Degree Type

Dissertation

Date of Award

2019

Degree Name

Doctor of Philosophy

Department

Veterinary Pathology

Major

Veterinary Pathology

First Advisor

Mark R. Ackermann

Second Advisor

Jesse M. Hostetter

Abstract

Human respiratory syncytial virus (hRSV) is a common cause of respiratory infection in human infants worldwide. Direct therapeutic methods for the prevention and treatment such as vaccination and antiviral therapy are limited. In studies within this dissertation, we determined the efficacy of orally administered small molecule fusion inhibitor and replication inhibitor in hRSV-infected neonatal lambs which model hRSV infection in infants. Furthermore, we evaluated the efficacy and treatment time window for administration of a combination treatment using both compounds. We determined that daily oral administration of small molecule fusion protein inhibitor (JNJ-53718678) and replication inhibitor (JNJ-64166037) first administered to hRSV-infected within 24 hpi, reduced the viral load and lung lesion in a dose-dependent manner. The combination treatment of both hRSV fusion inhibitor and replication inhibitor given at 24 hpi decreased the amount of virus and pulmonary lesion in a more profound manner than monotherapeutic administration of each compound. Interestingly, the delayed combination treatment starting at day 3 post infection demonstrated significant reduction of viral load and pulmonary lesion compared to monotherapy administered at similar time indicating a prolonged treatment time window. The small molecule inhibitor compounds used in this study are good therapeutic candidates for future tests in human clinical trials.

In addition, we were able to quantify and localize the hRSV viral RNA with RNA in situ hybridization in the infected lung tissue as well as effectively quantify the amount of RNA expression by modification of RNAscope H scoring evaluation method using an image analyzer software. A new approach for assessment of cytokine expression in lung of infected lambs was performed by creating a baseline of cytokine expression of Memphis 37 hRSV infected and non-infected lambs at 6 dpi through combining data from multiple lamb model studies.

Copyright Owner

Panchan Sitthicharoenchai

Language

en

File Format

application/pdf

File Size

158 pages

Available for download on Wednesday, March 24, 2021

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