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Document Type

Dissertation - University Access Only

Award Date

2015

Degree Name

Doctor of Philosophy (PhD)

Department / School

Veterinary and Biomedical Sciences

First Advisor

Christopher Chase

Second Advisor

Feng Li

Abstract

Influenza viruses infect a diverse array of avian and mammalian species, including humans. The influenza B virus (IBV) and influenza C virus (ICV) genera of Orthomyxoviridae employ humans as their reservoir but are capable of infecting other species. These viruses are the product of multi-lineage evolution, the result of different lineages co-circulating in the population, and are thought to be close to evolutionary stasis. In 2011, a novel virus was isolated from nasal swabs of a pig showing influenzalike symptoms, denoted C/swine/Oklahoma/1334/2011 (C/OK). Electron microscopy revealed an Orthomyxoviridae morphology and subsequent genetic and biochemical assays identified it as an ICV-like virus. With approximately 50% overall sequence homology to human ICV strains, it was initially suggested that C/OK represented a new subtype of ICV. Additional viruses were isolated from cattle with respiratory symptoms and a serosurvey showed approximately 88% of herds were seropositive for this new virus. To further characterize these novel viruses, additional studies were performed and illustrate the uniqueness of these new viruses. Differences were found in the splicing mechanisms of the matrix segment from other genera of influenza, agar gel immunodiffusion showed no cross-reactivity among the other genera of influenza and C/OK antibodies, and human ICV and C/OK-like viruses were not able to generate viable progeny in an in vitro x reassortment experiment. The inability of C/OK-like viruses to reassort with human ICV, as well as lack of antibody cross-reactivity, has led to the proposal that C/OK and the subsequent bovine isolates are members of a new genus of influenza, influenzavirus D. Additional research has determined these proposed influenza D viruses (IDV) have a reservoir in bovines with a global distribution. Further analysis showed at least two genetic and antigenically distinct clades of IDV co-circulate in cattle. Genetic changes in the hemagglutinin-esterase fusion (HEF) surface glycoprotein could attribute to the antigenic differences between these lineages. IDV’s role in bovine respiratory disease has not been determined. Influenza A Virus (IAV) has a waterfowl reservoir, consists of multiple subtypes, and is capable of causing disease in many species. Utilizing reverse genetics, a chimeric virus consisting of seven segments of IAV (polymerase basic 1, polymerase basic 2, polymerase acidic, nucleoprotein, neuraminidase, matrix, and non-structural protein) and the eighth RNA segment encoding the IDV hemagglutinin-esterase fusion (HEF) surface glycoprotein was constructed. The same virus was also rescued with a mutation in the HEF cleavage site, altering it from a trypsin-sensitive motif to an elastase-sensitive motif, resulting in an attenuated virus unable to replicate in vivo. A vaccination/challenge study in pigs evaluated these two chimeric viruses as potential IAV vaccines. The HEF replication deficient vaccine was not shed in nasal swabs and the vaccinated pigs failed to seroconvert, as measured by hemagglutination inhibition (HI). Pigs vaccinated with the replicating chimera vaccine were able to clear the challenge virus from the lung by day 5 post challenge, as evident by an approximate 5 log10 TCID50/mL reduction in lung titer compared to controls. These animals did not have measurable HI or neuraminidase xi inhibition titers to the challenge strain and very low serum neutralization titers, however an increase in IgA ELISA values was observed in the bronchial alveolar lavage fluids to the challenge virus, correlating with viral clearance. Influenza viruses are significant viral pathogens in many species, with novel viruses still emerging. The discovery of IDV in bovines warrants additional research to determine what role it plays in bovine respiratory disease. Influenza continues to be an important pathogen in the swine industry. An IAV/IDV chimeric replicating vaccine offers new technology for swine influenza vaccines. Further research is needed to evaluate if IAV/IDV chimeric vaccines can circumvent maternally-derived antibody interference and the extent of cross-protection afforded to genetically divergent strains. Future research findings on the novel proposed influenzavirus D genera of influenza could impact both the swine and cattle industries.

Library of Congress Subject Headings

Influenza viruses
Sendai virus
Cattle--Virus diseases
Swine--Virus diseases

Description

Includes bibliographical references (pages 120-123)

Format

application/pdf

Number of Pages

144

Publisher

South Dakota State University

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Rights Statement

In Copyright