Investigating Molecular Mediators of Neurotropic Flavivirus Infection

Author

Kehinde Damilare Fasae, University of Tennessee, KnoxvilleFollow

Date of Award

8-2025

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Hameeda Sultana

Committee Members

Brian Whitlock, Timothy Sparer, Talisha Moore

Abstract

Although often overlooked, almost everyone has been bitten by a mosquito, tick, or flea. These are causative agents of vector-borne diseases (VBDs). VBDs are currently a significant public health concern, causing several human illnesses and deaths yearly. Neurotropic flaviviruses, transmitted by mosquitoes or ticks, cause severe neurological illness and diseases in millions of individuals, leaving patients with permanent neurological damage. Although some vaccines are now available, the molecular mediators and mechanisms of viral transmission are not fully characterized. There is also a lack of antivirals to combat these infections. This work investigates molecular mediators of neurotropic flavivirus infection, demonstrating the role of extracellular vesicles (EVs) in viral infection spread or restriction and cellular factors that affect viral load.

First, we demonstrated that exosome-mediated infection can be hampered by altering their physicochemical stability. Reduced viral loads were observed in naïve recipient cells infected with infectious exosomes exposed to slightly high temperatures, sulphate salts, and alkaline pHs. In the second chapter, we showed that Zika Virus (ZIKV) infects neuronal cells differently, accompanied by distinct antiviral responses. With the quantification of EV-mediated infections in recipient cells being more robust than direct viral infection, this study also implies that ZIKV load increases within cells via exosomes, which bypass traditional plasma membrane receptors. The third study demonstrated the viral restricting effects of mesenchymal stem cell-derived EVs (MSC-EVs) in ZIKV-infected neurons. MSC-EVs promoted cell viability, reduced apoptotic gene expression, attenuated inflammatory mediators, induced interferon response, and reduced viral loads. Our findings suggest MSC-EVs as practical paracrine effectors that can limit neurotropic viral replication in the brain.

Finally, we showed that Myelin transcription factor 1 Like (MYT1L), a neuronal transcription factor involved in differentiation and maturation, supports Langat Virus (LGTV) persistence within neurons. Its expression increases upon viral infection, and its depletion in cells or haploinsufficiency in mice keeps the virus low. Since aberrations in MYT1L result in autism spectrum disorders, this study indicates the possible involvement of LGTV in neurodevelopmental disorders.

Overall, this work identifies molecular mediators of viral-induced neurological diseases, which, when manipulated or targeted, can limit viral infection in the brain, preventing neurological manifestations.

Recommended Citation

Fasae, Kehinde Damilare, "Investigating Molecular Mediators of Neurotropic Flavivirus Infection. " PhD diss., University of Tennessee, 2025.
https://trace.tennessee.edu/utk_graddiss/12703