Date of Award:

5-2026

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Animal, Dairy, and Veterinary Sciences

Committee Chair(s)

Brett L. Hurst (committee chair), E. Bart Tarbet (committee co-chair)

Committee

Brett L. Hurst

Committee

E. Bart Tarbet

Committee

Arnaud J. Van Wettere

Committee

Young-Min Lee

Committee

Brain B. Gowen

Abstract

Echoviruses are RNA viruses belonging to the enterovirus group, which includes common human viruses such as enterovirus A71, enterovirus D68, and coxsackieviruses. Several strains of echovirus circulate regularly among the general population, but infection typically results in asymptomatic to mild disease. Severe disease from echovirus infections is primarily observed in neonates and can result in acute hepatitis, aseptic meningitis, sepsis, and death. 

Our goal is to develop an animal infection model for echoviruses 11 and 30 that replicates the signs of severe disease seen in neonatal humans. Such a model would provide a tool to evaluate the efficacy of potential antiviral therapies against severe echovirus disease. Infection of Tg32-IFNAR mice with echovirus 11 Gregory/1954 at an infectious dose of 1 x 107.0 50% cell culture infectious doses (CCID50) per mouse resulted in 100% mortality and clinical signs of disease, including profound lethargy, tremors, and abnormal gait. Viral replication was observed in multiple tissues, with particularly high virus titers in the liver. Serum alanine aminotransferase (ALT) concentrations were significantly elevated, indicating liver damage. Histologic evaluation of liver tissues revealed severe hepatic necrosis by day 3 post-infection. 

Our next goal was to determine if a similar disease could be observed in Tg32-IFNAR mice with more recent echovirus isolates, echovirus 11 USA/2018-23090 and echovirus 30 USA/2002-10127. Infection with these isolates resulted in high morbidity and mortality, increased ALT concentrations, and severe hepatic necrosis. Interestingly, these more recent strains caused severe disease at a lower infectious dose of 1 x 102.5 CCID50 per mouse. Finally, we demonstrated that treatment with the antiviral compound 4’-fluorouridine (4’-FIU) significantly protected mice from mortality caused by echovirus 11 Gregory/1954 (100% survival), echovirus 11 USA/2018-23090 (80% survival), and echovirus 30 USA/2002-10127 (80% survival). 

In summary, we established that isolates of both echoviruses 11 and 30 cause severe disease in Tg32-IFNAR mice. The disease observed in infected mice replicates key clinical features of neonatal echovirus infections, including hepatic damage and increased ALT. We also demonstrated that historical isolates of echoviruses 11 and 30 are significantly less virulent than more recent isolates.

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