Antiviral Research xxx (2005) xxx–xxx
Ribavirin and cysteinyl leukotriene-1 receptor blockade as
treatment for severe bronchiolitis
Cynthia A. Bonvillea, Helene F. Rosenbergb, Joseph B. Domachowskea,∗
aDepartment of Pediatrics, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA
bLaboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Received 13 July 2005; accepted 19 October 2005
the CysLT1 cysteinyl leukotriene receptor antagonist, montelukast. We observed substantial virus replication in our mouse model of pneumovirus
infection and significant accumulation of cysteinyl leukotrienes in lung tissue, the latter detected at levels that correlate directly with granulocyte
recruitment to the airways. While administration of the nucleoside analog, ribavirin, reduced virus replication ∼2000-fold, the clinical outcomes
as measured by morbidity and mortality, in response to ribavirin monotherapy were indistinguishable from those of the no-treatment controls.
Similarly, montelukast therapy alone did not reduce granulocyte recruitment nor did it improve the clinical outcome. However, combined therapy
with ribavirin and montelukast resulted in a significant reduction in morbidity and a substantial reduction in mortality (50% survival at t=14
days and onward, compared to 10–20% survival in response to montelukast alone or to ribavirin alone, respectively, p<0.01). These findings
define further the independent contributions made by virus replication and by the ensuing inflammatory response to the detrimental sequelae of
pneumovirus infection in vivo.
© 2005 Elsevier B.V. All rights reserved.
Keywords: Pneumovirus; Chemokine; Montelukast; Ribavirin; Mice
Cysteinyl-leukotrienes (leukotrienes C4, D4 and E4) are
leukocyte-derived lipid proinflammatory mediators that make
prominent contributions to the pathophysiology of bronchial
asthma (Bigby, 2000; McMillan, 2001). Among these contribu-
tions, cysteinyl leukotrienes promote bronchospasm, wheezing
and enhanced eosinophil recruitment in response to allergen
provocation. Leukotriene antagonists, which function as selec-
tive, competitive inhibitors of these leukotrienes at serpentine
G protein coupled CysLT1 receptors found in bronchial smooth
muscle, lung macrophages, and peripheral blood cells, provide
significant clinical benefit (James and Sampson, 2001) and are
already approved for clinical use in the management of this dis-
The clinical similarities between acute episodes of bronchial
asthma and symptoms associated with primary respiratory syn-
∗Corresponding author. Tel.: +1 315 464 7505; fax: +1 315 464 7564.
E-mail address: firstname.lastname@example.org (J.B. Domachowske).
cytial virus infection (RSV; family Paramyxoviridae, subfam-
ily pneumovirus) suggested the possibility of pathophysiologic
and biochemical similarities. Several groups have reported on
cysteinyl-leukotriene synthesis and release and its association
with RSV infection and its related symptomatology (Volovitz
et al., 1988; VanSchaik et al., 1999; Behera et al., 1998), and
a recent randomized clinical trial suggested that leukotriene
antagonist therapy provided after emergence of primary RSV
symptoms could result in significant reduction in reactive air-
As part of an overall study of the pathogenesis of pneu-
movirus infection in vivo, we have developed a model of respi-
(Domachowske et al., 2000a, 2000b; Bonville et al., 2003). The
natural rodent pathogen, pneumonia virus of mice (PVM; also
family Paramyxoviridae, subfamily pneumovirus) is among the
closest known phylogenetic relatives of RSV, but, unlike RSV
when utilized in mouse models, PVM can replicate effectively
in mouse lung tissue and infection results in significant morbid-
0166-3542/$ – see front matter © 2005 Elsevier B.V. All rights reserved.
AVR-2034; No. of Pages 7
C.A. Bonville et al. / Antiviral Research xxx (2005) xxx–xxx
ity and mortality. Similar to severe RSV infection in humans,
PVM infection in mice is accompanied by a profound, acute
inflammatory response, which includes a prominent pulmonary
eosinophilia. We have identified the CC-chemokine MIP-1?
(CCL3) as the crucial mediator of the antiviral inflammatory
response to PVM (Domachowske et al., 2000b), analogous to
what has been inferred for RSV infection in human infants
(Harrison et al., 1999; Garofalo et al., 2001).
Using the PVM-infection model, we have recently reported
on the clinical utility of combined antiviral and specific anti-
MIP-1? immunomodulatory therapy, findings that underscore
the independent contributions of both virus replication and the
inflammatory response to the pathogenesis of this respiratory
virus infection in vivo (Bonville et al., 2003, 2004). Here we
present our findings on the responses of PVM-infected mice to
antiviral therapy when it is administered in conjunction with
cysteinyl-leukotriene receptor blockade. Our results suggest a
role for cysteinyl-leukotrienes in promoting the detrimental
sequelae of this infection, and as a target for development of
novel rational therapies.
2. Materials and methods
2.1. Mouse and virus stocks
C57Black/6 mice were obtained from Taconic Laborato-
ries, Germantown, NY. Mouse-passaged stocks of PVM (strain
J3666, ∼106pfu/ml, original stock virus obtained from Dr. A.J.
Easton, University of Warwick, Coventry, U.K.) were obtained
from clarified mouse lung homogenates as described previ-
ously (Domachowske et al., 2000a, 2000b) and stored in liquid
nitrogen. Virus stocks were defrosted and diluted in phosphate
buffered saline (PBS) immediately prior to intranasal inocula-
2.2. Establishing PVM infections in mice and treatment
Six- to 8-week-old mice were used in all experiments.
Mice subjected to brief isoflurane anesthesia were inoculated
intranasally with 60 plaque-forming units (pfu) of mouse-
passaged PVM strain J3666 in a 50ul volume of PBS at day
0. This viral inoculum was chosen because it produces moder-
ate to severe clinically symptoms in 100% of infected mice,
and at least 80% mortality if therapeutic intervention is not
initiated. Animals were weighed and observed daily. Clinical
scoring of infected mice was as initially devised by Cook et al.
(1998) with modifications as previously described (Bonville et
al., 2003). This clinical scoring system is based on observed
symptoms using a scale from 1 to 6: 1, healthy; 2, ruffled fur at
gic with labored breathing; 5, pre-morbid, with emaciation and
cyanosis; 6, death. Mice were sacrificed on days 0 through 7
post-inoculation for bronchoalveolar lavage fluid analysis and
total lung chemokine and cysteinyl leukotriene concentrations.
Lung PVM titers were determined from total lung homogenates
ical scores and mortality included four groups of 10 mice each.
To collect virologic, biochemical and histologic data, identi-
cal experiments were performed using 60 additional mice. Six
mice were sacrificed on day 0, then six mice in each treatment
arm were sacrificed on days 3, 5 and 7 for viral lung titers,
chemokine (MIP-1? and MCP-1) concentrations, and cysteinyl
leukotriene concentrations. Using appropriate diluent controls,
Group 1 received daily intraperitoneal montelukast (10mg/kg;
of intraperitoneal ribavirin (37.5mg/kg/dose; ICN Pharmaceu-
ticals), group 2 received montelukast, group 3 received twice
daily ribavirin and group 4 received diluent injections only. For
and continued until day 14. All procedures were reviewed and
approved by the Committee on the Humane Use of Animals,
SUNY Upstate Medical University.
2.3. Bronchoalveolar lavage, differential cell counts and
was harvested from six mice by trans-tracheal instillation and
removal of pre-chilled phosphate-buffered saline with 0.25%
ery of 1.2–1.5ml per mouse). Total and differential leukocyte
counts were obtained by light microscopic quantitative analy-
sis of methanol-fixed cytospin preparations stained with Diff
Quik (Fisher Scientific, Pittsburgh, PA). For histologic evalua-
tion, lungs were inflated with 10% formalin, dissected en bloc,
set in paraffin, and sectioned onto glass slides.
2.4. Lung homogenates, chemokine, cysteinyl leukotriene
and plaque assays
Mice were sacrificed as described above (six mice per condi-
tion per time point) and lungs were removed and transferred
into 1ml pre-chilled Iscove’s Modified Dulbecco’s Medium.
Lung tissue suspensions were subjected to blade homogeniza-
tion (Tissumizer, Tekmar, Cincinnati OH) and cellular debris
and stored at −80◦C or liquid nitrogen prior to analysis. Assays
for mouse MIP-1?, mouse MCP-1, and cysteinyl leukotrienes
were performed as per the manufacturer’s instructions (R&D
Systems) and results were corrected for total protein as deter-
mined by the Bradford colorimetric assay using bovine serum
albumin standards. Viral recovery was determined by standard
plaque assay on the BS-C-1 epithelial cell line (American Type
Culture Collection, Manassas VA).
2.5. Statistical analysis
Data points represent the average±S.E.M. of samples from
six mice in two or more separate trials. Fisher’s exact test was
employed for categorical (clinical) data. Pearson’s correlations
were performed for paired sets of continuous data. One-tailed
t-tests were used to compare continuous data. Kaplan Meier
C.A. Bonville et al. / Antiviral Research xxx (2005) xxx–xxx
analyses were performed using Statistica Software (StatSoft,
Tulsa, OK), all other statistics were per the algorithms of the
Microsoft Excel data analysis program.
3.1. PVM induced cellular, chemokine and leukotriene
Table 1 documents the cellular inflammatory responses seen
tory response to acute infection with PVM is virtually 100%
granulocytic, with eosinophils representing 10–15% of the total
leukocyte count at the earliest time points. No differences were
tion of cellular influx, or in the patterns of increased leukotriene
centration (pg/ml) and total granulocyte count (cells/ml) was
observed (r2=0.70; Fig. 1A) together with a similar corre-
lation between cysteinyl leukotriene concentration and BAL
eosinophils (r2=0.74; Fig. 1B).
3.2. Ribavirin treatment inhibits PVM replication in mouse
Table 2 documents virus titers on days 0–7 determined from
total lung homogenates obtained from mice inoculated on day 0
with 60pfu PVM. In the absence of ribavirin, pulmonary virus
titers increased to 1.3±0.7×108pfu/g lung tissue by day 7.
Twice daily ribavirin administration decreased lung virus titers
alone (*p<0.01 compared to PBS or montelukast only con-
Total and differential leukocyte counts determined in bronchoalveolar lavage fluid, and leukotriene concentrations in lung homogenates from mice inoculated with
60pfu of PVM on day 0
Day Total cells (×103/ml) Neutrophils (×103/ml) Eosinophils (×103/ml) Lymphocytes (×103/ml) Leukotriene (pg/ml)
94 ± 4
90 ± 6
117 ± 6a
200 ± 19a
243 ± 18a
218 ± 21a
186 ± 9a,b
173 ± 17a,b
65 ± 29
82 ± 14
98 ± 12
242 ± 36a
245 ± 27a
184 ± 30a
207 ± 18a
211 ± 36a,b
88 ± 9
93 ± 7
124 ± 14
188 ± 16a
200 ± 41a
238 ± 33a
172 ± 35a
189 ± 48a,b
Ribavirin and montelukast
90 ± 8
92 ± 4
111 ± 12
208 ± 14a
252 ± 40a
230 ± 22a
179 ± 16a
185 ± 9a
Data are expressed as the mean±S.E. from n=6 mice.
ap<0.01 compared to day 0.
bConcentrations from n=2 mice only.
C.A. Bonville et al. / Antiviral Research xxx (2005) xxx–xxx
Fig. 1. Bivariate scattergram of cysteinyl leukotriene concentrations (pg/ml) vs.
bronchoalveolar lavage (BAL) fluid (A) granulocyte counts (cells/ml) and (B)
eosinophil counts. Regression lines with Pearson coefficients are indicated.
trols) and to 8.2±2.4×104(*p<0.01 compared to PBS or
telukast. We conclude that montelukast alone has no effect on
3.3. Ribavirin treatment reduces virus-induced pulmonary
Concentrations of the proinflammatory chemokines MIP-1?
documented in Table 3. When compared to PBS-treated mice,
mice treated with ribavirin had lower mean pulmonary MIP-
1? and MCP-1 concentrations on day 7 post-inoculation (both
two-fold reductions,*p<0.01). This is also consistent with pre-
Fig. 2. Mean clinical scores of mice (n=6 per point) infected with pneumo-
nia virus of mice (PVM, strain J3666) on day 0 and treated with twice-daily
intraperitoneal ribavirin (37.5mg/kg/dose×2 doses/day, filled circles), once
daily montelukast (10mg/kg, open squares), both ribavirin and montelukast
(filled squares) or diluent control (PBS, open circles) beginning on day 3. Error
bars indicate±standard error of the mean (S.E.). Clinical scores in the ribavirin
plus montelukast treatment arm were lower compared to each of the other three
treatment arms on day 8 and thereafter (p<0.05), except for the PBS arm on
day 12 (p=0.13 compared to montelukast plus ribavirin).
vious findings (Bonville et al., 2003), and can be contrasted
to the ∼2000-fold drop in lung virus titer. Mice that received
both ribavirin and montelukast had the lowest overall mean pul-
monary MIP-1? and MCP-1 concentrations (24±4.5pg/mlmg
and 160±70pg/mlmg lung protein on day 7 post-infection,
of the intervention combinations tested had a measurable effect
on total lung cysteinyl leukotriene concentrations at the time
points tested (Table 1).
3.4. Co-administration of montelukast and ribavirin results
in reduced severity of clinical symptoms and improved long
Shown in Fig. 2 are the mean clinical scores from two sep-
arate experiments that included 10 mice in each treatment arm
(drugs and doses as per Table 3). While clinical scores were
similar in mice receiving no therapy, montelukast alone, or rib-
avirin alone, mice treated with both ribavirin and montelukast
had overall a much less severe clinical course, statistically sig-
nificant by day 8 and thereafter (*p<0.05 as shown). Percent
Virus titers (pfu/g lung tissue) from mice (n=6 per point) inoculated on day 0 with 60pfu of PVM strain J3666
DayPBS Montelukast onlyRibavirin onlyFold reduction Montelukast and ribavirinFold reduction
Virus titer (×104pfu/g lung tissue)
Montelukast (10mg/kg) was administered once daily; ribavirin (37.5mg/kg/dose), twice daily. All treatments were initiated on day 3 post-inoculation. Data are
expressed as the mean±S.E.
ap<0.01 compared to PBS-treated control, fold reduction calculated vs. PBS-treated control. ND is not detected.
C.A. Bonville et al. / Antiviral Research xxx (2005) xxx–xxx
Detection of proinflammatory chemokines MIP-1? and MCP-1 in lung tissue homogenates from mice (n=6 per point) inoculated on day 0 with 60pfu of PVM
DayPBS Montelukast onlyRibavirin only Fold reduction Montelukast and ribavirinFold reduction
MIP-1? (pg/mlmg lung protein)
MCP-1 (pg/mlmg lung protein)
Montelukast (10mg/kg) was administered once daily; ribavirin (37.5mg/kg/dose), twice daily. All treatments were initiated on day 3, and continued until day 14
post-inoculation. NA, is not assayed. Data expressed±S.E.M. from six mice at each time point from two separate experiments.
ap<0.01 compared to PBS-treated controls.
bp<0.01 compared to the ribavirin only group.
47±9 54 ±6
mean weight loss in the control arm was 11±3% original body
telukast alone group, while only 2±1% in the ribavirin plus
montelukast group (*p<0.01). Results from a separate survival
study (n=10 per treatment arm) shown in Fig. 3 demonstrated
control and ribavirin only groups, with 50% long-term survival
*p<0.01 when compared to each of the other groups. Observed
pulmonary histology on day 5 is shown in Fig. 4. Compared
to uninfected lungs (Fig. 4A), untreated, PVM-infected lungs
(Fig. 4B) show intense granulocytic inflammation. The granu-
observed when both ribavirin and montelukast are administered
as therapeutics (Fig. 4C).
We have shown that during acute, severe PVM infection,
pulmonary cysteinyl leukotriene concentrations increased two-
fold in direct correlation with absolute bronchoalveolar lavage
fluid granulocyte counts. These results are analogous to those
obtained by VanSchaik et al. (1999), who reported a substan-
tial increase in cysteinyl leukotriene concentrations in respi-
ratory secretions of infants and children infected with RSV.
As cysteinyl-leukotrienes are potent pro-inflammatory medi-
Fig. 3. Survival analysis of mice inoculated with 60pfu PVM on day 0, and treated with ribavirin (37.5mg/kg/dose×2 doses/day, filled circles), montelukast
(10mg/kg, open squares), both ribavirin and montelukast (filled squares) or diluent control alone (same volumes, open circles) beginning on day 3; n=10 mice per
group. Significantly improved survival of combined ribavirin and montelukast-treated mice (*p<0.01) was observed when compared independently to each of the
other three groups.
C.A. Bonville et al. / Antiviral Research xxx (2005) xxx–xxx
Fig. 4. Microscopic pulmonary anatomy in (A) uninfected lung, (B) PVM-infected lung (untreated), and (C) PVM-infected lung (treated with both montelukast and
ribavirin). Original magnification ×400, stained with hematoxalin and eosin.
ators known to cause bronchial obstruction, mucosal edema,
eosinophil recruitment, and increased bronchial hyperrespon-
siveness, they represent a rational target for the treatment of
acute viral bronchiolitis.
While administration of montelukast or ribavirin alone
viral bronchiolitis, the co-administration of ribavirin and mon-
telukast resulted in an overall decrease in symptom severity and
a reduction in mortality. These results are consistent with our
earlier studies (Bonville et al., 2003; Bonville et al., 2004) in
which we documented the reduction in morbidity and mortality
in response to co-administration of ribavirin and MIP-1? sig-
naling blockade with one major difference. MIP-1? blockade
consistently and reliably blocks the cellular inflammation seen
during the acute phase of PVM infection, while administration
of montelukast (with or without ribavirin) does not have any
measurable effect on granulocyte recruitment to the infected
lung. In contrast, when MIP-1? gene-deleted mice are chal-
lenged with PVM, they do not develop a granulocytic response
(Domachowske et al., 2000). Similarly, we demonstrated that
granulocytic influx is blocked when pharmacologic (Bonville et
al., 2003) or immunologic (Bonville et al., 2004) blockade of
MIP-1? is utilized during PVM infection. Despite the lack of
granulocytic inflammation in these contexts, the PVM-infected
mice develop the same degree of morbidity and mortality as
the untreated controls unless ribavirin is co-administered. In
our current study, we showed that combination therapy with
montelukast and ribavirin affords similar benefits in terms of
does not interfere with PVM-associated recruitment of granulo-
we did not observe any improvement in clinical outcome mea-
of only ribavirin to MIP-1? deficient mice (Domachowske et
al., unpublished data). Since MIP-1? deficient mice lack a cel-
lular inflammatory response to PVM, eosinophils, the major
telukast treatment becomes unnecessary. These results define
the independent contributions of virus replication and the ensu-
ing inflammatory response to the pathogenesis of respiratory
virus infection in vivo, and similarly, they explain why ribavirin
therapy alone, although clearly effective at reducing virus repli-
cation, is of limited clinical benefit overall in the pathogenesis
of RSV infection in infants.
The hypothesis that pneumovirus pathogenesis requires both
active replication of virus, and virus-induced inflammatory
responses, follows from the results presented. Effective ther-
apeutics for severe forms of infection will logically require
blocking virus replication and interfering with virus-induced
inflammatory responses. Combination therapy with ribavirin
and monoclonal anti-RSV F antibody in the cotton rat model
of human RSV infection resulted in clearance of virus within
inflammation, but delayed virus clearance. When the two inter-
ventions were combined, an antiviral and anti-inflammatory
effect was appreciated (Prince et al., 2002).
When we tested the potential anti-inflammatory proper-
ties of glucocorticoids in the PVM model, we noted that the
hydrocortisone-treated group exhibited elevated rates of viral
replication in the lung tissue and accelerated mortality, suggest-
ing that hydrocortisone suppresses elements crucial to the host
defense against the viral infection (Domachowske et al., 2001).
Patients that develop moderate to severe RSV bronchiolitis in
infancy are prone to the development of recurrent wheezing
and asthma in childhood (Pullan and Hey, 1982; Carlsen et
al., 1987; Long et al., 1995; Folkerts et al., 1998). The mech-
anism(s) responsible for this phenomenon are unknown, and
many have speculated as to whether RSV bronchiolitis actually
induces reactive airways disease or whether underlying and as-
yet-undefined host factors predispose some infants to the devel-
responses to respiratory virus replication in lung tissue. What-
ever causes this dysregulation to be established—whether it is
infection with a specific respiratory virus at a specific develop-
susceptible individual or all or none of the above—it is intrigu-
ing to consider the possibility that the inflammatory responses
characteristic of the asthmatic state represent the dysregula-
tion of the responses designed to promote innate antiviral host
In addition, we note that the levels of pro-inflammatory
chemokine concentrations (MIP-1? and MCP-1) present
in PVM-infected mice were reduced substantially by co-
C.A. Bonville et al. / Antiviral Research xxx (2005) xxx–xxx Download full-text
administration of montelukast and ribavirin. Although there is
no immediate explanation for this observation, we suggest that
immunomodulatory properties of ribavirin.
As alluded to earlier, results from the first published ran-
domized trial of montelukast treatment in the setting of post
tor modifiers during the subacute and convalescent phases of
RSV disease (Bisgaard, 2003). The infants that received mon-
telukast were free of any respiratory symptoms 22% of the days
and nights during the follow-up period, while the infants that
received placebo were symptom free only 4% of the time. The
study design aimed to evaluate the potential benefit of mon-
telukast following RSV bronchiolitis rather than on the acute
infection itself. Treatment was delayed by a median of 3 days
from hospitalization and up to 7 days from the onset of symp-
toms, but it is important to note that all of the patients continued
to have acute symptoms until day 13. The authors suggest that
montelukast treatment may have offered additional benefit if
started earlier in the course of inflammation. While this study
in infants supports a role for montelukast therapy following
RSV bronchiolitis, the present results from our mouse model
of severe bronchiolitis support a dual role for montelukast and
ribavirin during the acute phase of severe infection. Our current
PVM model does not allow study of the effects of montelukast
during convalescence because without dual therapy with mon-
telukast and ribavirin, the infection is nearly always fatal. Our
recent efforts to develop a non-lethal PVM challenge model,
and to incorporate whole body plethysmography into outcome
measures appear promising (Bonville et al., 2005, unpublished
This work was funded by a Merck Medical School Grant to
JBD and by NIAID intramural funding to HFR.
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