Doctoral Dissertation Defense

About this event

Melika Akaberi, Pharm D, a PhD Candidate and Post-Doc in Dr. Schulte's Lab will present her doctoral dissertation defense titled:

Molecular Mechanism of Symptomatic Rabies

Presentation Abstract: Rabies causes profound neurological dysfunction, and it is 100% fatal once symptoms appear. The rabies virus glycoprotein (RABV-G), best known for mediating viral attachment and membrane fusion, has also been proposed to interact with neuronal nicotinic acetylcholine receptors (nAChRs). This study investigated whether recombinant RABV-G directly modulates α4β2 and α7 nAChRs and whether these effects can be pharmacologically modified. Recombinant RABV-G ectodomains were expressed and purified in mammalian cells and characterized biochemically. Receptor function was evaluated using two-electrode voltage-clamp electrophysiology in Xenopus laevis oocytes, while receptor binding was examined by surface plasmon resonance (SPR) using acetylcholine-binding protein (AChBP) as a soluble receptor model. RABV-G produced concentration-dependent modulation of both α4β2 and α7 nAChRs at physiological pH, whereas these effects were largely lost at acidic pH, demonstrating dependence on glycoprotein conformation. Sequence variation within the proposed receptor-interacting region altered the direction of receptor modulation. An engineered, well-behaved RABV-G variant retained receptor-binding and functional activity while exhibiting improved biochemical properties and increased apparent affinity for AChBP compared with wild-type protein. Finally, the α7-selective positive allosteric modulator PNU-120596 and α4β2-selective modulator dFBr altered RABV-G-associated binding and functional responses. Together, these findings support a model in which RABV-G functions not only as a viral attachment and fusion protein but also as a direct modulator of neuronal receptor activity. Pharmacological modification of these effects provides proof of concept for targeting host-receptor dysfunction as a complementary strategy for understanding and potentially mitigating symptomatic rabies.

From Cummings School of Veterinary Medicine