Principal Investigator: Daniela Ribeiro
Reference: PTDC/BIA-CEL/31378/2017, POCI-01-0145-FEDER-031378
Funding Entity: Portuguese Foundation for Science and Technology (FCT): under the scope of the Operational Program “Competitiveness and internationalization”, in its FEDER/FNR component.
Total funding: € 239 939.40
Funding for iBiMED: € 239 939.40
Description:
Society is exposed to a constant threat posed by viral pathogens. Viral infections are the main cause of epidemics and pandemic diseases, with strong consequences on life quality and economy. Most of the existing prophylactics or therapeutics are specifically developed for each virus or strain, being prone to resistance upon mutation and not directly applicable for emerging or engineered viral hazards. Hence, there is a clear need to develop broad-spectrum antiviral strategies by investigating universal mechanisms adopted by different viruses e.g. throughout their life-cycle or host-cell infection, that may expose common targets for antiviral therapy.
The main objective of this project is to study the peroxisome-dependent cellular mechanisms of infection and antiviral innate immunity that are common to different viruses of high medical and economical relevance. As crucial subcellular compartments, peroxisomes are highly dynamic and able to adapt their number, morphology and metabolism to changes in the cellular environment. To clarify the role of peroxisomes on the cellular antiviral signalling, the effect of several viruses on peroxisome morphology, proliferation and metabolism will be analysed and interpreted in detail. We will also identify the exact steps of the viral infection cycle that trigger the peroxisome- or mitochondria-dependent signalling events as well as the event that triggers the switch between these two pathways. We furthermore aim at unravelling the different steps of the peroxisome-dependent antiviral signalling cascade. We have recently demonstrated that the human cytomegalovirus protein vMia localizes at peroxisomes where it interacts with the mitochondrial antiviral signalling protein (MAVS) and inhibits the peroxisome-dependent antiviral signalling pathway. Our results showed that peroxisomes suffer fragmentation upon viral infection but, importantly, that this morphology change is not essential for the vMia inhibition of the downstream signalling from MAVS. In this project we will deepen our studies by investigating in more detail the mechanisms involved on the vMia-induced peroxisome fragmentation and vMia-induced inhibition of the peroxisome-dependent antiviral signalling. Our results may contribute to the discovery or novel cellular targets that can be explored by the pharmaceutical industry, leading not only to the discovery of specific viral combat strategies but also to the potential development of broad-spectrum antiviral therapeutics.
Selected publications: