Genome-wide CRISPR/Cas9 screen identifies MAT2A as a critical host factor for BK Polyomavirus

Abstract

BK polyomavirus (BKPyV) is a ubiquitous human pathogen that causes major complications for renal transplant patients (polyomavirus-associated nephropathy) and hematopoietic stem cell transplant patients (haemorrhagic cystitis). There are currently no effective antivirals available against BKPyV. As polyomaviruses are small DNA viruses that express very few proteins and utilise host DNA polymerases for their replication, there is limited possibility of targeting viral proteins for therapeutic intervention. As such, there is increasing interest in targeting host pathways to inhibit these viruses. To identify host genes required for BKPyV infection we have conducted the first genome-wide CRISPR/Cas9 screen in BKPyV infected cells. This led to the identification of methionine adenosyltransferase 2A (MAT2A), which we have validated as a host dependency factor for BKPyV infection. MAT2A is a druggable host enzyme that synthesises S-adenosylmethionine, the principal co-factor and methyl donor within cells. We have found that a small molecule inhibitor of MAT2A is a potent antiviral drug inhibiting BKPyV replication, offering a new therapeutic option for treatment of BKPyV diseases.