Virus entry and innate immune signaling during RNA virus infections.

Invading pathogens are recognized by genetically encoded sensors that trigger innate immune responses. Surprisingly, the molecular details of innate viral sensing are poorly understood.

While many studies focus on transcriptional or post-transcriptional changes upon infection, I propose a fundamentally different approach: I will use cellular thermal shift assays to identify and study proteins involved in sensing viruses. I will compare how different pathogenic RNA viruses are recognized by different pattern recognition receptors.

This approach will allow, for the first time, to resolve the molecular events in a temporal manner.

A better understanding of the fundamental concepts of innate antiviral immunity will contribute to better treat viral and associated autoimmune diseases and guide the development of vaccines and antivirals.In a parallel project, I will make use of camelid-derived nanobodies to probe and neutralize the surface glycoproteins of henipaviruses, which cause respiratory illness and encephalitis with fatality rates of 50-100%.

I will define vulnerable parts of the glycoproteins and probe their function during virus attachment and fusion. This will directly yield nanobodies with potential for passive immunization, therapeutic applications, or diagnostics.

In addition, it will increase our understanding of the henipavirus cell entry, help to understand naturally occurring variants, define (new) vulnerable epitopes, and has implications for vaccine design.