New Wellcome Trust Award

Host Mitochondria dysfunction by viral hijacking as a key pathogenicity mechanism in COVID-19
 
Project team: PI: Prof Kostas Tokatlidis IMCSB, Co-I: Prof Carl Goodyear (III), Dr Malcolm Watson (NHS/GGC), Dr Malcom Sim (NHS/GGC), Dr Ian SALT (ICAMS)
 
Summary: The exact mechanisms of pathogenicity underlying COVID-19 are still unknown. However, in severe cases, patients present with increased levels of lactate and profound hypoxia and multiple organ failure. Furthermore, recent studies have shown that SARS-Cov-2 does not induce an appropriate anti-viral/Interferon response. Notably, the ability to control hypoxia and cytokine/chemokine responses is heavily dependent on mitochondrial-driven metabolism. These observations suggest a dysregulated mitochondrial state. Importantly, several SARS-COV-2 viral proteins (e.g. Orf9b) interact with mitochondrial proteins (e.g. mitochondria antiviral signalling protein (MAVS), and have the potential to fundamentally affect mitochondria biogenesis, dynamics and oxidative metabolism. In support of this concept, viral proteins from several viruses (influenza and other corona viruses) are known to exert these deleterious effects. It is therefore essential that the impact of these viral protein-mitochondrial interactions are investigated, as they have the potential to drive key pathogenic mechanisms during infection. In this project we aim to dissect this pathogenic mechanism induced by hijacking of host cell mitochondria by the virus. We will elucidate mitochondria dysfunctions using primary patient cells (adipocytes and monocytes) or transfection of viral proteins in cell culture. We will evaluate mitochondrial defects in biogenesis, protein expression/assembly, dynamics, OXPHOS and ROS. In a second, parallel, approach we will use our expertise on isolated mitochondria and purified proteins to reconstitute the interactions between the viral and mitochondrial proteins to gain an in-depth understanding of the interactions. The elucidation of this pathogenic mechanism has the potential to lead to new therapeutic approaches targeting the translocation of the viral proteins to mitochondria and mitigation of the bioenergetic defects to redress the energy crisis of the host cells upon infection.

First published: 21 July 2020

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