A3: Posttranslational protein modifications as Achilles’ heel of pathogenic RNA viruses

Project description

Due to their small genome, viruses are highly dependent on functions of the host organism. Many of those functions are regulated by cell-encoded posttranslational protein modifications for which a substantial number of pharmaceutical inhibitors are available.

Rift Valley Fever Virus (RVFV) is a mosquito-borne zoonotic pathogen endemic in parts of Africa. In large and devastating outbreaks, it typically kills thousands of farm animals and hundreds of humans. In the preceding funding period, we used a high-throughput genetic screen and identified a pro-viral host cell factor for RVFV that binds to posttranslational protein modifications. Inhibition of this factor in a human organoid model reduced viral RNA synthesis and progeny particle production. In addition, proteomic analyses showed that a viral protein is modified is a manner that the host cell factor can bind, and mutation of the relevant site led to a reduction of viral RNA synthesis.

Scientific goal:

We aim to elucidate the molecular mechanism and exploit it to specifically inhibit RVFV infection. Moreover, we will test available pharmaceutical inhibitors, and also screen for other pathogenic RNA viruses that may depend on this mechanism.

DRUID Collaboration partners:

A1 Becker, A2 Grünweller, B2 Ziebuhr, C1 Bender/Hildt, D1 Friebertshäuser/Steinmetzer, E3 Rahlfs/ Przyborski, E4 Spengler, E6 Schiffmann, E7P Krijnse Locker

References A3: 1. Wuerth & Weber (2016) Viruses 8, 174*. 2. Barr, Weber, Schmaljohn (2020) Fields Virology, vol 1, p 706-749*