Virus entry into cells: host protein networks guiding virus infection and how we can block them
Viruses need to enter host cells to replicate, spread and cause disease. During this entry process, viruses hijack cellular protein interaction networks. Viruses bind to attachment factors and receptors on the cell surface and use entry cofactors to trigger a coordinated and productive uptake into cells.
It is of clinical relevance to understand the molecular details of virus entry, since these host entry factors can be targeted with drugs. In particular protein interactions specifically induced and/or used by viruses are attractive drug targets. Importantly, such host targeting agents have the big advantage of being refractory to the development of drug resistance mutations.
Studying virus entry is furthermore significant, as host entry factors can determine, which tissues in the human body and/or which species a specific virus can infect. It can thus help understand the diseases caused by viruses and the potential risk of zoonotic infections, i.e. the spread of viruses from animals to humans.
Our research aims at elucidating the protein networks operating during the entry of mosquito-transmitted viruses of the Flaviviridae and Togaviridae families including Chikungunya virus and Zika virus. Viruses of these two families can cause pathologies ranging from arthritis to encephalitis and microcephaly. While some of the viruses under investigation are well adapted to the human host, others are not. Our goal is to identify host factors for virus entry and to investigate if these host factors are causative for tissue and species tropism.
The methods we apply are state of the art quantitative proteomics in conjunction with RNA interference, CRISPR/Cas9 knockout techniques, pharmacological perturbation and in vitro infection assays. We have developed affinity enrichment mass spectrometry methods, which allow us to monitor snapshots of protein networks engaged during virus entry. This is the basis of our follow up work using tissue culture infection assays with virus isolates and reporter strains as well as in vivo work in mice and mosquitoes.
Our work is highly collaborative with tight connections to world-leading national and international experts in arbovirus biology, mouse and mosquito work, as well as high resolution mass spectrometry. The current projects are funded by the Knut and Alice Wallenberg foundation and Umeå university. Please also visit the website of our second branch in Germany (www.twincore.de/en/gerold), with which we work closely together, and our joint Twitter account (https://twitter.com/GeroldLab).