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Radiofrequency telemetry and immunologic correlates as predictors of acute inhalational alphavirus infection in a nonhuman primate model

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 (Unpublished)

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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:
CreatorsEmailPitt UsernameORCID
Ma, Henryhem53@pitt.eduhem53
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee MemberAyyavoo, Velpandivelpandi@pitt.edu
Committee ChairHartman, Amyhartman2@pitt.edu
Committee MemberKlimstra, Williamklimstra@pitt.edu
Thesis AdvisorReed, Douglasdsreed@pitt.edu
Committee MemberTeichert, Tobiasteichert@pitt.edu
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: Graduate 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: 31 Jul 2020 03:11
URI: http://d-scholarship.pitt.edu/id/eprint/39346

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