Two consecutive central prolines of an internal fusion peptide of mouse hepatitis virus serves a pivotal role in axonal transport

Rout, Saurav Saswat (2019) Two consecutive central prolines of an internal fusion peptide of mouse hepatitis virus serves a pivotal role in axonal transport. Masters thesis, Indian Institute of Science Education and Research Kolkata.

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Abstract

Mouse hepatitis virus (MHV) infection in mice causes meningoencephalitis and myelitis with subsequent axonal loss and demyelination which mimics certain pathological feature of human neurological disease multiple sclerosis (MS). MHV induced neuro-inflammation can follow “inside-out” mechanism, where pathology initiates within axons and leads to damage to its outer myelin covering. Previous study with RSA59 (PP) and RSMHV2 (P) demonstrated that spike (S) protein (host attachment protein) is one of the major genomic determinants of pathogenic properties and viral spread from brain to the spinal cord as well as from grey to white matter and causes white matter myelin loss and axonal degeneration. Fusion peptide (FP) in S is key player that mediate intercellular viral spread. The proline residue often present in the FP of viruses like Ebola virus, vesicular stomatitis virus and hepatitis C virus has alluded its importance by mutational studies. To find out the role of two consecutive central proline in fusion peptide in S of MHV, two recombinant strains RSA59 (P) and RSMHV2 (PP) were generated using site-directed mutagenesis. Our recent study has shown that this central proline mutation in FP plays a unique role in anterograde axonal transport from the brain to spinal cord, and the spread may be anterograde or retrograde depending on which track the virus is following. In our previous study, demyelinating strain RSA59 (PP) of MHV induces optic neuritis, but whether it is due to retrograde axonal transport or the traumatic injury due to disruption of retinal ganglionic cell axon during intracranial inoculation is not known. Using this two proline mutated recombinant strains of MHV we examined the importance of two consecutive central prolines in spreading to optic nerve via retrograde axonal transport. Recombinant strains carrying two prolines were able to travel from the site of inoculation to retina in the acute stage (day 3 and 6 p.i.) of inoculation, and induced demyelination in the optic nerve during the chronic phase (day 30 p.i.) of infection. However, recombinant strains carrying single proline were unable to transport to the retina and showed little or no demyelination in optic nerve. Thus, these data indicate that two central prolines are an essential feature of the fusion peptide of MHV for retrograde axonal transport to the eye and targeting fusion peptide interaction with axonal transport machinery is a potent therapeutic for CNS viral infections and associated diseases.

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