Towards reversing immune suppression in rabies virus infection

Project summary

Zoonotic viruses are animal viruses with the potential to cause severe, or even fatal, disease in humans. The most deadly zoonotic virus is rabies virus (RABV) yearly causing at least 60.000 deaths worldwide. Up to present it is not understood why an efficient immune response is not being mounted upon RABV infection whereas innate immune cells will be exposed to the virus at the site of infection.

The key objective of this research proposal will be to answer this question by identifying the mechanism by which RABV suppresses the immune response and to determine whether this immune suppression can be reversed. I hypothesize that RABV causes a direct inhibitory effect on innate immune cells at the site of infection, resulting in a suppressive effect on the adaptive humoral immunity. Our preliminary findings in human specimens and experimental infections have demonstrated a profound lack of B cell activation in both humans and animals and thus so far support my hypothesis.

The proposed study will focus on the three following research questions:
1) What are the dynamics of the adaptive immune response upon RABV infection?
2) How is the innate immune response affected by RABV infection? 3) Can early interference with the immune system induce an efficient immune response?

We will first structurally evaluate the adaptive immune response upon RABV by using a mouse model and will then focus on identifying the mechanisms behind the suppression.

The proposed study applies a One Health approach combining expertise from human and veterinary medicine and engages in collaborations with departments within Erasmus MC that bring in expertise on virology, immunology and neuro-anatomy. The outcome will offer leads for the  development of innovative intervention strategies against RABV.