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INTRODUCTION

Pestiviruses of domestic animals include bovine viral diarrhea virus (BVDV) of cattle, border disease virus (BDV) of sheep, and classic swine fever virus (CSFV) of pigs. The latter virus is also known as hog cholera virus (HCV). These viruses were initially found to be associated only with their species of origin but are now recognized to infect numerous other animal species indicating they are not speciesspecific. This chapter focuses on BVDV and hosts other than cattle in which infection results in disease, virus isolation, or seroconversion. Additionally, cell types supporting the growth of BVDV in vitro are also discussed.

Concern exists over non-bovine hosts of BVDV for a number of reasons. In many agricultural situations, cattle and other wild and domestic ruminants share the same pasture, range, and water source. Transmission of virus from non-bovine hosts to cattle may affect control programs and/or productivity in cattle herds. Similarly, spread of BVDV from cattle to sheep, goats, and wild ruminants may affect the productivity of domestic animals or the health of wildlife populations. In addition, infection of species such as swine with BVDV may interfere with HCV control programs through false positive test results. In Europe, formal monitoring of wildlife for domestic animal pathogens (such as pestiviruses) is carried out in some countries (Frolich et al., 2002). This type of surveillance would be needed should control programs for pestiviruses be considered in North America.

An additional concern worldwide is the possible BVDV contamination of biologics (particularly modified live virus vaccines) used in non-bovine hosts. Biologic manufacturers may use BVDVcontaminated fetal bovine serum in vaccine production as a result of inadequate testing or improper

quality control standards. Pandemics may start when a pathogen “jumps” from one species to another. The parvovirus jump from feline to canine hosts may be an example of such a pandemic occurring due to contaminated biologics.

DISEASE SYNDROMES IN NON-BOVINE HOSTS DUE TO NATURAL BVDV INFECTION

Reports of disease resulting from natural infection with BVDV in species other than cattle are infrequent. BVDV was initially isolated from litters of dying piglets as well as from stillborn pigs in 1988 (Terpstra and Wensvoort, 1988). In a subsequent report, these authors reported a series of 19 naturally occurring and 8 experimentally induced incidences of congenital BVDV infections in pigs (Terpstra and Wensvoort, 1991). The disease was restricted to the involved litter without any horizontal transmission. The signs resembled those of CSF with pigs showing signs of infection at birth and dying by 4 months of age. Postpartum infections, in contrast, usually resulted in subclinical disease. Rarely, congenitally infected pigs may survive and become lifelong carriers of the virus, shedding the virus in urine, semen, and pharyngeal fluid (Terpstra and Wensvoort, 1997).

Outbreaks of a disease resembling border disease in sheep have been reported as a result of BVDV being spread from persistently infected calves (Carlsson, 1991). BVDV has also been isolated from congenitally infected kids and lambs showing enteric symptoms resulting in death in the first week of life (Nettleton et al., 1980). BVDV was also detected in a stillborn alpaca by reverse transcription-polymerase chain reaction (RT-PCR) (Goyal et al., 2002). The virus was subsequently isolated and typed as BVDV type 1b. BVDV may have been the cause of death for this alpaca although no gross or histologic lesions

were found. Mucosal disease-like lesions have been described in a free-ranging white-tail deer from which a cytopathic BVDV was isolated (Ludwig and McClurkin, 1981). BVDV type 1a was isolated from a free-ranging female mule deer in Wyoming (Van Campen et al., 2001). The deer was emaciated, weak, salivating, and had lung abscesses from which

Arcanobacter pyogenes was cultured.

DISEASE SYNDROMES IN NON-BOVINE HOSTS DUE TO EXPERIMENTAL BVDV INFECTION

BVDV has also been shown to produce disease in a range of domestic animals following experimental challenge. Oral-intranasal infection with field strains of BVDV in pregnant gilts produced intrauterine infection in 1 of 20 gilts, with an additional 3 gilts having reduced fetal numbers compared to corpora lutea and 2 gilts being barren (Stewart et al., 1980). Intranasal and subcutaneous administration of a vaccine strain of BVDV (Oregon C24V) in pregnant sows in the second trimester of gestation produced asymptomatic seroconversion during second and third trimesters of pregnancy (Kulscar et al., 2001). Some of the piglets born at term had clinically apparent disease consistent with that caused by CSFV, indicating transplacental infection. Fifty-seven percent of the piglets died by 60 days of age, but neither the sows nor their progeny shed the virus. Similarly, a BVDV or BDV that was present as a contaminant in a CSF vaccine induced congenital pestivirus infection in piglets born on eight swine farms utilizing the vaccine (Wensvoort and Terpstra, 1988).

Experimental, intranasal challenge of 2-month- old pigs with various doses of type 1 and type 2 BVDV was performed to evaluate the pathogenicity of the two BVDV isolates in a swine model (Paul et al., 1999). Neither virus induced clinical signs although both were reisolated antemortem and postmortem. Type 2 BVDV isolate that was experimentally more pathogenic in calves failed to produce disease in pigs. indicating the virulence was speciesspecific. These reports support the arguments that congenital infection of pigs with BVDV may result in disease but postnatal infection rarely produces clinical signs (Terpstra and Wensvoort, 1988; Terpstra and Wensvoort, 1991).

Transplacental infection of ovine fetuses with BVDV has been studied extensively in sheep. BVDV can cross the placenta and produce fetal lesions within 10 days postinfection (Hewicker-Traut-

wein, 1994). Type 2 BVDV has also been shown to produce congenital lesions in sheep fetuses (Scherer et al., 2001). BVDV infection of pregnant ewes, like BDV infection, results in abortions, stillbirths, unviable lambs, and viable lambs that are both virus-pos- itive and virus-negative (Scherer et al., 2001). Because of the similarity of BVDV to BDV, and the behavior of the BVDV in the pregnant ewe, experimental challenge of vaccinated ewes with BVDV has been used to evaluate protective immunity, including fetal protection, afforded by various BVDV vaccines (Brushke et al., 1996).

BVDV can produce pulmonary lesions in 6–8- month-old lambs following intranasal and intrabronchial challenge (Meefhan et al., 1998). Newborn lambs and kids challenged with BVDV isolates most consistently have CNS lesions (Jewett et al., 1990; Loken et al., 1990). Deer and elk have also been experimentally challenged with BVDV to determine whether these wild ruminants are capable of becoming infected and shedding the virus (Tessaro et al., 1999; van Campen et al., 1997). Both deer and elk can be infected, shed the virus, and seroconvert to the virus (Terpstra and Wensvoort, 1997; van Campen and Williams, 1996). In addition, lateral transmission to nonchallenged in-contact animals has been demonstrated with elk (Tessaro et al., 1999). Experimental infection of pregnant does with a deer isolate of BVDV resulted in mummified fetuses, stillborn fawns, and live fawns (Ludwig and McClurkin, 1981).

VIRUS ISOLATION AND

SEROCONVERSION IN NON-BOVINE HOSTS

As stated in the previous section, BVDV has been isolated from sheep, goats, and pigs undergoing natural infections (Carlsson, 1991; Pratelli et al., 1999; Terpstra and Wensvoort, 1988). BVDV has also been isolated from German roe deer (Tessaro et al., 1999), Scottish deer (Fischer et al., 1998), and exotic captive ruminants (Nattleton, 1990). Isolation of pestiviruses from a variety of ruminants other than cattle indicates that many species not yet studied may harbor them (Doyle and Heuschele, 1983). Recently, persistent infection has been documented in a family of captive mousedeer indicating that this phenomenon also occurs in cervids (Grondahl et al., 2003). This finding has significant implications for eradication campaigns.

Serological surveys also provide useful information on which species may become infected with BVDV and the seroprevalence within those species.

A survey of 1,133 dairy cows, 3,712 ewes, and 1,317 adult pigs in Norway found that 18.5% of cattle, 4.5% of sheep, and 2.2% of pigs were seropositive for BVDV (Loken et al., 1991). Of the swine that tested positive, all had higher antibody titers against BVDV than against CSFV indicating that exposure was likely to BVDV rather than to CSFV. No such comparisons were made between BVDV antibody titers in the seropositive sheep, so it is unclear whether these titers are a true reflection of BVDV seroprevalence. In a study of ruminants in Namibia, neutralizing antibodies to BVDV were found in 58% of cattle, 14% of sheep, and 4.6% of goats (Depner et al., 1991). Again no attempt was made to differentiate the pestivirus species causing these high serologic titers. In a similar study in Northern Ireland, 5.3% of ewes and 30.4% of flocks were found positive to BDV (Graham et al., 2001). Upon further testing it was found that all sheep had higher titers to BVDV type 1 than to BDV. In addition, the only pig found seropositive of 680 tested for HCV actually had higher titers to BVDV type 1 than to CSFV. These studies point out the importance of determining which pestivirus a group of animals is infected with or is responding to serologically, especially when control programs are being considered. Serologic evidence also exists for pestivirus infection of goats (Nattleton, 1990).

Serologic surveys of approximately 50 captive and free living ruminant species distributed within the families of Camelidae, Cervidae, Antelocapridae, and Bovidae have shown presence of pestivirus antibodies (Loken, 1995; Nattleton et al., 1980). Seventeen different species of African wildlife have tested positive for antibodies to BVDV (Hambli and Hedger, 1979). In North America, 2% of pronghorn antelope and 31% of American Bison have antibodies to BVDV (Stauber et al., 1980; Taylor et al., 1997). Seropositivity in caribou herds may range from 41–100% ((Dieterich, 1987; Elazhary et al., 1981; Stuen et al., 1993; van Campen and Williams, 1996) but with moose the seroprevalence ranges from 12-18% (Kocan et al., 1986; Thorsen and Henderson, 1971). This suggests that wild ruminants that are part of large herds, such as caribou and bison herds, may have higher seroprevalence than more solitary wild ruminants such as the moose or those that travel in smaller groups such as the antelope (van Campen and Williams, 1996).

Two percent of llamas in Argentina have antibodies to BVDV indicating that imported llamas may also harbor this virus and may transmit to cattle herds if in close proximity (Puntel et al., 1999).

However, the seroprevalence of BVDV antibodies in deer has not been shown to be affected by cattle population densities in deer habitats (Frolich, 1995). Sequence analysis of BVDV isolated from roe deer found the isolate to be genetically unique compared to other BVDV isolates (Frolich and Hofmann, 1995). It is likely that BVDV-strains circulate independently within deer populations, with transmission rarely occurring between deer and domestic livestock (Fischer et al., 1998). Serologic evidence for BVDV infection in rabbits has been shown with 40% of free ranging rabbits in Germany having antibody titers to BVDV in one report (Frolich and Streich, 1998). None of the rabbit spleens examined in this study were positive for BVDV.

Some evidence exists for BVDV infection in humans (Giangaspero et al., 1993). The seroprevalence of BVDV antibodies in one study of human subjects in Zambia ranged from 14.75% in healthy non–HIV- infected humans to 19.2% in HIV-infected individuals with chronic diarrhea. The increased seroprevalence in this latter group was statistically significant leading the authors to speculate that some interaction between HIV and BVDV may exist. There are a number of concerns, however, that arise from this report:

•No other reports have documented seroconversion to BVDV in humans who work with BVDV or BVDV-infected animals.

•BVDV has not been successfully grown in primate cells, raising doubts about the potential for infection and seroconversion in primates.

•Antibody titers against other pestiviruses were not determined, making it difficult to conclude whether the antibodies detected were specifically against BVDV

•The researchers failed to provide evidence that no reagents used in their investigation were contaminated with BVDV or BVDV antibodies.

CELL LINES SUPPORTING THE GROWTH OF BVDV AS POSSIBLE INDICATORS OF HOST RANGE

In a large survey of 41 common cell lines, cells of cattle, sheep, goat, deer, bison, rabbit, domestic cat, and swine origin were found capable of supporting BVDV growth. A subpopulation of these cell lines including those of cattle, sheep, goat, deer, bison, rabbit, and domestic cat origin were found to be contaminated by BVDV using immunohistochemical and polymerase chain reaction procedures (Bolin et al., 1994). This study not only points out the abil-