*c Cambridge University Press 2008 Animal Health Research Reviews 8(2); 207–213

ISSN 1466-2523 DOI: 10.1017/S1466252307001405

Bovine respiratory syncytial virus infection:

immunopathogenic mechanisms
Laurel J. Gershwin*
Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine,
University of California, Davis, Davis, CA 95616, USA

Received 17 October 2007; Accepted 30 October 2007

Abstract
Bovine respiratory syncytial virus (BRSV) causes severe respiratory disease in young cattle.
Much like the human respiratory syncytial virus, BRSV induces immunomodulation in the
infected host, favoring a Th2 response. Several groups have demonstrated IgE responses to
BRSV proteins during infection and particularly in response to vaccination with formalin-
inactivated vaccine in the field and experimentally. Newer vaccine modalities that favor a shift
to Th1 cytokine production have provided promising results. Infection with BRSV is a major
contributor to the multi-pathogen disease, bovine respiratory disease complex. This review
stresses the unique immunomodulatory aspects of BRSV infection, vaccination and its
interaction with the host’s immune system.

Keywords: bovine respiratory syncytial virus, IgE, vaccine, immunomodulation

Introduction exacerbation in humans and in cattle (reviewed in Meyer

Bovine respiratory syncytial virus (BRSV) is a pathogen
of cattle that can cause disease by itself and also as a
member of the bovine respiratory disease complex
(BRDC). As such it is an extremely important bovine
pathogen. The impact of BRSV on the economy of the
cattle industry is considerable. Some studies estimate that
more than 60% of epizootic respiratory disease in dairy
herds is caused by BRSV infection (Meyer et al., 2007). In
addition, this figure may be as high as 70% in beef herds.
With mortality varying from 2–3% to as high as 20% in
some outbreaks, the disease can exert a strong negative
impact on the dairy and beef industries.
BRSV is closely related to a human virus, respiratory
syncytial virus (RSV), which is the most important cause
of infectious lung disease in children less than two years
of age, as well as the elderly and immune compromised
human population (Falsey, 2007; van Drunen Littel-van
den Hurk et al., 2007). The pathogenesis of disease in
both the bovine and human hosts is closely related to
the host response to virus infection. Immune modulation
by vaccination has been shown to induce disease
*Corresponding author. E-mail: ljgershwin@ucdavis.edu
et al., 2007). Much has been learned about BRSV during
the 30 plus years since its original discovery. However,
there are still unanswered questions regarding the
variable pathogenesis, mechanisms of immune protection
and modes of transmission within the cattle population.
Several excellent reviews have recently dealt with
molecular aspects of BRSV (Valarcher and Taylor, 2007)
and with recent vaccine research (Meyer et al., 2007).
Thus, this review will concentrate on the immunopatho-
genesis resulting from the interaction of BRSV with the
host’s immune system.
Characteristics of the virus
BRSV is an enveloped single negative strand RNA virus
in the genus Pnuemovirus within the family Paramyxovir-
idae. Examination of the virus using electron microscopy
shows the virus to be pleomorphic or filamentous. The
size ranges from 35 to 150 nm in diameter; in addition, it
can attain a filamentous shape with a diameter between
60 and 100 nm (reviewed in Trudel et al., 1989; Valarcher
and Taylor, 2007). The envelope is composed of host cell
lipid and contains three transmembrane glycoproteins.
There are 11 proteins encoded by the genome of BRSV.
208
The G protein is the largest [approximately 260 amino
acids (AAs)]; the fusion (F) protein is synthesized as a 547
AA precursor that is cleaved into F1 and F2 subunits;
and the smallest of the three membrane proteins is the
small hydrophobic (SH) protein (Samal and Zamora,
1991). The role of the G protein in cell attachment prior to
infection has been established. An immune response to
the heavily glycosylated G protein has been associated
with protection (Taylor et al., 1997). In addition to the
membrane bound form of G protein a soluble form has
been described (Hendricks et al., 1987). The F protein
binds the virus to the cell thereby facilitating infection.
The F protein causes fusion of infected cells to form
syncytia with uninfected cells thereby facilitating virus
spread. A 27 AA peptide released from the F protein after
proteolytic cleavage into F1 and F2 may have a role in
pathogenesis as a virokinin with smooth muscle constric-
tion activity (Zimmer et al., 2003).
The viral proteins forming the nucleocapsid include the
nucleocapsid protein (N), the phosphoprotein (P) and the
RNA-dependent RNA polymerase (L). In addition to these
proteins, there is a matrix protein composed of three
forms (M, M2.1 and M2.2) and there are two non-
structural proteins NS1 and NS2. These non-structural
proteins are important in resistance to interferons (IFNs) a
and b (reviewed by Valarcher and Taylor, 2007).
BRSV has been considered to be relatively stable
genetically. However, recent studies by Deplanche et al.
(2007) have shown that although there is great genetic
stability of the G protein there is genetic heterogeneity
resulting from frequent mutations in the G-coding region,
resulting in quasispecies. Earlier studies on field isolates
from Europe and North America showed that there has
been a continuous evolution of sequences of the N, G,
and F proteins in BRSV isolates since 1967 – possibly the
result of selective pressure from vaccination (Valarcher
et al., 2000).
BRSV infection
Much like human RSV infection, which is most severe in
small children, BRSV infection of calves is generally more
severe than infection in older animals (Van der Poel et al.,
1994). Adult cattle can become infected, but generally
the disease is less severe than in the younger animals.
Infection is characterized by pyrexia, anorexia, depres-
sion, cough, increased respiratory rate, and in the most
severe cases dyspnea with open-mouth breathing and
wheezes. Pathological evaluation of lungs of animals that
die shows large areas of consolidation, occasionally with
emphysematous bulla in those most severely affected.
Histologically, there is evidence of bronchiolitis and
interstitial pneumonia. Staining sections for BRSV antigen
using immunoperoxidase reveals the presence of virus in
bronchial epithelial cells and sometimes in type 2 alveolar
cells. In experimental models in which the day of
L. J. Gershwin
infection is known, viral shedding usually begins around
day 3 or 4, and rarely lasts past day 10. Virus can usually
be isolated at necropsy on day 7 but will usually not be
detectable in the lung by day 10 of infection (personal
observation).
In BRSV infection, the extent of lung damage does not
correlate with the relatively short duration of the viral
infection in the host and the limited distribution of the
virus in the body. The host response to the virus accounts
for the majority of the lung pathology. In fact, the ability
of the virus to modulate the host immune response has far
ranging implications, which impact on the response to
vaccination, to secondary bacterial invaders and to
inhaled environmental antigens.
Experimental BRSV infection
The lack of a successful infection protocol for inducing
severe BRSV disease hampered early attempts to study
pathogenesis of the infection. Thus, a variety of different
protocols have been developed to induce experimental
infection with BRSV. These are summarized in Table 1.
Gnotobiotic calves taken by caesarian section and kept in
isolation units were used by three groups (Kimman et al.,
1987; Van der Poel et al., 1994; McInnes et al., 1999). The
ages of the calves varied from 2 days (LeBlanc et al., 1991)
to 6 months (West et al., 1998). Two groups administered
the virus by a combination of intratracheal and intranasal
routes for four consecutive days (Kimman et al., 1987;
Ciszewski et al., 1991). Three groups (Otto et al., 1996;
West et al., 1998; Woolums et al., 1999a, b) administered
the virus by aerosol. Minimal tissue culture passage
appears to be important for induction of moderate to
severe clinical signs of disease. The presence of low titers
of maternal antibodies specific for BRSV does not appear
to prevent infection. These various infection protocols
have been used to establish details on BRSV pathogenesis
as well as potential efficacy of vaccine formulations and
vaccination protocols.
Immunopathogenesis of BRSV infection: host–viral
interaction
Early observations of children infected with RSV showed
that some developed severe disease, characterized by
wheezing, while others developed only mild upper
respiratory tract symptoms. Further examination of these
children showed that many of the severely affected
patients had detectable RSV-specific IgE antibodies in the
serum and nasopharyngeal secretions (Welliver et al.,
1981). Furthermore, many children had increased levels
of histamine in nasal secretions. Later studies demon-
strated a T-helper cell type skew in RSV-infected children
with severe disease. Demonstration of interleukin-4 (IL-4)
production by lymphocytes from these patients was
 Bovine Respiratory Syncytial Virus Infection 209

supportive of a Th2 modulation of the immune response

University of Saskatoon, Canada, FIHPCV=Federal Institute for Health Protection of Consumers and Veterinary Medicine, Germany, IAH=Institute of Animal Health, Compton,
MSU=Michigan State University, UCD=University of California, Davis, UU=University of Utrecht, The Netherlands, CVI=Central Veterinary Institute, Lelystad, The Netherlands,
Stewart and Gershwin, 1989
(Román et al., 1997). Early studies by Stewart and

Van der Poel et al., 1994

Woolums et al., 1999b
Gershwin (1989) demonstrated the presence of BRSV-

Ciszewski et al., 1991

Kimman et al., 1987

LeBlanc et al., 1991
specific IgE in the serum of calves experimentally infected

West et al., 1998

with BRSV. Subsequent studies by this group using a

Otto et al., 1996

posterior mediastinal lymph cannulation procedure
Taylor, 1995 to obtain efferent lymph from the lung demonstrated that
References

in experimentally-infected calves there was a correlation

between severity of clinical signs and the presence of
BRSV-specific IgE in serum and lymph. Moreover, the
presence of RNA coding for IL-4 in lymphocytes draining
the lung was temporally related to BRSV infection
Increased pulmonary resistance

(Gershwin et al., 2000).

and airways hyperreactivity

The lack of a commercially available vaccine for RSV to

protect the human population is a result of a serious
vaccine failure in the 1960s (Kim et al., 1969). At that time,
Moderate to severe

Moderate to severe

Moderate to severe
Severity of disease

a formalin inactivated alum adjuvanted vaccine in clinical

trials caused disease exacerbation in vaccinated children
subsequently infected naturally with field virus; there
were two deaths and 80% of those infected were
hospitalized (Openshaw et al., 2001). The cattle industry
Mild

Mild
Mild

Mild

Mild

has not been hampered with concerns that BRSV killed

vaccine might enhance disease and has had several
products in heavy use for many years. However, there
freshly tissue culture harvested

have been numerous reports of vaccine-induced

Field isolate (Asquith) in lung
wash from newborn calves
Snook strain, cell propagated

BRSV exacerbation (some published observations, many

Field (CA-1), low passage,

unpublished observations). One report documented a

Field isolate (Odijk) not
tissue culture passed

severe outbreak among cattle vaccinated with a modified

live vaccine in the Netherlands (Kimman et al., 1989).
Virus isolate used

IgM levels indicated the presence of the virus in the

Field, frozen

herd at the time of vaccination; yet vaccinated cattle were

Field isolate

Field isolate

Field isolate
ATCC strain

more severely affected than unvaccinated cattle. A report

from Belgium documented severe fatal BRSV in cattle
vaccinated with a killed BRSV vaccine (Schreiber et al.,
2000). The reported lung lesions were reminiscent of
those seen in the children who had vaccine-exacerbated
disease, including eosinophilia, severe proliferative alveo-
IT and IN for 4 days

IT and IN for 4 days

IT and IN for 4 days

litis, bronchiolitis obliterans and areas of emphysema.

The vaccine administered to the calves described by
Schreiber et al. (2000) was killed with b-propiolactone
Method of

IT and IN

Intranasal
infection

and was incorporated in a saponin/aluminum hydroxide

Aerosol

Aerosol

Aerosol
Aerosol
Table 1. Models of experimental BRSV infection

adjuvant.
Experimental reproduction of vaccine exacerbated
England. IT=intratracheal and IN=intranasal.

BRSV disease has been accomplished by several groups.

6 weeks, caesarian derived,

Gershwin et al. (1998) used a protocol fashioned after that

6 months isolation reared
Calf age/colostrum status

6–8 weeks, conventional

6–8 weeks, conventional

described in the ill-fated human trial (Kim et al., 1969) to

2–3 days, conventional

1 month conventional

colostrum deprived

colostrum deprived

produce a formalin killed alum adjuvanted vaccine, and a

10 days, gnotobiotic,

3–4 weeks, SPF, +/

sham vaccine lacking virus for control animals. In this

study, conventionally raised calves were immunized twice
seronegative

at a 2-week interval followed by challenge with virulent

17–24 days

BRSV by aerosol exposure 42 days after the initial

vaccination. Clinical signs, pulmonary function, virus
shedding and antibody responses were monitored during
the 10 days after infection. Two calves in the vaccinated/
FIHPCV

infected group had to be humanely euthanized on the

Group

UCD

UCD
MSU

MSU

seventh day post infection due to severe dyspnea and

IAH

CVI
UU

US

a moribund state. Overall the vaccinated group was

210
significantly more severely affected than the control sham
vaccinated/infected group. Moreover, pulmonary func-
tion testing revealed significantly greater pulmonary
resistance and decreased lung compliance in the vacci-
nated calves. Additionally, lung pathology scoring
revealed lesions characteristic of the vaccine exacerbated
disease seen in the children (severe alveolitis, bronchio-
litis obliterans, etc.) (Gershwin et al., 1998).
Further studies using sera from the calves in the vaccine
enhancement experiment demonstrated a correlation
between severity of clinical signs and serum BRSV-
specific IgE levels. Using Western blot analysis on
sequential serum samples it was shown that vaccination
induced a strong IgE response to several BRSV proteins
in the most severely affected calves. In comparison, calves
in another experiment in which vaccine enhanced disease
did not occur showed little or no IgE, but IgG antibodies
were induced by vaccination (Kalina et al., 2004).
The induction of a Th2 response by vaccination with
formalin killed BRSV vaccine was further confirmed by
demonstration of significantly decreased levels of IFN-g
produced by peripheral blood lymphocytes from the
vaccinated/infected calves compared with the sham
vaccinated/infected calves in the above described study
(Woolums et al., 1999a). These results support the
contention that immunomodulation towards the Th2
response is involved in pathogenesis of vaccine-induced
disease exacerbation.
Disease exacerbation following vaccination with forma-
lin inactivated alum adjuvanted BRSV vaccine has also
been demonstrated by Antonis et al. (2003) in the
Netherlands. This group used colostrum deprived specific
pathogen free calves obtained by caesarean section and
housed in isolators, unlike the conventionally raised
calves used in the previously described study. The
duration of time between the final vaccination and
experimental BRSV challenge was also different (5
months in the Antonis study versus 3 weeks in the
Gershwin study). Despite these differences, both experi-
ments demonstrated more severe disease in vaccinated
calves and the presence of IgE antibodies in the serum of
vaccinated/infected calves.
Recognition of the disease enhancing effects of killed
adjuvanted RSV vaccines prompted Mapletoft et al. (2006)
to formulate an inactivated BRSV vaccine with CpG
containing deoxyoligonucleotides (ODN) intended to
switch the immune response towards a protective Th1
response. Numerous studies using CpG ODN in murine
and human cells have shown that these sequences bind to
Toll-like receptors and stimulate secretion of IL-1, IL-6, IL-
12 by antigen presenting cells, and IL-6, IL-10, and IFN-g
by lymphocytes (Bharadwaj et al., 2007). In this trial,
which included calves vaccinated with formalin-
inactivated BRSV with and without the CpG ODN, the
observations included decreased clinical signs and virus
titers in lung as well as increases in IgG2 levels and IFN-g
production by peripheral blood mononuclear cells. The
L. J. Gershwin
presence of IgG2 and IFN-g in cattle are hallmarks of a
Th1 type response (Estes and Brown, 2002).
A presumed association between RSV and allergic
asthma in children has been substantiated by epidemio-
logical studies in humans (Juntti et al., 2003; Becker,
2006). Experimentally, mouse models have been used
to demonstrate that RSV infection can predispose for
development of an allergic response to allergen by its
immunomodulatory effect (Barends et al., 2004). More-
over, studies with mouse models have shown that the
RSV G protein contains a domain that likely functions to
skew the Th1/Th2 cytokine balance (Johnson and
Graham, 1999; reviewed in Becker, 2006). Although cattle
do not develop asthma as a clinical syndrome, the
development of IgE antibodies to inhaled pollens and
molds has been documented (Olchowy et al., 1995).
Studies by our group examined whether BRSV infection
could facilitate development of IgE antibodies to Micro-
polyspora faeni (renamed Saccharopolyspora rectivir-
gula), the causal agent of Farmer’s lung and Bovine
Farmer’s lung disease (Gershwin et al., 1994), and/or
cause exacerbation of IgE responses of calves already
sensitized to the mold allergen prior to BRSV infection.
In one experiment, calves were either exposed to virus
only, exposed to aerosolized M. faeni over a 24-day
period and then challenged with M. faeni during
BRSV infection, similarly M. faeni aerosol exposed and
challenged but sham infected, or exposed to aerosolized
M. faeni, infected with BRSV without M. faeni challenge.
BRSV-specific IgE was associated with increased lung
pathology and clinical disease and M. faeni aerosolization
enhanced development of BRSV-specific IgE. Significantly
increased concentrations of prostaglandin I2 were as-
sociated with M. faeni aerosol exposure, particularly
when combined with BRSV infection. After M. faeni
challenge exposure, thromboxane B2 concentrations
were significantly greater in the BRSV and M. faeni
challenge-exposed calves. M. faeni-specific IgE concen-
trations had a highly significant direct correlation with
prostaglandin E2 concentrations in samples taken 30 min
after the second M. faeni challenge exposure. Histamine
concentrations were significantly greater in calves
infected with BRSV than in uninfected controls regardless
of M. faeni exposure (Gershwin and Giri, 1992). These
studies confirmed the synergistic effect of allergen
exposure and BRSV infection in modulating the lung
environment for a type 1 hypersensitivity response.
More recently, we used technetium labeled ovalbumin
(OA) to examine the clearance of allergen from the lungs
of calves during a BRSV infection. In this study, after
baseline clearance of labeled OA was performed, each
calf was infected by aerosol with BRSV; an aerosol of
technetium labeled OA was administered on several days
throughout infection. Gamma camera imaging was
performed to determine the half time for clearance of
the OA from the lungs. BRSV infection caused an increase
in the time it took for the allergen to be cleared from the
Bovine Respiratory Syncytial Virus Infection
lungs (Gershwin et al., in press). Increased exposure to
allergen coupled with the Th2 environment suggests that
BRSV may facilitate enhanced sensitization to inhalants.
Potentially, sensitization to allergens present in dust may
play a role in the development of chronic respiratory
disease in some cattle.
Kalina et al. (2006) extended these observations to
examine the effect of fungal allergen Alternaria alternata
aerosol exposure (prior to and during BRSV infection) on
both the primary immune response and the clinical
outcome of a secondary BRSV infection. Experimental
groups included BRSV infected calves aerosol exposed to
Alternaria and to sham Alternaria; exposures were
initiated 6 days before BRSV infection and continued
through the sixth day of infection. The second set of
aerosols/infection began just over 3 months from the
primary BRSV infection and continued as described for
the primary infection. Alternaria aerosols did not
influence the clinical course of the primary infection;
however, the Alternaria exposed/BRSV infected animals
had a significantly lower mean clinical score for the
secondary infection than those exposed to sham Alter-
naria and BRSV infection. Exposure to Alternaria
facilitated IgE antibody production in BRSV infected
calves during the primary and secondary infections. At
necropsy the Alternaria exposed BRSV infected calves
had greater numbers of lung eosinophils and IL-4
secreting peripheral blood mononuclear cells, as deter-
mined by flow cytometry. Paradoxically, BRSV infection
enhanced Th2 responses against inhaled Alternaria. Yet
animals with higher IgE responses to inhaled Alternaria
did not have more severe disease when infected a second
time with BRSV.
BRSV infection and polymicrobial infections
BRSV has been associated with several bacterial patho-
gens in the BRDC. Like bovine herpes virus, BRSV can
predispose to infection with Mannheimia haemolytica,
Pasteurella multocida and Histophilus somni. However,
the immunomodulatory capability of BRSV adds another
dimension to the pathogen interaction. Our group
examined the effect of BRSV infection on subsequent
H. somni infection, using well-developed model systems
(Gogolewski et al., 1989; Woolums et al., 1999a, b;
Gershwin et al., 2005). The working hypothesis was that
H. somni infection would be enhanced because of the
need for bacteria-specific IgG2, in cattle the product of
a Th1 response (Estes and Brown, 2002). The BRSV
infection was well established by day 6 after virus aerosol
thereby inducing a Th2 environment when the bacteria
were administered by intratracheal inoculation. Indeed
infection was more severe and bacteria persisted longer in
the lungs in dually infected calves as compared with those
infected with single pathogens. Moreover, a H. somni-
specific IgE response was detected in dually infected
211
cattle. Protein specificity of the IgE has been examined
(Corbeil et al., 2006). Further details on this work are
presented in the review on H. somni.
The effect of BRSV infection on a previously estab-
lished immune response to H. somni appears to be less
effective in modulation. In a subsequent experiment, we
hypothesized that combining BRSV vaccination with
H. somni vaccination would induce cytokine shifts
resulting in greater IgE production to both pathogens
and enhanced disease. Concurrent vaccination followed
by concurrent infection with single agents or both BRSV
and H. somni showed increased BRSV-specific serum IgE
levels for the calves with the most severe disease, while
no difference was detected in the IgE levels to H. somni
among groups. Moreover, those calves with the least
evidence of disease showed increased levels of IFN-g
message and H. somni-specific IgG2 antibodies. The
BRSV vaccine induced the expected Th2 response, but
the H. somni bacterin induced a strong IgG2 response,
which proved to be protective (Berghaus et al., 2006).
Taken together with the experiments on unvaccinated
calves described above, it is suggestive that viral replica-
tion may be an important factor for modulation by
BRSV of the immune response to H. somni towards a
Th2 response. Additionally, a well established Th2
environment induced by the BRSV replication prior to
introduction of H. somni antigens may be required for
BRSV modulatory effects on the immune response to
H. somni.
Summary
It is well documented that much of the clinical and
pathological observations in BRSV infection result from
the host response to the virus. There are unique aspects of
this virus that facilitate development of pro-inflammatory
responses that fail to induce protection and long-lived
immunity. When examined, most observations made
on human RSV have proven to be shared with BRSV.
Thus, it is likely that continued efforts to develop new
vaccination strategies would have reciprocal benefits for
both species.
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