Ma, Henry
(2020)
Radiofrequency telemetry and immunologic correlates as predictors of acute inhalational alphavirus infection in a nonhuman primate model.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Eastern and Venezuelan Equine Encephalitis Virus (EEEV/VEEV) are two neurotropic alphaviruses that can produce acute febrile encephalitis in humans. Though rare, encephalitis caused by either EEEV or VEEV can produce long-term neurological sequelae. The need for development of medical countermeasures (MCM) to prevent EEEV/VEEV encephalitis remains imperative in the face of decades of research to develop VEEV as biological weapons. To this day, no licensed vaccines nor therapeutics exist to prevent or treat EEEV or VEEV encephalitis.
EEEV and some VEEV strains remain registered as Select Agents, and MCM development against EEEV/VEEV must occur in animal models that capture key aspects of human disease pursuant to the US FDA Animal Rule. Infection of cynomolgus macaques (Macaca fascicularis) by aerosol reproduces febrile encephalitis, neurological disease, and brain lesions seen in human infection. However, in macaques, encephalitic disease remains poorly characterized by quantitative measures. Improvements in tracking of encephalitis through traditional physiological biomarkers can also expand the data derived from the infected animals. The monitoring of electrical activity in the brain through electroencephalography (EEG) or intracranial pressure (ICP) can provide a more exacting estimate of when encephalitic disease begins and ends.
This study investigates a telemetered cynomolgus macaque model of aerosol-induced equine encephalitis virus infection with a focus on the natural history of disease and to assess the feasibility of the use of such data to delineate the onset and resolution of encephalitis. Macaques infected with EEEV aerosols became febrile three days post infection, and were euthanized at humane study endpoint at 5-6 days post-challenge. EEEV-infected animals demonstrated increases in delta EEG and increased ICP concurrent with fever. VEEV-infected macaques exhibited no fatal illness; all subjects survived the aerosol challenge and displayed characteristic biphasic febrile illnesses that self-resolved. In VEEV disease, macaques experienced a global decrease in EEG power and increased ICP in the second febrile period.
The public health significance of these findings lies within the improved ability to detect the onset and resolution of encephalitic alphavirus disease for the evaluation of MCM efficacy. These methods can aid evaluation of vaccines and therapeutics against other emerging infections.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
30 July 2020 |
| Date Type: |
Publication |
| Defense Date: |
1 June 2020 |
| Approval Date: |
30 July 2020 |
| Submission Date: |
10 July 2020 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
238 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Alphavirus, Aerosol, Radiofrequency Telemetry, Electroencephalography, EEG, Equine Encephalitis Virus, EEEV, ICP, intracranial pressure, VEEV |
| Date Deposited: |
31 Jul 2020 03:11 |
| Last Modified: |
01 Jul 2022 05:16 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39346 |
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