Date of Award

Spring 5-2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

Committee Chair

Fengwei Bai

Committee Chair Department

Biological Sciences

Committee Member 2

Glenmore Shearer Jr.

Committee Member 2 Department

Biological Sciences

Committee Member 3

Mohamed O. Elasri

Committee Member 3 Department

Biological Sciences

Committee Member 4

Yanlin Guo

Committee Member 4 Department

Biological Sciences

Committee Member 5

Faqing Huang

Committee Member 5 Department

Chemistry and Biochemistry

Abstract

West Nile virus (WNV) is a positive-sensed, single-stranded RNA flavivirus that can cause human neuroinvasive diseases, including encephalitis, meningitis, and flaccid paralysis. The mechanisms by which WNV enters the central nervous system and the host-factors that are involved in WNV-neuroinvasiveness are not completely understood. Osteopontin (OPN), a multifunctional glycoprotein, has been implicated as a bio-marker for a number of neuroinflammatory diseases. In particular, secreted (s)OPN has been implicated to participate in recruitment of polymorphonuclear neutrophils (PMN) to sites of its expression, while PMNs have been suggested to act as WNV reservoirs. Therefore, sOPN recruitment of PMNs may contribute to neuroinvasive WNV infection via the ‘Trojan horse’ mechanism of viral entry into the brain. Therefore, we hypothesize brain-infiltration of PMNs during neuroinvasive WNV pathogenesis is in part mediated by sOPN. Our results show that sOPN expression was significantly increased in human sera, human neuronal cells line, murine plasma, brain homogenates and primary neuronal supernatant following WNV infection, indicating a role for OPN in WNV pathogenesis. In addition, after challenge with WNV in vivo, Opn-/- mice exhibited a higher (70%) survival rate than wild-type (WT) mice (30%). Consistent with this, qPCR analysis between WT and Opn-/- mice demonstrated comparable levels of viremia; yet, reduced viral burden in the brains of Opn-/-mice compared to WT controls. Analysis of brain-

infiltrating leukocytes displayed reduced PMNs and PMN-chemokine expression levels in Opn-/- mice brains. Importantly, intracerebral supplement of recombinant OPN (rOPN) into Opn-/-mice resulted in increased PMN-brain infiltration, increased viral load and reduced overall survival. Together, these data suggest OPN facilitates WNV neuroinvasion in a mouse model.

ORCID ID

0000-0002-1657-3618

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