| This project investigates the hypothesis that part of the neurotrophic effect of Herpes virus1
(HSV1) may be linked to an interaction of herpes virus 1 glycoprotein D (HSV1 gD) with
nicotinic acetylcholine receptors (nAChRs). nAChRs are ligand-gated ion channel receptors
important in both the central and peripheral nervous systems. Viruses like rabies virus and
SARS-CoV-2 have been shown to interact with nAChRs, potentially through similarities in
structure to the LY6 family of proteins, a similarity shared with alpha bungarotoxin (𝞪-Bgtx).
HSV1 gD is a key glycoprotein that interacts with host receptors. We have found that the HSV1
gD structure contains a loop region similar to a three-fingered toxin (3FTx) loop in 𝞪-Bgtx loop
2. An In-silico structural homology search using the known alpha7 receptor antagonist, 𝞪-Bgtx
identified structural homology between HSV1 gD and 𝞪-Bgtx, a homology shared with other
LY6 proteins. Some sequence homology was present but was limited. We conducted a Surface
Plasmon Resonance (SPR) binding study of HSV1 gD to test its ability to bind acetylcholine
binding protein (AChBP) using the whole ectodomain and fragments of HSV1 gD that included
the homologous loop region. We also conducted functional studies to determine the effect of
HSV1 gD on alpha7 nAChRs expressed in Xenopus oocytes using two-electrode voltage clamp
(TEVC) electrophysiology. We found that the whole ectodomain of HSV1 gD, as well as the
small Ly6 homologous loop region, binds and inhibits α7 and α4β2 nAChRs functions. This
confirms that the neurotoxin-like loop region of HSVgD is capable of interacting with nAChRs.
Molecular docking studies were also conducted that indicate a possible binding site for HSV1 gD
near the critical C and F loops of the nAChRs at a location similar to 𝞪-Bgtx. Structural
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homology studies also identified similar regions in other neurotropic viruses which suggests that
this binding region may be a common motif in neurotropic viruses.
Keywords: Neurotropic virus, Rabies, Herpes virus, HSV1 gD, nAChRs, Encephalitis,
Bungarotoxin, Ly6 protein, 3FTx protein, structure homology, Electrophysiology. |