Degree Type

Dissertation

Date of Award

2006

Degree Name

Doctor of Philosophy

Department

Veterinary Microbiology and Preventive Medicine

First Advisor

Randy E. Sacco

Second Advisor

Michael J. Wannemuehler

Abstract

Respiratory syncytial virus is the most prominent viral pathogen in infants and children causing severe lower respiratory tract infections and pneumonia. To date, there are no vaccines available and the immune response mounted to virus is ineffective due to recurrent infections throughout childhood. There is a need for neonatal models of natural infection with RSV and the data reported in this dissertation is derived from a neonatal lamb model of bovine respiratory syncytial virus (BRSV) infection. Given the central importance of antigen presenting cells (APCs) in the initiation of the host immune response, these studies described here examined modulation of lung APCs by BRSV. Tissue derived dendritic cells (DCs) and monocyte derived DCs (MDDCs) from neonatal lambs were first characterized and found to be similar in phenotype and function to their counterparts in other species. However, there were striking differences phenotypically and functionally between the tissue derived DCs and MDDCs. Secondly, neonatal lambs were inoculated with BRSV and lung DCs isolated after infection. Interestingly, BRSV was found to replicate within lung DCs and alveolar macrophages (AMs), inducing a mixed cytokine response. Of note was a 10 to 15-fold increase in IL-4 transcribed in both lung DCs and AMs. BRSV induced a high expression level of CD 14 on lung DCs during first few days of infection. Overall, lung DCs can be infected by BRSV and surface antigen expression and tracer uptake abilities were initially decreased compared to DCs from control lambs. Thirdly, quantitative differences in cytokine gene expression were seen between AMs infected with BRSV in vitro and AMs isolated from BRSV infected lambs. Neonatal AMs infected with BRSV in vitro produced different amounts of inflammatory cytokines when compared to TLR3, TLR4, or inactivated BRSV stimulation. In general, these studies show that BRSV infects both neonatal lung DCs and AMs in vivo, inducing a mixed cytokine and chemokine response. The virus has an effect on neonatal AM cytokine production in vitro and induces lower levels of gene transcription than known TLR3 and TLR4 agonists. Taken together, these studies provide information on the effects of BRSV infection in neonatal lamb APCs.

DOI

https://doi.org/10.31274/rtd-180813-12232

Publisher

Digital Repository @ Iowa State University, http://lib.dr.iastate.edu

Copyright Owner

Sasha Jean Fach

Language

en

Proquest ID

AAI3229069

File Format

application/pdf

File Size

136 pages

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