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Immune Interaction between Respiratory Syncytial Virus Infection and Allergen
Sensitization Critically Depends on Timing of Challenges
R. Stokes Peebles, Jr.,1 Koichi Hashimoto,1
Robert D. Collins,2 Kasia Jarzecka,1 Jamye Furlong,1
Daphne B. Mitchell,1 James R. Sheller,1
and Barney S. Graham3
Departments of 1Medicine and 2Pathology, Vanderbilt University
School of Medicine, Nashville, Tennessee; 3Vaccine Research
Center, National Institutes of Health,
Bethesda, Maryland
In some studies, respiratory syncytial virus (RSV) infection is
highly associated with the development of asthma and allergic
sensitization in children [1, 2]. Severe RSV bronchiolitis during
infancy was found to increase the prevalence of both asthma
and allergic sensitization in children up to age 7.5 years [2].
Other studies show no association between RSV infection and
an increased risk for developing allergic disease [3, 4]. Therefore, it is unclear whether severe RSV infection predisposes to
the development of allergy and airway disease or whether allergic disease predisposes to more severe respiratory symptoms
from RSV infection.
Several recent studies suggest that infection with some pathogens early in life may protect against the subsequent development of allergic symptoms [5–7]. A possible protective effect
of early viral infection may be the strong interferon (IFN)
response induced by most viral pathogens [8]. IFN-g, in particular, may skew the CD4 T lymphocyte profile toward a type 1 profile and inhibit the development of type 2 responses to allergens
[8]. By reducing the capacity to mount a type 2 response, viral
infections may decrease the development of allergic sensitivity
and asthma [8]. Our work and that of others show that primary
Received 27 June 2001; revised 4 September 2001; electronically published
13 November 2001.
Animals in this study were cared for in accordance with the Guide for the Care
and Use of Laboratory Animals (NIH publication 86-23, revised 1985).
Financial support: National Institutes of Health (AI-45512, GM-15431, and
HL-03730); American Lung Association of Tennessee.
Reprints or correspondence: Dr. Barney S. Graham, Vaccine Research
Center, Bldg. 40, Rm. 2502, 40 Covent Dr., MSC 3017, National Institutes of
Health, Bethesda, MD 20892-3017 ([email protected]).
The Journal of Infectious Diseases
2001;184:1374–9
q 2001 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2001/18411-0002$02.00
RSV infection in BALB/c mice induces a dominant type 1
cytokine profile [9– 11]. On the basis of these findings, we
hypothesized that the allergic phenotype in mice with RSV
infection before allergic sensitization with ovalbumin (OVA)
would be reduced in comparison with that of noninfected mice
that had been allergically sensitized. Viral infections are exacerbating factors for preexisting allergic asthma [12]. Therefore, we
also hypothesized that mice with RSV infection after allergen
sensitization would have airway hyperresponsiveness (AHR),
compared with allergically sensitized mock-infected mice.
Both of our hypotheses were tested in a well-characterized murine model of allergic sensitization with OVA by varying the
time course of intranasal (inl) infection with RSV [10, 13, 14].
Methods
Study protocol. Two protocols were used, with 2 groups of mice
in each protocol (figure 1). The pathogen-free 8-week-old female
BALB/c mice were purchased from Charles River Laboratories. In
the RSV before OVA protocol, the RSV-OVA group was infected
inl with 107 plaque-forming units of RSV on day 0, and the mockOVA group was mock infected inl with culture media on the
same day. Lungs from 4 mice in each group were excised to obtain
plaque-forming units on day 4, the day of peak viral replication
[15]. On day 14, both groups were injected intraperitoneally (ip)
with 0.1 mL (10 mg) of chicken OVA, grade V (Sigma Chemical),
complexed with 2 mg of Al(OH)3, as described elsewhere [13]. For
8 days (days 28– 35), the mice were placed in an acrylic box and
were exposed to aerosols of 1% OVA diluted in sterile PBS dispersed by an ultrasonic nebulizer (Ultraneb 99; DeVilbiss) for
40 min each day. On day 37, mice were killed, and specimens were
obtained from mice for histopathology (4 mice), cytokine measure-
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Severe respiratory syncytial virus (RSV) infection has been hypothesized to be a risk factor
for the development of allergy and asthma, but epidemiologic studies in humans have been
inconclusive. By use of a well-characterized murine model of RSV infection and allergic sensitization with ovalbumin, the effect of a preceding severe RSV infection on the development of
the pulmonary allergic inflammatory response and airway hyperresponsiveness (AHR) was
tested. The impact of prior allergic sensitization on RSV-induced illness, as measured by
weight loss, also was evaluated. RSV infection before allergic sensitization decreased allergeninduced AHR, production of interleukin-13 in lung tissue, and lung eosinophilia. In contrast,
allergic sensitization before RSV infection increased AHR and decreased RSV-related weight
loss and lung levels of interferon-g but did not alter viral clearance. These data provide evidence that RSV-associated AHR occurs in hosts with allergic responses and that allergic
inflammation is diminished when preceded by RSV infection.
JID 2001;184 (1 December)
Immune Interaction between RSV and Allergy
1375
lung supernatants, lungs from each group were analyzed for cytokine levels, as described elsewhere [14].
Statistical analysis. Results are expressed as mean ^ SEM.
Results of histopathologic analysis of cellular composition of the
lung, measurements of cytokines, weight loss, and dose-response
curves to methacholine were compared by analysis of variance.
Differences were considered to be significant at P , :05.
Results
ments (4 mice), and methacholine challenge and bronchoalveolar
lavage (BAL) cell counts and differentials (8 mice).
In the OVA before RSV protocol, on day 0, the OVA-RSV and
OVA-mock groups were injected ip with 0.1 mL (10 mg) of chicken
OVA, grade V, complexed with 2 mg of Al(OH)3, as described
above. On days 14– 21, the mice were placed in an acrylic box and
were exposed to aerosols of 1% OVA diluted in sterile PBS dispersed by an ultrasonic nebulizer (Ultraneb 99) for 40 min each
day. The OVA-RSV group was infected inl with 107 pfu of RSV on
day 35; the OVA-mock group was mock infected inl with culture
medium on the same day. Lungs from 4 mice in each group were
excised for plaque-forming units and cytokines on days 39 and 41,
the days of peak viral replication and peak IFN-g response, respectively. On day 49, mice were killed for histopathology (4 mice) and
methacholine challenge and BAL cell counts and differentials (8
mice). In addition, on day 0, another group was infected with
107 pfu of RSV on day 35, to serve as a control for OVA-RSV in
measurement of illness and in lung supernatant IFN-g experiments.
Cells and virus. RSV strain A2 was provided by R. Chanock
(NIH). Master stocks and working stocks of RSV were prepared as
described elsewhere [15].
Mouse infection. On day 0 in the RSV before OVA protocol and
on day 35 in the OVA before RSV protocol, mice were infected with
RSV or were given mock-infected culture medium inl, as described
elsewhere [15].
Methacholine challenge. Mice were anesthetized with ip injections of pentobarbital sodium (85 mg/kg), and a tracheostomy
tube was placed. The internal jugular vein was cannulated, and a
microsyringe was attached to intravenous tubing for methacholine
administration. The mice then were placed in a whole body plethysmography chamber and were mechanically ventilated. Changes in
lung resistance and compliance were measured as described elsewhere [13].
Protocol for examining lung sections. The lung sections were
prepared and examined by one observer in a blinded fashion, as
described elsewhere [14].
Quantitation of interleukin (IL)– 5, IL-13, and IFN-g in lung tissues. Levels of IL-5, IL-13, and IFN-g in lung tissues of the 4
groups of mice were measured by commercial ELISA kits (R&D
Systems), according to the manufacturer’s protocols. Using ground
Figure 2. Results of methacholine challenge, done as outlined in
Methods. Shown is protocol for respiratory syncytial virus infection
(RSV) before ovalbumin (OVA) on day 36. Data are representative
of 3 separate experiments (n ¼ 8 for each group). Data points are
mean ^ SEM, measuring lung resistance. *P , :05 vs. RSV-OVA
group.
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Figure 1. Time line of experimental protocol. Histopath, Histopathologic analysis; Mock, mock infection; OVA ip, intraperitoneal
injection of ovalbumin formulated with Al(OH)3; pfu, viral replication
in plaque-forming units; RSV, respiratory syncytial virus infection.
Prior RSV infection decreases allergen-induced AHR. To
determine the effect of prior RSV infection on the development
of allergen-induced AHR, methacholine challenges were performed on the RSV-OVA and mock-OVA groups on day 36, as
outlined in the RSV before OVA protocol (figure 1). At the final
dose of methacholine, 3700 mg/kg, the mock-OVA group had
significantly greater lung resistance than the RSV-OVA group
(16:2 ^ 2:3 vs. 5:7 ^ 0:9 cm of H2O/mL/s, respectively;
P , :05; figure 2). Thus, RSV infection before allergen sensitization inhibited the development of allergen-induced AHR.
Allergen sensitization before RSV infection increases RSVinduced AHR. To determine the effect of RSV infection on
AHR after allergen sensitization, methacholine challenges were
performed on the OVA-RSV and OVA-mock groups on day 49
in the OVA before RSV protocol (figure 1). The OVA-RSV
group had significantly greater AHR than the OVA-mock
group (5:3 ^ 1:8 vs. 2:8 ^ 0:5 cm of H2O/mL/s, respectively;
P , :05; figure 3). Therefore, RSV infection after allergic sensitization increases AHR.
Allergen sensitization before RSV infection reduces RSVinduced weight loss. In addition to AHR, weight loss is another
measure of RSV-induced pathophysiology. Therefore, we
weighed mice in the OVA-RSV and RSV groups daily after
RSV infection (figure 4). The OVA-RSV group had significantly
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Peebles et al.
less weight loss than the RSV group (P , :05), in contrast to the
greater AHR in the OVA-RSV group. In addition, the peak
weight loss was shifted from day 9 after infection (day 44 of the
OVA before RSV protocol) in the RSV group to day 7 after
infection (day 42 of the OVA before RSV protocol). Thus, allergic sensitization before RSV infection protects against RSVinduced weight loss.
RSV replication in the lung. RSV titers were measured in
the lung on days 39 and 41 (4 and 6 days after RSV infection,
respectively), to assess the impact of allergic sensitization on
viral clearance. The day 39 (4 days after RSV infection) geometric mean RSV titers in lungs of mice in the OVA-RSV and
RSV groups were 4:8 ^ 0:1 log10 and 4:6 ^ 0:1 log10 pfu/g,
respectively [15]. On day 41 (6 days after RSV infection), the
levels of viral replication in both the OVA-RSV and RSV groups
were 1:9 ^ 0:6 log10 and 1:7 ^ 0:6 log10 pfu/g, respectively.
Therefore, there was no effect of prior allergic sensitization on
peak virus titer or on viral clearance.
Prior RSV infection decreases allergen-induced lung eosinophilia. Histology was done on day 36 in the RSV before OVA
protocol, to examine the effect of RSV infection on the development of allergen-induced inflammation in the lung after
subsequent allergic sensitization (figure 5A). The mock-OVA
group had marked lung eosinophilia (3+) in both the bronchovascular and perivenous compartments, whereas there was
minimal lung eosinophilia in these lung compartments in the
RSV-OVA group. There was no difference in lung lymphocyte
cell count in either the bronchovascular or perivenous compartment between the mock-OVA and RSV-OVA groups. These
results indicate that RSV infection before allergic sensitization
decreases eosinophilic inflammation in response to an aerosolized allergen.
RSV infection after allergen sensitization results in increased
numbers of lung lymphocytes. Histologic analysis was done
on day 49 in the OVA before RSV protocol, to examine the
composition of lung inflammation as a result of RSV infection
after allergen sensitization (figure 5B). The OVA-mock and
OVA-RSV groups had lung lymphocytosis (2+) in the bronchovascular compartments; only the OVA-RSV group had lung
lymphocytosis (2+) in the perivenous compartment. No eosinophils were seen in either group at this time point.
Prior RSV infection decreases allergen-induced lung IL-13
production. To determine how RSV diminishes allergeninduced AHR [16], we measured the concentration of IL-13 in
lung supernatants in the RSV before OVA protocol on day 36.
We chose to measure IL-13 because it is considered to be a central mediator of allergic asthma [16]. We found that the amount
of IL-13 in the lung supernatants of the mock-OVA group was
133:8 ^ 32:0 pg/mL, compared with ,62.5 pg/mL (the limit of
detection in this assay) in all samples from the RSV-OVA
group. This difference in amounts of IL-13 in the lung supernatants between the 2 groups was statistically significant
(P , :05). Therefore, RSV infection before allergen sensitization decreases a type 2 cytokine that affects the physiologic
response to allergic inflammation in the lung. IL-5 levels were
measured in lung supernatants of both groups but were
undetectable.
Allergen sensitization before RSV infection decreases level of
RSV-induced IFN-g. We next measured the concentration of
IFN-g in lung supernatants in the OVA before RSV protocol on
days 39 and 41. We found a significant increase in IFN-g
levels in the RSV group, compared with the OVA-RSV
group (2178:3 ^ 22:7 vs. 278:5 ^ 142:6 pg/mL, respectively;
P ¼ :0004). Allergen sensitization before RSV infection
Figure 4. Weights of mice challenged with either respiratory syncytial virus (RSV; ovalbumin [OVA]–RSV and RSV groups) or medium
(mock group) on day 35 of protocol “OVA before RSV,” measured
daily after challenge for 12 days. Data are representative of 3 separate
experiments (n ¼ 9 for each group). Data points are mean ^ SEM.
*P , :05 vs. RSV group.
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Figure 3. Results of methacholine challenge, done as outlined in
protocol for respiratory syncytial virus infection (RSV) before
ovalbumin (OVA) on day 49. Data are representative of 3 separate
experiments (n ¼ 5 for each group). Data points are mean ^ SEM,
measuring lung resistance. *P , :05 vs. OVA-mock group.
JID 2001;184 (1 December)
JID 2001;184 (1 December)
Immune Interaction between RSV and Allergy
profoundly reduced the ability of the RSV-infected mice to
mount a type 1 immune response.
Discussion
Epidemiologic studies investigating the effect of RSV infection on the development of allergic inflammation and asthma
have produced conflicting results [1–4]. RSV infection in
young children that is so severe as to require hospitalization
for respiratory failure has been cited as a predisposing factor
for the development of allergic disease [2]. An alternative
possibility is that RSV bronchiolitis is more severe in children
with the allergic phenotype. We used a well-characterized
murine model [10, 13, 14] to determine the effect of RSV on
the development of the allergic phenotype and to examine the
effect of prior allergic sensitization on subsequent RSV infection. We found that RSV infection 2 weeks before allergic
sensitization significantly decreased allergen-induced AHR,
IL-13 production, and eosinophilic inflammation in the lung,
when compared with mock-infected, allergically sensitized mice.
In contrast, RSV infection after allergic sensitization led to significantly increased AHR. This is of particular interest, since we
showed earlier that RSV infection alone has no effect on AHR [13].
The interaction between viral infections and allergic disease is
currently an area of intense investigation and controversy. The
“hygiene hypothesis,” an explanation for the increase in allergic
disease over the past 30 years, postulates that infections in very
early life that result in an intense type 1 immune response are
protective against the subsequent development of atopy
[17–19]. Japanese schoolchildren with a positive tuberculin
response had a lower rate of asthma development and lower
serum IgE levels and blood cytokine levels biased toward a
type 1 profile than children who had a diminished delayed hypersensitivity response to Mycobacterium tuberculosis [5]. Infection with measles virus [20] and hepatitis A virus [21] seem to
be protective against the development of allergic disease in
epidemiologic studies. Viral and bacterial infections during
infancy also may prevent the development of allergic disease.
For instance, children at increased risk of infection, specifically,
young children with >1 older sibling and children who attend
day care within the first 6 months of life, are protected against
the development of asthma [6].
To our knowledge, our results are the first to show in a murine model that RSV infection before allergic sensitization with
OVA protects against the development of the allergic phenotype. Other animal studies also conclusively show that viral
infections protect against the development of type 2 inflammation characteristic of allergic disease. Specifically, prior
influenza virus lung infection protects against the eosinophilic
lung inflammation and type 2 cytokine secretion that occurs
when RSV attachment protein immunization is followed by
RSV infection [22]. This protective effect was long lived when
spleen cells from influenza-infected mice were transferred to
influenza-naive mice [22]. Of particular relevance to our studies,
prior RSV infection prevented the enhanced pulmonary inflammatory response seen after RSV challenge in BALB/c mice
immunized with formalin-inactivated RSV [23]. Both the RSV
attachment protein and formalin-inactivated RSV vaccine models, similar to allergic disease, are dependent on production of
type 2 cytokines.
Our results are inconsistent with those of Schwarze et al. [24],
who reported that RSV infection in BALB/c mice before allergic
sensitization causes increased allergic inflammation. This group
reported that primary RSV infection in BALB/c mice, independent of allergen sensitization, causes AHR and induces the production of IL-5 and eosinophilia [24]. However, we and others
have found that BALB/c mice do not produce significant eosinophilia and instead have an IFN-g response after primary RSV
infection [10, 25–29]. The methodologic differences between
our findings and those of Schwarze et al. are that we used a
virus inoculum of 107 pfu and documented RSV replication in
the lung; Schwarze et al. used a 105 pfu inoculum and did not
document replication of RSV in lung tissue [24].
Although we determined that RSV infection before allergic
sensitization decreased AHR, we found increased AHR when
RSV infection occurred after allergic sensitization. We reported
earlier that RSV infection alone does not cause AHR in noninfected BALB/c mice [10]. Thus, prior allergen sensitization
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Figure 5. A, Tabulation of histologic analysis showing numbers of
eosinophils (eos) and lymphocytes (lymphs) and their distributions in
bronchovascular (BV) and perivenous (PV) locations. A, respiratory
syncytial virus (RSV)–ovalbumin (OVA) and mock-OVA groups on
day 36 of protocol ‘‘RSV before OVA.’’ *P , :05 vs. RSV-OVA
group. B, OVA-RSV and OVA-mock groups on day 49 of protocol.
*P , :05 vs. OVA-mock group.
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changes the AHR response to RSV infection. In this model, we
infected mice 14 days after the last exposure of the mice to aerosolized OVA. From our previous work, we found that levels of
type 2 cytokines in the lung supernatants are not detectable by
ELISA 5 days after the last exposure to OVA aerosol [10]. Possible explanations for the effect that prior OVA sensitization has
on RSV-induced AHR may include alteration in the distribution
of lung dendritic cell populations, leading to altered antigen
presentation and abnormal induction of T cell subsets; altered
composition of memory CD4 T cells; or persistent, low-level
production of type 2 cytokines in the lung.
Contrary to current dogma, in our studies, the increased AHR
seen with RSV infection after allergen sensitization occurred in
the setting of increased lung lymphocytes rather than eosinophilia. Thus, AHR associated with RSV infection and perhaps other
viral infections is not strictly correlated with lung eosinophilia. It
seems unlikely that eosinophil degranulation products were present at the time we measured the RSV-induced AHR, since the
methacholine challenge measurements were made 2 weeks
after RSV infection and 4 weeks after the last exposure to AHR,
at times >1 week after lung eosinophils are undetectable by histopathologic analysis [13].
In this model, allergic sensitization before RSV protected
against RSV-induced weight loss. This was a surprising finding,
because these mice had increased RSV-induced AHR. The
diminished weight loss seen in the OVA-RSV group was associated with decreased lung IFN-g levels but with no change in viral
replication or delay in viral clearance. We do not believe that the
difference in IFN-g levels explains the weight loss difference,
because our group showed earlier that RSV infection caused
weight loss both in mice lacking IFN-g and in mice treated with
anti–IFN-g antibodies (authors’ unpublished data). Therefore,
decreased lung IFN-g levels may cause the increase in AHR
seen with RSV infection after allergen sensitization but is not
sufficient to explain the reduced weight loss.
In summary, we show in this model that RSV infection
before allergic sensitization protects against the development
of allergen-induced AHR and allergic airway inflammation,
whereas RSV infection after allergic sensitization increases
RSV-induced AHR. The AHR does not correlate with weight
loss, lung eosinophilia, or changes in virus titer but correlates
with a decrease in lung IFN-g levels. Thus, the timing of
RSV infection in relationship to allergic sensitization is critical
in many clinically important features of RSV-induced disease,
particularly AHR. Our data support the concepts that severe
RSV-associated airway dysfunction occurs in a host with
underlying allergic disease and that RSV does not directly
induce the allergic phenotype.
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Immune Interaction between RSV and Allergy
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