Professor Jason Mackenzie is renowned for his multi-disciplinary research on virus replication, particularly through his expertise in electron microscopy. His work has advanced understanding of flavivirus and norovirus replication, revealing the 3D structure of the flavivirus replication complex and identifying the first tissue system for studying norovirus. He has also explored the roles of cellular organelles and the cytoskeleton in these processes, collaborating widely on these efforts both nationally and internationally.
Join Jason at FHMRI’s Inspiring Leaders Seminar Series on Wednesday 30 October 2024.
What inspired your career focus on virus replication, and how have your research approaches evolved over time?
This was quite serendipitous actually as I was watching a video about medical research over the summer before university and went “I want to do that”. The video was about Louis Pasteur and then the more I learnt about Virology the more I loved it. I had never done Biology in high school and I thought Biology is so cool but Virology is totally amazing and viruses are awesome! Research approaches have remained fairly steady with looking at intracellular replication. I guess things just get more and more detailed the more you know but also we have had to move into preventatives and therapeutics due to funding constraints and opportunities
How has your expertise in electron microscopy advanced your understanding of virus replication and the development of antiviral strategies?
Enormously! The most amazing thing about EM is the ability to actually visualise what is happening inside cells during infection. Every cell is slightly different so it is your interpretation to understand what is going on and to design experiments and questions that can relate to what you are seeing. It is quite incredible to be able to comprehend aspects of cell biology and cell function and then throw in virus infection. Viruses are incredible cell biologists so it is fabulous to “see” biology as it happens. Interpreting what you are seeing also enables you to understand aspects of how the virus is manipulating the cell, utilising key components or inducing specific cellular responses (eg. Autophagy etc) so you can explore potential interventions to reduce the impact of infection and see the results.
What are some of the most significant breakthroughs from combining molecular, biochemical, and immunological approaches in your research?
The key observations were the localisation and function of viral proteins during replication and the key viral “organelles” utilised during this process. Folks has observed many of the ultrastructural changes in intracellular membranes but had no idea what they were for or doing for the virus. We advanced this with cryo-sectioning and immunogold labelling with specific antibodies. And subsequently extended this using cryo-electron tomography to visualise the viral replication complex in 3D. I think also visualising virus assembly and maturation was an important observation. The identification for the role of cellular lipids played a big part in our research program and showing how viruses redistribute lipids (cholesterol, phospholipids, ceramide) to establish replicative organelles but additionally disable innate immune activation pathways was a very key, interesting and exciting breakthrough.
What role do you see for electron microscopy in the future of virology, particularly in studying emerging viral threats?
There is definitely a role here, particularly with the significant advancements in cryo-EM but also in observing and understanding intracellular virus replication. Virus particle structures don’t change a lot within families so gaining good structural insight into virus particles and viral proteins can help a lot with therapeutic or preventative development. This goes hand-in-hand with knowing how a virus replicates in cells and what it does to the cellular organelles or pathways and processes. Does it induce autophagy or apoptosis on increased lipid droplets? Having this knowledge can highlight and indicate intervention strategies.
How has your international recognition in virology shaped collaborative efforts in studying global viral outbreaks?
I would have to say that it probably hasn’t helped studying global viral outbreaks at this point but it has provided me with some fabulous international collaborations which have shaped my career. First and foremost was the opportunity to gain an Alexander von Humboldt Fellowship to study at the EMBL, Heidelberg, Germany. That was an amazing experience and I got to work with a fabulous mentor who I stay in touch with now. The other opportunity was working on norovirus which happened from a conversation at a meeting when the virus was discovered and I went to the researchers and said “Hey I look at how viruses replicate in cells, do you want me to look at yours?”. The rest is history and some great colleagues around the world now in this space but also still with flaviviruses and looking at other viruses such as SARS-CoV-1 before it was cool