Bovine Viral Diarrhea: Aetiology, Clinical forms and Immunosuppressive potential of the causative agent

Pashu Sandesh, 14 feb 2023

Dr Ragini Mishra¹ and Dr Sonam Bhardwaj²

Bovine Viral Diarrhea (BVD) virus is a member of the genus Pestivirus and the family Flaviviridae. There are two recognized species of BVDV (1 and 2). BVDV infects mainly cattle by producing a perse range of clinical outcomes from asymptomatic, or a transient mild disease, to severe cases of acute disease leading to death. BVDV infections are most common in cattle but can occur in a wide variety of domesticated and wild ruminants including white-tail and mule deer, bison, elk, and sheep. In addition to acute infections, BVDV strains may establish a persistent infection which is because of exposure in utero to a noncytopathic BVDV. Persistently infected animals that become superinfected with cytopathic BVDV may develop the mucosal disease (MD), a more severe form of BVD. The BVDV replicates in the mucosal epithelium and associated lymphoid tissues, followed by viremia and then subsequent viral replication in different organ systems throughout the body. With more virulent strains, infections can be associated with a wide range of clinical signs including fever, diarrhoea, as well as respiratory and reproductive dysfunctions. The latter is because of the immunosuppressive effect of BVDV and secondary infections rather than the virus itself.

The bovine viral diarrhoea virus leads to increased susceptibility to secondary infections because of its ability to cause immunosuppression. Some pathogens induce disease alone, but in the presence of BVDV, the effect of the disease is enhanced. There are multifactorial mechanisms responsible for BVDV-induced immunosuppression; however, the ability of the virus to induce quantitative and qualitative defects in leukocytes provides the largest contribution. Transient leukopenia occurs in most cattle acutely infected with BVDV, which may be more severe with BVDV 2 as compared to the BVDV 1 strains. In general, highly virulent strains of BVDV induce more significant depressions in the white blood cell count than less virulent strains.

During acute infection lymphoid depletion is observed in the thymus, spleen, lymph nodes, and gut-associated lymphoid tissues (Peyer’s patches). Decreased functional responses in immune system cells have also been observed during acute BVDV infection, and affected cells include lymphocytes, neutrophils, monocytes, and macrophages. BVDV infection is important in polymicrobial disease, and the bovine respiratory disease complex in feedlot animals and intensively housed calves is the best example of this disease process. The role of BVDV in the bovine respiratory disease complex is debatable as to whether BVDV-induced immunosuppression or primary infection of the respiratory tract plays a major role, but BVDV is isolated from pneumonic cattle more frequently than other viruses. BVDV may play a secondary role in the bovine respiratory disease complex through immunosuppression. 

The BVD virus interacts with its host either transiently or persistently. The transient infection stimulates an antiviral immune reaction similar to that seen in other transient viral infections. In contrast, being associated with immunotolerance specific for the infecting BVD viral strain, the persistent infection differs fundamentally from other persistent infections like those caused by lentiviruses. Whereas the latter is characterized by complex viral evasion of the host's adaptive immune response by mechanisms such as antigenic drift and interference with the presentation of T cell epitopes, the BVD virus avoids the immune response altogether by inducing both humoral and cellular immune tolerance. This is made possible by the invasion of the fetus at an early stage of development.

BVD virus also manipulates key elements of the host's innate immune response in addition to adaptive immunity. The non-cytopathic biotype of the BVD virus, which persistently infects its host, fails to induce type I interferon. Also, persistently infected cells are resistant to the induction of apoptosis by double-stranded RNA. They do not produce interferon when treated with this pathogen-associated molecular pattern (PAMP) that signals a viral infection. Moreover, when treated with interferon, cells persistently infected with non-cytopathic BVD virus do not clear the virus. However, despite this lack of effect on persistent infection, interferon readily induces an antiviral state in these cells, as shown by the protection against infection by unrelated viruses.

Overall, the BVD virus manipulates the host's interferon defence in a manner that optimises its chances of maintaining the persistent infection and decreases the risks that heterologous viral infections may carry for the host. Thus, since not all potential host cells are infected in animals persistently infected with the BVD virus, heterologous viruses replicating in cells uninfected with the BVD virus will still trigger the production of interferon. Interferon produced by such cells will curtail the replication of heterologous viruses only, be that in cells already infected with BVD virus, or in cells in which the heterologous virus may replicate alone. From an evolutionary viewpoint, this strategy clearly enhances the chances of transmission of the BVD virus to new hosts, as it attenuates the negative effects that global immunosuppression would have on the survival of persistently infected animals.

Dr Ragini Mishra¹ (PhD Scholar- Division of Veterinary Microbiology, ICAR-IVRI, Izatnagar-243122, Bareilly)

Dr Sonam Bhardwaj² (PhD Scholar- Division of Livestock Production and Management, ICAR-IVRI, Izatnagar-243122, Bareilly)