Dissertation
Neuropathogenesis of the acute phase response to influenza virus in mice
Washington State University
Doctor of Philosophy (PhD), Washington State University
08/2008
DOI:
https://doi.org/10.7273/000005604
Abstract
Influenza virus infection causes severe systemic clinical signs in infected mice. Non-neurotropic human strains of influenza virus are believed to be confined to the respiratory tract following intranasal (IN) infection. Characteristic symptoms of influenza infection include changes in body temperature, locomotor activity and sleep patterns. These symptoms are part of the acute phase response (APR), or flu syndrome. Such symptoms are in part regulated by cytokines such as tumor necrosis factor alpha (TNF[alpha]) and interleukin 1 beta (IL1[beta]). However, it remains to be established whether the cytokines that act on the brain to induce the APR are produced in the brain or if they are made systemically and then reach the brain through the blood or other routes. To better understand the pathophysiology of the APR, we have characterized the presence of extrapulmonary virus in the brain and its effect on cytokine up-regulation. Furthermore, we characterized the role of the olfactory pathway in the ontogenesis of the APR after intranasal inoculation with influenza virus. We used for all our experiments a human mouse adapted strain of influenza virus named PR8. Virus was found in the mouse olfactory bulb (OB) as early as 4 h post-challenge where the virus appeared to go into partial replication. The virus co-localized in microglia and astrocytes but not in neurons. An increase in TNF[alpha], IL1[beta] and interferon-induced enzymes was also observed in the OB after viral challenge. Cytokines were produced by microglia, astrocytes and neurons in the OB. Surgical transection of the olfactory nerve (ONT) prior to the viral challenge delayed the virus-induced hypothermia. Additionally, the number of viral antigen-, TNF[alpha]? and IL1[beta]? immunoreactive (IR) cells was reduced in the OBs of mice that received the ONT. We also examined brain regions that have direct and indirect connections with the OB. No viral antigen-IR was observed in any of these regions; however, an increase in the number of TNF[alpha]? and IL1[beta]? IR cells was observed in selected regions along the olfactory pathway. Taken together, these data elucidate in part some of the possible mechanisms involved in the ontogenesis of the influenza-induced APR in infected mice.
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Details
- Title
- Neuropathogenesis of the acute phase response to influenza virus in mice
- Creators
- Victor Hugo Leyva-Grado
- Contributors
- James M. Krueger (Chair)Lynn Churchill (Committee Member) - Washington State University, Department of Integrative Physiology and NeuroscienceMary Sanchez-Lanier (Committee Member)Joseph W Harding (Committee Member) - Washington State University, Department of Integrative Physiology and Neuroscience
- Awarding Institution
- Washington State University
- Academic Unit
- College of Veterinary Medicine
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 194
- Identifiers
- 99901054535001842
- Language
- English
- Resource Type
- Dissertation