PEER REVIEWED Role of Bovine Viral Diarrhea Virus in the Bovine I Respiratory Disease Complex Daniel L. Grooms, DVM, PhD Michigan State University Department of Large Animal Clinical Sciences East Lansing, Michigan, USA 48824-1314 6 7 Introduction NS3 which is unique to CP-BVDV. • The major neutralizing epitopes of BVDV are Bovine viral diarrhea virus (BVDV) is one of the found in the glycoprotein E2.8 Not surprisingly, most important infectious agents of cattle. The annual analysis of this area has identified regions in which economic loss caused by BVDV is difficult to quantify nucleotide and amino acid sequences vary significantly but certainly is significant. The insidious nature of between different BVDV isolates.9 These differences BVDV combined with the biology of the virus and help to explain the wide antigenic diversity of BVDV. complex disease pathogenesis has made control and Recently, BVDV isolates have been divided into prevention of this virus challenging. two genotypes, identified-as Type I and Type II BVDV.10 BVDV has been associated with many clinical This classification is based on significant nucleotide diseases.1 There is little doubt that BVDV plays a role sequence differences in the 5' noncoding region of the in bovine respiratory disease (BRD). The exact nature viral genome. Correlated with this are different and the significance of this role is not understood and at reactivity patterns to panels of monoclonal antibodies times is controversial. This review will attempt to directed against the E2 protein, suggesting significant present past and current information on the role that antigenic variation. In addition, type II BVDV has been BVDV plays in BRD. associated with outbreaks of disease which are characterized by higher morbidity and mortality.11 The Agent Clinical Disease BVDV is a member of the genus Pestivirus within the family Flaviviridae.2 Other members of the Acute Infection: The outcome of acute infection is pestivirus genus include hog cholera virus of swine and dependent on several factors, including the health and border disease virus of sheep. Prototypes of other immune status of the host and the virus strain. In genera in the flaviviridae family include hepatitis C susceptible cattle, the majority of acute infections are virus and yellow fever virus. subclinical. Mild disease, often referred to as bovine BVDV is a small enveloped virus which contains a viral diarrhea (BVD), may be characterized by diarrhea, single strand of positive sense RNA as its genomic fever, anorexia, leukopenia and production loss (milk or material. The RNA is translated in the cytoplasm of body condition).1 Peracute/acute forms of BVD have host cells into a single polyprotein which is then been described in the United Kingdom, Canada and the processed into mature viral proteins. This results in the United States in which mortality rates were as high as production of 4 structural and o or 7 nonstructural 20%. 11-13 Mortality rates from BVDV outbreaks among proteins.3 veal calves in Quebec was 22% in 1993, a four fold Cytopathic (CP) and noncytopathic (NCP) biotypes of increase from normal losses.11 Type II BVDV has been BVDV are recognized based on their ability to cause­ associated with these outbreaks in the United States. 4 5 cytopathology in cell culture. • Several types of mutational Acute BVDV infection has also been reported to cause a events within specific regions of the BVDV genome have hemorrhagic syndrome characterized by thrombocy­ been described which result in the production of the protein topenia with resulting petechial and ecchymotic MAY, 1998 7 hemorrhages, bloody diarrhea and epistaxis. 14 Only junctions are evident. These cattle may survive for as type II BVDV isolates have been identified in long as 18 months. Recently, delayed-onset mucosal association with hemorrhagic syndrome. disease has been described. This is thought to involve genetic recombination between the persistent NCP­ Reproductive Outcomes: BVDV has been associ­ BVDV and an externally-introduced, heterologous CP­ ated with a variety of events leading to reproductive BVDV such as of vaccine origin. In this case, mucosal wastage which may represent the largest economic loss disease may take up to 4 weeks to occur following associated with BVDV infection.15 Infection of exposure to the CP-BVDV. Persistently infected cattle susceptible cows around the time of breeding can result exposed to heterologous CP-BVDV can also mount an in reduced conception rates by mechanisms that are not immune response to the CP-BVDV and clear the virus yet understood. Infection during early gestation can with no significant clinical outcome. lead to early embryonic death manifested by reduced pregnancy rates or return to estrus. Transplacental Role in Bovine Respiratory Disease infection can result in fetal death at any stage of gestation although this occurs most commonly during Bovine respiratory disease is the most frequent the first 4 months. Fetal infection before 125 days of cause of morbidity and mortality in North American gestation with NCP-BVDV may result m feedlots and is the major cause of economic loss.17 It is immunotolerance to the virus. Immunotolerance generally agreed that Pasturella haemolytica is the results in the birth of calves persistently infected (PI) major contributor to pneumonic lesions.18 Considerable with BVDV. Fetal infection has also been associated research has focused on the mechanisms by which P. with a variety of congenital defects which are dependent haemolytica colonizes the lungs. Many predisposing on the time of virus exposure and the stage of factors have been implicated in reducing the local organogenesis. Some of the more common defects clearance mechanisms of the lungs including stress include cerebellar hypoplasia, cataracts, and growth from weaning, transportation, mixing of cattle, retardation. Transplacental infection late in gestation handling, and processing. Viruses, including parainflu­ most often results in the birth of normal calves which enza-3, bovine respiratory syncytial virus, bovine are seropositive to BVDV. BVDV has been associated herpes virus-1, coro:µavirus, and BVDV, have been with both late term abortions and weak calf syndrome, implicated as predisposing causes of BRD. although numerous other causes of these conditions BVDV has been implicated in bovine respiratory have been identified. disease since it was first described by Olafson, MacCallum and Fox in 1946.19 Although not conclusive, Mucosa! Disease: Classic mucosal disease is a rare, both circumstantial and experimental evidence suggest highly fatal manifestation of BVDV which is that BVDV is involved in BRD.20 characterized by extensive mucosal ulceration of the entire gastrointestinal tract and severe lymphoid Clinical: Circumstantial evidence that BVDV is depletion. Mucosal disease occurs when cattle involved in BRD comes from clinical pathological persistently infected with BVDV become superinfected observation. As mentioned earlier, clinical descriptions with CP-BVDV. 16 The most common source of CP­ of cattle undergoing acute BVDV infection often involve BVDV is believed to be from specific mutations of the respiratory signs. In Sweden, severe respiratory persistently infecting NCP-BVDV. External sources of disease outbreaks were described involving both BVDV CP-BVDV include live vaccines, acutely infected cattle and Pl-3.21 In the United States, BVDV has been and other cattle with mucosal disease. The outcome of reported as the most commonly isolated virus from superinfection with CP-BVDV is largely dependent on pneumonic lungs 22 and in outbreaks of BRD.23 the antigenic homology between the two biotypes. Experimental studies attempting to reproduce Identical homology, as would be expected following a respiratory disease with BVDV alone have resulted in mutational event of the persistent NCP-BVDV, results mild lesions. In studies by Potgeiter et al., calves in acute mucosal disease with death usually occurring infected with BVDV alone had less severe clinical signs in less than 1 week from onset of clinical signs. Chronic and pulmonary pathology when compared to calves 24 25 mucosal disease is believed to occur when the NCP and infected with both BVDV and P. haemolytica , (Table CP viral pairs are not completely homologous as might 1). Synergistic effects between BVDV and P. 24 26 27 34 be expected following postvaccinal mucosal disease. haemolytica , BHV-1 and BRSV • have been Cattle with chronic mucosal disease exhibit weight loss, documented. Differences in pneumopathogenicity have unthriftiness, persistent nasal and ocular discharge been demonstrated for isolates of BVDV25 (Table 1). and intermittent to chronic diarrhea. Chronic erosive These findings suggest an immunocompromising role lesions of mucosal surfaces and mucocutaneous for BVDV in bovine respiratory disease. 8 THE BOVINE PRACTITIONER-NO. 32.2 Table 1. Experimental production of respiratory Table 3. Association between initial titer and tract disease in calves with BVDV and P. seroconversion to putative respiratory haemolytica (Adapted from: Potgeiter et al., disease agents (Adapted from: Martin SW et Am J Vet Res 1984;45;1582-1585 and Am J al., Can J Vet Res 1989;53:355-362). Vet Res 1985;46:151-153) Odds Ratioa Treatment Clinical Scorea Lung Pathologyh Agent Initial Titer Seroconversion BVDV 72c (3) 1.0 2.0 Phh 1.89 1.08 BVDV 72 (2) 1.75 4.5 Ph-cytoxc 0.71 1.97 BVDV 2724d (2) 1.0 1.5 Pl3 0.42 1.54 Phd (2) 1.0 14.5 BHVl 1.25 1.57 Ph (2) 1.0 15.0 BRSV 0.42 1.36 Ph & BVDV 72 (5) 7 .5 56.0 BVDV 0.63 1.49 Ph & BVDV 72 (3) 7. 58.0 a Risk of developing respiratory disease given either an Ph & BVDV 2724 (2) 2. 75 30.0 initial titer or seroconversion to a specific agent. a 0=No signs, l0=Severe signs.(#)= Number tested h Ph = Pasturella haemolytica h Percent of lung affected. cPh-cytox = P.haemolytica cytotoxin c BVDV strain 72 - cytopathic biotype a BVDV strain 2724 - noncytopathic biotype importance of colostral antibodies, a protective effect d Ph = Pasturella haemolytica against respiratory disease has been shown in calves being born to BVDV seropositive dams.