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Defining the Role of Alpha-Macroglobulins in the Pathogenesis of Flavivirus Encephalitis.

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Title:Defining the Role of Alpha-Macroglobulins in the Pathogenesis of Flavivirus Encephalitis.
Authors:Krause, Keeton K.
Contributors:Biomedical Sciences (Tropical Medicine) (department)
Date Issued:May 2018
Publisher:University of Hawaiʻi at Mānoa
Abstract:West Nile Virus (WNV) and Japanese Encephalitis Virus (JEV) are positive sense, singlestranded
RNA viruses belonging to the family Flaviviridae, where the primary mode of
transmission occurs through arthropod vectors such as mosquitos. WNV and JEV are the leading
etiological agents for arboviral encephalitis in humans, and sporadic outbreaks continue to occur
over time resulting in symptomatic infections that account for thousands of deaths each year.
Although a number of vaccines have been developed to prevent JEV infections in highly
endemic regions, issues with efficacy exist and the vaccine often fails to protect at risk
populations from the development of encephalitis, which can be fatal. For both WNV and JEV,
no clinically approved therapies currently exist for treatment of the central nervous system
(CNS) involvement, which can lead to encephalitis, the most severe, and highly fatal form of the
disease. Alpha-macroglobulins, which are physiological proteinase inhibitors have been shown
to bind to viral proteins and enhance viral infections in vitro. Moreover, in humans alphamacroglobulins
such as pregnancy zone protein (PZP) and alpha-2-macroglobulin (A2M) also
serve as immune-modulatory proteins where their normal functions within the body include
binding and shuttling of protease inhibitors, growth factors, cytokines, hormones, disease factors,
and various small molecule nucleophilic ligands. Previous reports from our laboratory have
shown the up-regulation of alpha-macroglobulins in wild type (WT) mice after a lethal
subcutaneous WNV infection. Therefore, to define the role of a-macroglobulins during
flavivirus infection in vivo, we investigated the susceptibility of mice deficient in amacroglobulins
(PZP and MUG-1 double knockout; DKO) against lethal subcutaneous infection
with either WNV or JEV. Results of our study show that DKO mice are completely resilient to
lethal flaviviral infections of WNV and JEV. Likewise, DKO mice had a significantly milder
clinical disease through the course of the study, and this outcome can be coupled with the finding
of significantly reduced viral burden in the blood, peripheral organs (kidney and spleen), and
brains of the DKO mice when compared to WT mice. The DKO mice had a significantly reduced
inflammatory response which was characterized by lower concentrations of pro-inflammatory
cytokines and chemokines in the blood, spleen, and brain of DKO mice when compared to WT.
Consistent with the multiplex immunoassay data, DKO mice also displayed a significantly
decreased level of mRNA corresponding to immune genes in response to WNV infection when
compared to WT. Overall, the data from this study demonstrates the significant impact that
alpha-macroglobulins have in the pathogenesis of flavivirus-associated encephalitis in mice.
Description:M.S. Thesis. University of Hawaiʻi at Mānoa 2018.
URI:http://hdl.handle.net/10125/62211
Rights:All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
Appears in Collections: M.S. - Biomedical Sciences (Tropical Medicine)


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