The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons
This week we profile a recent publication in Immunity from Dr. Andrew Oberst (pictured, above)
and Dr. Brian Daniels (pictured, below) at the University of Washington.
Can you provide a brief overview of your lab’s current research focus?
My lab has been focused on programmed cell death, and on how the immune system reacts to dying cells. Much of that effort has focused on non-apoptotic forms of cell death, such as necroptosis and pyroptosis. These cell death programs are triggered by infection or stress, and are generally considered inflammatory and immunogenic. This is in contrast to apoptosis, which is a form of cell death that occurs during normal development and tissue homeostasis, and is generally immunologically silent, or even immunosuppressive. This broad focus has led us in a number of different directions, including efforts to induce immunogenic death of tumor cells as well as studies of cell death as a host response to infection.
What is the significance of the findings in this publication?
In this paper, we identify an unexpected effect of the “necroptotic” cell death pathway in neurons infected with neurotropic flaviviruses: we find that this pathway remodels neuronal metabolism to limit viral replication. Our study focused on Zika virus, as well as the related pathogen West Nile virus; both of these infect humans, and neuroinvasive infection with these viruses can cause serious complications or even death. We previously found that in neurons, activation of the necroptotic machinery (the sensor ZBP1, and the kinases RIPK1 and RIPK3) did not cause cell death, but rather drove a transcriptional response; this was an unexpected and unexplored function of this pathway (see Daniels, B.P., et al., Cell 2017).
In the current study, we identify a role for this pathway in cell-intrinsic viral restriction in neurons. That is, activation of the “necroptotic” pathway limits the number of viral particles shed from infected neurons. Interestingly, the mechanism of this restriction is related to a change in neuronal metabolism. RIPK activation upregulates and enzyme called IRG1, which produces a metabolite called itaconate. This inhibits neuronal metabolism, and unexpectedly this inhibition blocks viral replication. What’s significant about this is that it identifies metabolic changes as an innate immune response. That is, neurons actually alter their metabolism “on purpose” to reduce viral replication, and we think this allows the host immune system to “get ahead” of the replicating virus.
What are the next steps for this research?
An interesting open question is exactly how altered neuronal metabolism blocks viral replication. We suspect that it may be related to the fact that the same nucleotide triphosphate molecules that our cells use to generate energy are used as building blocks for the viral genome. Reduction in the energetic metabolism of the host cells could thereby starve a replicating virus of the material it needs to copy itself.
Another interesting question is how this metabolic shift in response to infection affects neuronal function long-term. These infections cause long-term sequelae even after they’re cleared, such as memory loss and problems with motor function. We’re interested in understanding whether the metabolic changes induced by viral infection contribute to these issues.
This research was funded by:
I’m funded by the NIH, with grants from NIAID, NINDS and NCI. I’m also a Cancer Research Institute Wade F.B. Thompson Scholar.