Research Projects

The periodical emergence of highly pathogenic human Coronaviruses has been sustainably posing heavy burden and threat to humans. In light of the COVID-19 pandemic caused by the β-coronavirus SARS-CoV-2, research efforts have been directed towards developing therapeutics to control the virus spread. Given the limitations of working with infectious human coronaviruses like limited access to BSL-3 facilities, the mouse hepatitis virus (MHV), which is a fellow β-coronavirus (CoV) is being used to gain insights into the human CoV pathology. A recent study from the PI’s laboratory has uncovered the therapeutic potential of a host gap junction protein connexin 43 (Cx43) against a fellow β-CoV, MHV-A59. The study highlighted the importance of Cx43 expression at the cell surface, to reduce MHV infectivity and spread. Studies from the PI’s laboratory have shown that Cx43 trafficking and expression is altered upon MHV-A59 infection. The mechanisms involving altered trafficking are well studied by the PI’s lab and with this proposal we aim to investigate the mechanism behind altered Cx43 expression. The MHV-A59-induced disease is a well-established model for viral-induced demyelination which mimics pathological hallmarks of human neurological disease Multiple Sclerosis. Intracranial inoculation of MHV-A59 in mice causes a biphasic disease characterised by acute neuro-inflammation which peaks at Day 5 post infection (p.i) and chronic neuroinflammatory demyelination which peaks at Day 30 p.i. Previous studies from the lab have shown downregulation of Cx43 expression in the brain at Day 5 p.i. Interestingly, this downregulation of Cx43 expression coincides with the peak of acute neuroinflammation. As the acute neuroinflammation resolves, the Cx43 expression returns to its normal basal levels. Whether a mechanistic link exists between neuroinflammation and alteration of Cx43 expression remains to be elucidated. In this proposal we will explore the regulation of Cx43 expression by the balance between the pro-inflammatory (TNF-α) and anti-inflammatory (TGF-β1 and IL-10) taking the advantage of our established MHV induced model which shows distinct acute-innate, innate-adaptive bridging, and chronic-adaptive stages of inflammation at different time points .The preliminary findings, supported by previously published literature from other international and national research groups have led us to TNFα-TGFβ1 and IL-10 signalling traid being important for regulating Cx43 expression in vivo. Our objective is to further dissect the downstream signalling of TNFα-TGFβ1 and IL-10 in controlling Cx43 expression. Finally, we aim to modulate these cytokines or their downstream pathways to develop a cytokine-based therapy to stabilise Cx43 expression in the CNS which may be implicated in reduced acute stage β-CoV infectivity and spread as well as reduction in chronic stage demyelination.