Identification of conserved amino acid substitutions during serial infection of pregnant cattle and sheep with bovine viral diarrhea virus

Authors: KUCA, THIBAUD - Auburn University; PASSLER, THOMAS - Auburn University; NEWCOMER, BENJAMIN - Auburn University; Neill, John; GALIK, PATRICIA - Auburn University; RIDDELL, KAY - Auburn University; ZHANG, YIJING - Auburn University; WALZ, PAUL - Auburn University

Submitted to: Frontiers in Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/9/2018
Publication Date: 6/6/2018
Citation: Kuca, T., Passler, T., Newcomer, B.W., Neill, J.D., Galik, P., Riddell, K.P., Zhang, Y., Walz, P.H. 2018. Identification of conserved amino acid substitutions during serial infection of pregnant cattle and sheep with bovine viral diarrhea virus. Frontiers in Microbiology. 9:1109. https://doi.org/10.3389/fmicb.2018.01109.
DOI: https://doi.org/10.3389/fmicb.2018.01109

Interpretive Summary: Bovine viral diarrhea virus (BVDV) is a ubiquitous pathogen of cattle, causing disease that ranges from subclinical to severe acute hemorrhagic syndrome. BVDV is most commonly isolated from cattle but can also cause disease in and be isolated from sheep, goats, deer, camelids and pigs. BVDV exist in two forms, cytopathic and noncytopathic. When a susceptible animal is infected with a noncytopathic BVDV strain in the first trimester of pregnancy, the fetus can become persistently-infected, and following birth, spread the virus for the remainder of its life. The BVDV RNA genome encodes a single large protein. This protein is processed to produce the final viral proteins. BVDV is also known for rapid rate of genetic change. More changes are introduced into the genomic RNA during infections of pregnant animals. The enzyme responsible for copying the RNA genomes of these viruses is known to introduce errors at a relatively high rate during the infection process. Many of the changes are found in the virus envelope proteins that can resist previous immunity. Changes have also been noted that appear to make it possible for BVDV to more efficiently infect species other than cattle. This study was conducted to examine the changes that occur in the genomic RNA of BVDV that caused sequential infections in pregnant cattle and sheep. The goal was to define changes that occurred in BVDV that may be involved in changing immune characteristics as well as changes that may enhance infection in species other than cattle. Sequence analysis of the viruses isolated from infected animals revealed that more changes occurred following infections of sheep than cattle. This was most likely due to adaptation to the new host. After several sequential infections, the number of changes was reduced. These experiments have provided insight into how BVDV adapts to new host and may indicate the source of greatest change.

Technical Abstract: Bovine viral diarrhea virus (BVDV) is an economically important pathogen of cattle that can also infect a wide range of domestic and wild species including sheep, goats, deer, camelids, and pigs. BVDV isolates are genetically highly diverse and previous work demonstrated that greater numbers of genetic changes occurred during acute infections of pregnant cattle than of non-pregnant cattle. However, only limited information exists regarding changes during BVDV infections in species other than cattle. The purpose of this study was to determine the changes introduced in the open reading frame (ORF) of the BVDV genome during serial infection of pregnant cattle and sheep. Serial experimental inoculations were performed in six pregnant heifers and six pregnant ewes using BVDV-1b isolate AU526 in the first heifer and ewe, and serum from the preceding acutely infected dam thereafter. Complete ORF sequences were determined for 23 BVDV-1b isolates including AU526, one isolate from each pregnant dam, and one isolate from each VI-positive offspring born to these dams. Sequence comparison revealed that greater numbers of substitutions were introduced during serial infection of pregnant sheep than of pregnant cattle. Furthermore, multiple amino acid changes were gradually introduced and conserved in both species. These host-specific changes occurred primarily in the E2 coding region and were more abundant in ovine isolates, and thus may be involved in host adaptation. These results suggest that BVDV infections in heterologous hosts may serve as a significant source of viral genetic diversity and may be associated with adaptive changes.