-13 in BALB/c mice sensitized against
CRA following RSV infection significantly reduced airway
hyperreactivity. Furthermore, mice lacking IL-17A signaling
exhibited significantly greater numbers of eosinophils and lym-
phocytes as well as increased levels of IL-13 protein in the lung
following RSV infection of OVA-sensitized mice.54 In addi-
tion, the IL-17A–deficient mice had significantly elevated air-
way resistance compared with wild-type (WT) mice. These
data suggest that, while Th2-biased immune responses may
be critical to mediate RSV-induced inception of asthma,
Th17 responses limit airway hyperreactivity potentially by
inhibiting a pathogenic Th2 immune response.
The development and use of alternative animal models is a
crucial step to further investigate the relationship between
severe RSV infection and asthma. While mice are an appealing
model due to their availability and relatively low cost, mice are
semi-permissive for RSV replication. In contrast, cotton rats
exhibit approximately 100-fold greater peak viral titers com-
pared with BALB/c mice following RSV infection but do not
show overt clinical signs of illness.64,70 A study by Hassantou-
fighi et al26 has established a cotton rat model to investigate the
relationship between RSV and asthma as outlined in Fig. 2D.
Infection of cotton rats with RSV following sensitization to the
fungus Aspergillus fumigatus (Af) induces upregulation of IL-4,
IL-5, and IL-13 as well as a significant increase in airway
hyperreactivity following methacholine challenge. Further-
more, treatment of the Af-sensitized cotton rats with palivizu-
mab 2 days following RSV infection significantly reduced
airway hyperreactivity. This initial study indicates that RSV
exacerbates allergic immune responses and that prophylactic
treatment to prevent RSV infection may help either prevent
or reduce the severity of asthma.
Nonhuman primates, specifically macaque monkeys, repre-
sent another animal model for RSV infection and show mild signs
of clinical illness.48,83 In addition, rhesus monkeys (Macaca
mulatta) experience elevated airway hyperresponsiveness and
Knudson and Varga
increased plasma IgE following sensitization to house dust mite
antigen and subsequent allergen rechallenge.72,99 However, there
has been no investigation to determine the impact of RSV infec-
tion on allergic immune responses in nonhuman primates. Due to
the high degree of genetic similarity between humans and mon-
keys, establishment of a nonhuman primate model to investigate
the role of RSV infection on the development of asthma would be
of great benefit.
Summary
RSV infection is the leading cause of lower respiratory tract
infections in children worldwide. It is a significant cause of
morbidity and mortality in infants. To date, there are no
licensed vaccines for RSV, and only limited supportive care
is provided for severe cases. A number of studies have
established a strong correlation between severe RSV infec-
tion and the development of asthma during childhood.
While genetic mutations may contribute to susceptibility
toward asthma inception, it is highly likely that other envi-
ronmental factors such as an early RSV infection may act as
an initial trigger event. However, additional studies are
required to elucidate the underlying immunological mechan-
isms of how RSV infection contributes to the subsequent
induction of asthma. These studies must take into consider-
ation the use of large cohorts over several decades with pre-
cise assessment of any genetic predispositions to accurately
determine if early severe RSV infection has a causal rela-
tionship to the development of asthma. Further use of pro-
phylactic treatment with palivizumab may also help
determine if infants with a genetic predisposition to allergic
responses still develop asthma independent of having a
severe RSV infection early in childhood. Overall, these
studies would help ascertain whether RSV prophylaxis is a
viable option to indirectly prevent asthma inception in chil-
dren with family histories of such disease.
Further investigation of these questions needs to be vigor-
ously pursued using animal models. The accessibility, rela-
tively low cost of maintenance, and broad availability of
reagents and genetic mutations in mice will allow for thorough
investigation of all of these questions. While models of allergen
sensitization and RSV infection have been defined, there has
been little investigation of the cellular composition and
changes in pulmonary architecture in these murine models. The
development of new models in other animals such as cotton rats
and nonhuman primates would also be beneficial since RSV
replicates to a greater extent in these animals compared with
mice. Together, nonhuman models will help tease apart the
immunological mechanisms associated with severe RSV infec-
tion that may mediate asthma inception, which cannot be eval-
uated in human studies. Furthermore, not only will this help to
determine if RSV prophylaxis/vaccination is beneficial in the
prevention of asthma, but it will also allow for the development
of novel strategies to limit chronic disease following the devel-
opment of asthma.
103
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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