Degree Type

Dissertation

Date of Award

2019

Degree Name

Doctor of Philosophy

Department

Veterinary Pathology

First Advisor

Mark R. Ackermann

Second Advisor

Jodi D. Smith

Abstract

Respiratory Syncytial Virus (RSV)is one of the most common causes of acute lower respiratory tract infection in humans that can cause severe infections in infants and the elderly. It is estimated that annually 33 million lower respiratory tract infections in children were associated with RSV worldwide. However, in the US alone there were 75000-125,000 hospitalizations due to RSV in infants per year. Although most RSV infections of the lower respiratory tract are caused by RSV alone, occasionally, secondary bacterial infection further increases lung damage and disease severity. Despite the widespread infections by RSV throughout the world, till now there are no approved vaccines or therapeutic compounds to treat RSV infection other than Ribavirin and prophylactic administration of Palivizumab. There are several animal models of RSV infection, but neonatal lambs infected with RSV have several advantages for modeling RSV infection in infants such as similarity in pulmonary architecture, immune response, and respiratory tract size, viral replication, and lesion development.

To further extend the neonatal lamb model to evaluate secondary bacterial infection associated with RSV, lambs coinfected with RSV and Streptococcus pneumoniae were used to determine feasibility, susceptibility and disease development. Lambs developed severe disease when coinfected with both microorganisms with more severe suppurative bronchitis and pneumonia. Streptococcus pneumonia infection enhanced the severity of RSV in lambs when lambs were coinfected with both microorganisms.

To evaluate the efficacy of some antiviral compounds, two antiviral compounds efficacy were tested in the neonatal lamb model of RSV infection. First, three regimens of JNJ-49214698, a small molecule RSV fusion protein inhibitor were tested (prophylactic, early treatment, late treatment). JNJ-49214698 prevented RSV infection when given before infection and reduced RSV induced lung lesion when used to treated established infection. Additionally, late treatment at day 3 post RSV infection had a wide window for RSV treatment. Secondly, 3 doses of RSV-NFI, an RSV non-fusion inhibitor were tested for efficacy. RSV-NFI was well tolerated and reduced RSV induced lung lesions and viral titer.

Copyright Owner

SarhadAlnajjar

Language

en

File Format

application/pdf

File Size

140 pages

Available for download on Tuesday, March 31, 2020

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