Bovine viral diarrhoea and mucosal disease

Previous authors: L N D POTGIETER

Current authors:
E J DUBOVI - Professor of Virology, MS, PhD, Animal Health Diagnostic Center, 240 Farrier Road, Ithaca, New York, 14853, USA

GENERAL INTRODUCTION: FLAVIVIRIDAE

Introduction

Bovine viral diarrhoea (BVD) and mucosal disease (MD) are two of several disease syndromes in cattle caused by bovine viral diarrhoea virus (BVDV). The primary economic impact of BVDV is mainly at the level of the bovine embryo or foetus, resulting in embryonal/foetal death, teratogenesis, persistent infection or inapparent infection and post-natal poor performance. A late consequence of some foetal infections is the birth of calves with persistent infections that subsequently result in the development of MD, a severe form of BVD with an unusual aetiology. Primary post-natal infections in cattle usually result in a mild form of BVD characterized by inappetance, fever and leukopenia. However, instances of severe and sometimes fatal BVDV-induced disease of cattle showing fever, diarrhoea, respiratory disease and/or a generalized haemorrhagic syndrome have been reported. Several detailed reviews on various facets of the disease have been published.^{6, 17, 23, 113, 138, 178, 183, 210, 220}

Bovine viral diarrhoea was first described in 1946 in the USA by Olafson and co-workers.¹⁶³ The disease was characterized by abortions, fever, inappetance, diarrhoea, and ulceration of the gastrointestinal tract. Morbidity was high and the mortality in outbreaks was 4 to 8 per cent. A syndrome consistent with mucosal disease, initially referred to as ‘X disease’, was first recorded in Canada, also in 1946, by Childs.⁵⁸ Ramsey et al. coined the term ‘mucosal disease’ in 1953 based on their observations of the nature of the disease and lesions in  Iowa, USA.¹⁸⁶

Aetiology

Bovine viral diarrhoea virus is a member of the Pestivirus genus of the family Flaviviridae.¹⁴⁰ (See General Introduction: Flaviviridae). Currently, four species of pestiviruses are recognized by the International Committee on Taxonomy of Viruses; BVDV-1, BVDV-2, border disease virus and classical swine fever/hog cholera virus. (see Border disease and Classical swine fever) The number of species within the genus Pestivirus will certainly increase as “atypical” pestiviruses of swine and wild ungulates are formally classified.  A novel BVDV virus referred to as Hobi or BVDV-3 may generate a third species within the bovine pestivirus group.^{208, 210} Many different genotypes (subtypes) have been reported within the species, but their biological relevance has yet to be determined.

Bovine viral diarrhoea virions are spherical particles approximately 50 nm in diameter, with a tightly adherent envelope containing glycolipids.¹⁴⁰ The virions are difficult to detect by negative-stain electron microscopy, but roughly spherical particles with a 20 to 25 nm core are readily detectable in infected cells where the virus replicates entirely within the cytoplasm.¹⁰¹ Because the virus has a lipid-rich envelope, it is susceptible to most common disinfectants.¹⁴⁰

The BVDV genome consists of a single strand of RNA with positive polarity and contains one large open reading frame (ORF) that encodes a polyprotein of approximately 3900 amino acids (Figure 1). This open reading frame is preceded by a short untranslated region (UTR) that functions to initiate protein synthesis.¹⁷⁶ Protein maturation is the consequence of co-translational and post-translational cleavage of the polyprotein by viral and host cell proteases. Except for the first protein encoded by the BVDV genome (Npro — a viral protease), the structural proteins are encoded by the first third of the genome (5’ end), whereas the non-structural proteins are encoded by the last two-thirds of the genome.²²⁰

The structural proteins include the internal capsid protein (C) and the virion surface envelope proteins. Erns (or E0) is only loosely associated with the virion and has intrinsic RNase activity. This RNase activity was reported to inhibit interferon responses in infected cells.^{119, 144} E1 is a transmembrane glycoprotein that forms a dimer on the virion surface with glycoprotein E2 (Figure 1). The latter, the major virion glycoprotein, is the principal target of virus-neutralizing antibodies, is the receptor-binding protein of the virus, and determines host-range.

The non-structural (NS) proteins (p7, NS2-3, NS2, N3, NS4A, NS4B, NS5A, and NS5B) are not incorporated into mature virions and function in viral replication/RNA synthesis and viral morphogenesis.  NS5B is an RNA-dependent RNA polymerase, but replication of the RNA genome requires NS3-NS5B proteins acting in concert.  As seems the general rule with viral proteins, multiple functions are present within a single viral protein.  So, NS3 has a serine protease domain, helicase activity and NTPase activity.  In addition to enzymatic activities, NS3 either alone or in concert with uncleaved NS2-3 protein, is essential for viral morphogenesis. Npro as the first protein translated is an auto-protease that releases itself from the next protein in the ORF, capsid protein C.  Npro is not essential for virus replication in vitro, but it does have the ability to antagonize the induction of an IFN-1 response, albeit weakly.   In conjunction with Erns, Npro may play a role in suppressing the antiviral responses in infected animals.²²⁰

Figure 1 The structural...