Degree Type

Dissertation

Date of Award

2012

Degree Name

Doctor of Philosophy

Department

Veterinary Pathology

First Advisor

Mark R Ackermann

Abstract

Respiratory syncytial virus (RSV) is the most frequent cause of bronchiolitis in infants and children worldwide. Many animal models including rodents and several other species have been utilized to study RSV, but most studies investigate disease in adult animals and fail to address the unique physiology and immunology that makes infants more susceptible to severe disease. Our group and others have used the perinatal lamb to model infant RSV disease as lambs have a similar pulmonary development and are susceptible to RSV. Lambs develop mild clinical symptoms including fever, tachypnea, and malaise as well as mild to moderate gross and histologic lesions when experimentally infected with bovine or human RSV; preterm lambs develop more severe disease with bRSV. The lamb model has a strong foundation and forms a valid model for moderate disease as evidenced by clinical alteration of respiration as well as gross and histologic lesions, but there is need for a model of more severe disease. Human RSV A2 strain replicates in lambs and causes disease but other strains may have enhanced virulence. Memphis 37 is an RSV-A strain isolated from a pediatric case and used in studies in human adult subjects.

The overarching goal of the studies undertaken was to develop a model of enhanced RSV that could be utilized for investigating the pathogenesis of enhanced disease as well as therapeutic regimens. The central hypothesis for these studies was that Memphis 37 causes moderate to severe disease in neonatal lambs as measured by alterations in respiration as well as gross and histologic lesions.

Memphis 37 (M37) strain hRSV caused moderate disease in perinatal lambs as measured by clinical disease (expiratory effort or tachypnea), post-mortem gross lesions, and histologic lesions with abundant RSV-antigen immunoreactivity as well as significant viral mRNA levels. Nebulized Memphis 37 hRSV caused similar disease in lambs to hRSV strain A2. Memphis 37 hRSV grown in HEp-2 cells induced increased expiratory effort and greater lesion scores (gross and histologically) as well as increased antigen immunoreactivity as compared to Vero-grown M37. Nebulization and intranasal inoculation are reproducible methods of inoculation that caused a unique distribution pattern of lesions when compared to each other or fiberoptic intrabronchial inoculation. In conclusion, Memphis 37 hRSV will cause disease in perinatal lambs and shows promise for use in a model of severe RSV disease.

Copyright Owner

Rachel Jean Derscheid

Language

en

Date Available

2012-10-31

File Format

application/pdf

File Size

108 pages

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