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*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


et al., 2007). Much has been learned about BRSV during
Bovine respiratory syncytial virus (BRSV) is a pathogen the 30 plus years since its original discovery. However,
of cattle that can cause disease by itself and also as a there are still unanswered questions regarding the
member of the bovine respiratory disease complex variable pathogenesis, mechanisms of immune protection
(BRDC). As such it is an extremely important bovine and modes of transmission within the cattle population.
pathogen. The impact of BRSV on the economy of the Several excellent reviews have recently dealt with
cattle industry is considerable. Some studies estimate that molecular aspects of BRSV (Valarcher and Taylor, 2007)
more than 60% of epizootic respiratory disease in dairy and with recent vaccine research (Meyer et al., 2007).
herds is caused by BRSV infection (Meyer et al., 2007). In Thus, this review will concentrate on the immunopatho-
addition, this figure may be as high as 70% in beef herds. genesis resulting from the interaction of BRSV with the
With mortality varying from 2–3% to as high as 20% in host’s immune system.
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 Characteristics of the virus
syncytial virus (RSV), which is the most important cause
of infectious lung disease in children less than two years BRSV is an enveloped single negative strand RNA virus
of age, as well as the elderly and immune compromised in the genus Pnuemovirus within the family Paramyxovir-
human population (Falsey, 2007; van Drunen Littel-van idae. Examination of the virus using electron microscopy
den Hurk et al., 2007). The pathogenesis of disease in shows the virus to be pleomorphic or filamentous. The
both the bovine and human hosts is closely related to size ranges from 35 to 150 nm in diameter; in addition, it
the host response to virus infection. Immune modulation can attain a filamentous shape with a diameter between
by vaccination has been shown to induce disease 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.
*Corresponding author. E-mail: ljgershwin@ucdavis.edu There are 11 proteins encoded by the genome of BRSV.
208 L. J. Gershwin

The G protein is the largest [approximately 260 amino infection is known, viral shedding usually begins around
acids (AAs)]; the fusion (F) protein is synthesized as a 547 day 3 or 4, and rarely lasts past day 10. Virus can usually
AA precursor that is cleaved into F1 and F2 subunits; be isolated at necropsy on day 7 but will usually not be
and the smallest of the three membrane proteins is the detectable in the lung by day 10 of infection (personal
small hydrophobic (SH) protein (Samal and Zamora, observation).
1991). The role of the G protein in cell attachment prior to In BRSV infection, the extent of lung damage does not
infection has been established. An immune response to correlate with the relatively short duration of the viral
the heavily glycosylated G protein has been associated infection in the host and the limited distribution of the
with protection (Taylor et al., 1997). In addition to the virus in the body. The host response to the virus accounts
membrane bound form of G protein a soluble form has for the majority of the lung pathology. In fact, the ability
been described (Hendricks et al., 1987). The F protein of the virus to modulate the host immune response has far
binds the virus to the cell thereby facilitating infection. ranging implications, which impact on the response to
The F protein causes fusion of infected cells to form vaccination, to secondary bacterial invaders and to
syncytia with uninfected cells thereby facilitating virus inhaled environmental antigens.
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- Experimental BRSV infection
tion activity (Zimmer et al., 2003).
The viral proteins forming the nucleocapsid include the The lack of a successful infection protocol for inducing
nucleocapsid protein (N), the phosphoprotein (P) and the severe BRSV disease hampered early attempts to study
RNA-dependent RNA polymerase (L). In addition to these pathogenesis of the infection. Thus, a variety of different
proteins, there is a matrix protein composed of three protocols have been developed to induce experimental
forms (M, M2.1 and M2.2) and there are two non- infection with BRSV. These are summarized in Table 1.
structural proteins NS1 and NS2. These non-structural Gnotobiotic calves taken by caesarian section and kept in
proteins are important in resistance to interferons (IFNs) a isolation units were used by three groups (Kimman et al.,
and b (reviewed by Valarcher and Taylor, 2007). 1987; Van der Poel et al., 1994; McInnes et al., 1999). The
BRSV has been considered to be relatively stable ages of the calves varied from 2 days (LeBlanc et al., 1991)
genetically. However, recent studies by Deplanche et al. to 6 months (West et al., 1998). Two groups administered
(2007) have shown that although there is great genetic the virus by a combination of intratracheal and intranasal
stability of the G protein there is genetic heterogeneity routes for four consecutive days (Kimman et al., 1987;
resulting from frequent mutations in the G-coding region, Ciszewski et al., 1991). Three groups (Otto et al., 1996;
resulting in quasispecies. Earlier studies on field isolates West et al., 1998; Woolums et al., 1999a, b) administered
from Europe and North America showed that there has the virus by aerosol. Minimal tissue culture passage
been a continuous evolution of sequences of the N, G, appears to be important for induction of moderate to
and F proteins in BRSV isolates since 1967 – possibly the severe clinical signs of disease. The presence of low titers
result of selective pressure from vaccination (Valarcher of maternal antibodies specific for BRSV does not appear
et al., 2000). 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
BRSV infection vaccination protocols.

Much like human RSV infection, which is most severe in


small children, BRSV infection of calves is generally more Immunopathogenesis of BRSV infection: host–viral
severe than infection in older animals (Van der Poel et al., interaction
1994). Adult cattle can become infected, but generally
the disease is less severe than in the younger animals. Early observations of children infected with RSV showed
Infection is characterized by pyrexia, anorexia, depres- that some developed severe disease, characterized by
sion, cough, increased respiratory rate, and in the most wheezing, while others developed only mild upper
severe cases dyspnea with open-mouth breathing and respiratory tract symptoms. Further examination of these
wheezes. Pathological evaluation of lungs of animals that children showed that many of the severely affected
die shows large areas of consolidation, occasionally with patients had detectable RSV-specific IgE antibodies in the
emphysematous bulla in those most severely affected. serum and nasopharyngeal secretions (Welliver et al.,
Histologically, there is evidence of bronchiolitis and 1981). Furthermore, many children had increased levels
interstitial pneumonia. Staining sections for BRSV antigen of histamine in nasal secretions. Later studies demon-
using immunoperoxidase reveals the presence of virus in strated a T-helper cell type skew in RSV-infected children
bronchial epithelial cells and sometimes in type 2 alveolar with severe disease. Demonstration of interleukin-4 (IL-4)
cells. In experimental models in which the day of 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 L. J. Gershwin

significantly more severely affected than the control sham presence of IgG2 and IFN-g in cattle are hallmarks of a
vaccinated/infected group. Moreover, pulmonary func- Th1 type response (Estes and Brown, 2002).
tion testing revealed significantly greater pulmonary A presumed association between RSV and allergic
resistance and decreased lung compliance in the vacci- asthma in children has been substantiated by epidemio-
nated calves. Additionally, lung pathology scoring logical studies in humans (Juntti et al., 2003; Becker,
revealed lesions characteristic of the vaccine exacerbated 2006). Experimentally, mouse models have been used
disease seen in the children (severe alveolitis, bronchio- to demonstrate that RSV infection can predispose for
litis obliterans, etc.) (Gershwin et al., 1998). development of an allergic response to allergen by its
Further studies using sera from the calves in the vaccine immunomodulatory effect (Barends et al., 2004). More-
enhancement experiment demonstrated a correlation over, studies with mouse models have shown that the
between severity of clinical signs and serum BRSV- RSV G protein contains a domain that likely functions to
specific IgE levels. Using Western blot analysis on skew the Th1/Th2 cytokine balance (Johnson and
sequential serum samples it was shown that vaccination Graham, 1999; reviewed in Becker, 2006). Although cattle
induced a strong IgE response to several BRSV proteins do not develop asthma as a clinical syndrome, the
in the most severely affected calves. In comparison, calves development of IgE antibodies to inhaled pollens and
in another experiment in which vaccine enhanced disease molds has been documented (Olchowy et al., 1995).
did not occur showed little or no IgE, but IgG antibodies Studies by our group examined whether BRSV infection
were induced by vaccination (Kalina et al., 2004). could facilitate development of IgE antibodies to Micro-
The induction of a Th2 response by vaccination with polyspora faeni (renamed Saccharopolyspora rectivir-
formalin killed BRSV vaccine was further confirmed by gula), the causal agent of Farmer’s lung and Bovine
demonstration of significantly decreased levels of IFN-g Farmer’s lung disease (Gershwin et al., 1994), and/or
produced by peripheral blood lymphocytes from the cause exacerbation of IgE responses of calves already
vaccinated/infected calves compared with the sham sensitized to the mold allergen prior to BRSV infection.
vaccinated/infected calves in the above described study In one experiment, calves were either exposed to virus
(Woolums et al., 1999a). These results support the only, exposed to aerosolized M. faeni over a 24-day
contention that immunomodulation towards the Th2 period and then challenged with M. faeni during
response is involved in pathogenesis of vaccine-induced BRSV infection, similarly M. faeni aerosol exposed and
disease exacerbation. challenged but sham infected, or exposed to aerosolized
Disease exacerbation following vaccination with forma- M. faeni, infected with BRSV without M. faeni challenge.
lin inactivated alum adjuvanted BRSV vaccine has also BRSV-specific IgE was associated with increased lung
been demonstrated by Antonis et al. (2003) in the pathology and clinical disease and M. faeni aerosolization
Netherlands. This group used colostrum deprived specific enhanced development of BRSV-specific IgE. Significantly
pathogen free calves obtained by caesarean section and increased concentrations of prostaglandin I2 were as-
housed in isolators, unlike the conventionally raised sociated with M. faeni aerosol exposure, particularly
calves used in the previously described study. The when combined with BRSV infection. After M. faeni
duration of time between the final vaccination and challenge exposure, thromboxane B2 concentrations
experimental BRSV challenge was also different (5 were significantly greater in the BRSV and M. faeni
months in the Antonis study versus 3 weeks in the challenge-exposed calves. M. faeni-specific IgE concen-
Gershwin study). Despite these differences, both experi- trations had a highly significant direct correlation with
ments demonstrated more severe disease in vaccinated prostaglandin E2 concentrations in samples taken 30 min
calves and the presence of IgE antibodies in the serum of after the second M. faeni challenge exposure. Histamine
vaccinated/infected calves. concentrations were significantly greater in calves
Recognition of the disease enhancing effects of killed infected with BRSV than in uninfected controls regardless
adjuvanted RSV vaccines prompted Mapletoft et al. (2006) of M. faeni exposure (Gershwin and Giri, 1992). These
to formulate an inactivated BRSV vaccine with CpG studies confirmed the synergistic effect of allergen
containing deoxyoligonucleotides (ODN) intended to exposure and BRSV infection in modulating the lung
switch the immune response towards a protective Th1 environment for a type 1 hypersensitivity response.
response. Numerous studies using CpG ODN in murine More recently, we used technetium labeled ovalbumin
and human cells have shown that these sequences bind to (OA) to examine the clearance of allergen from the lungs
Toll-like receptors and stimulate secretion of IL-1, IL-6, IL- of calves during a BRSV infection. In this study, after
12 by antigen presenting cells, and IL-6, IL-10, and IFN-g baseline clearance of labeled OA was performed, each
by lymphocytes (Bharadwaj et al., 2007). In this trial, calf was infected by aerosol with BRSV; an aerosol of
which included calves vaccinated with formalin- technetium labeled OA was administered on several days
inactivated BRSV with and without the CpG ODN, the throughout infection. Gamma camera imaging was
observations included decreased clinical signs and virus performed to determine the half time for clearance of
titers in lung as well as increases in IgG2 levels and IFN-g the OA from the lungs. BRSV infection caused an increase
production by peripheral blood mononuclear cells. The in the time it took for the allergen to be cleared from the
Bovine Respiratory Syncytial Virus Infection 211

lungs (Gershwin et al., in press). Increased exposure to cattle. Protein specificity of the IgE has been examined
allergen coupled with the Th2 environment suggests that (Corbeil et al., 2006). Further details on this work are
BRSV may facilitate enhanced sensitization to inhalants. presented in the review on H. somni.
Potentially, sensitization to allergens present in dust may The effect of BRSV infection on a previously estab-
play a role in the development of chronic respiratory lished immune response to H. somni appears to be less
disease in some cattle. effective in modulation. In a subsequent experiment, we
Kalina et al. (2006) extended these observations to hypothesized that combining BRSV vaccination with
examine the effect of fungal allergen Alternaria alternata H. somni vaccination would induce cytokine shifts
aerosol exposure (prior to and during BRSV infection) on resulting in greater IgE production to both pathogens
both the primary immune response and the clinical and enhanced disease. Concurrent vaccination followed
outcome of a secondary BRSV infection. Experimental by concurrent infection with single agents or both BRSV
groups included BRSV infected calves aerosol exposed to and H. somni showed increased BRSV-specific serum IgE
Alternaria and to sham Alternaria; exposures were levels for the calves with the most severe disease, while
initiated 6 days before BRSV infection and continued no difference was detected in the IgE levels to H. somni
through the sixth day of infection. The second set of among groups. Moreover, those calves with the least
aerosols/infection began just over 3 months from the evidence of disease showed increased levels of IFN-g
primary BRSV infection and continued as described for message and H. somni-specific IgG2 antibodies. The
the primary infection. Alternaria aerosols did not BRSV vaccine induced the expected Th2 response, but
influence the clinical course of the primary infection; the H. somni bacterin induced a strong IgG2 response,
however, the Alternaria exposed/BRSV infected animals which proved to be protective (Berghaus et al., 2006).
had a significantly lower mean clinical score for the Taken together with the experiments on unvaccinated
secondary infection than those exposed to sham Alter- calves described above, it is suggestive that viral replica-
naria and BRSV infection. Exposure to Alternaria tion may be an important factor for modulation by
facilitated IgE antibody production in BRSV infected BRSV of the immune response to H. somni towards a
calves during the primary and secondary infections. At Th2 response. Additionally, a well established Th2
necropsy the Alternaria exposed BRSV infected calves environment induced by the BRSV replication prior to
had greater numbers of lung eosinophils and IL-4 introduction of H. somni antigens may be required for
secreting peripheral blood mononuclear cells, as deter- BRSV modulatory effects on the immune response to
mined by flow cytometry. Paradoxically, BRSV infection H. somni.
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 Summary
time with BRSV.
It is well documented that much of the clinical and
pathological observations in BRSV infection result from
BRSV infection and polymicrobial infections the host response to the virus. There are unique aspects of
this virus that facilitate development of pro-inflammatory
BRSV has been associated with several bacterial patho- responses that fail to induce protection and long-lived
gens in the BRDC. Like bovine herpes virus, BRSV can immunity. When examined, most observations made
predispose to infection with Mannheimia haemolytica, on human RSV have proven to be shared with BRSV.
Pasteurella multocida and Histophilus somni. However, Thus, it is likely that continued efforts to develop new
the immunomodulatory capability of BRSV adds another vaccination strategies would have reciprocal benefits for
dimension to the pathogen interaction. Our group both species.
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; References
Gershwin et al., 2005). The working hypothesis was that
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