Many fundamental biological discoveries have been made in <em abp="1258">C. elegans</em>. The discovery of Orsay virus has enabled studies of host-virus interactions in this model organism. To identify host factors critical for virus infection, we designed a forward genetic screen that utilizes a virally induced GFP reporter. Following chemical mutagenesis, two <em abp="1259">viro</em> (virus induced reporter off) mutants that failed to express GFP were mapped to <em abp="1260">
sid-3</em>, a non-receptor tyrosine kinase, and <em abp="1261">B0280.13</em>, an orthologue of human WASP (Wiskott-Aldrich Syndrome Protein). Both mutants yielded 5-6 logs lower Orsay RNA levels than the parent strain, which approximates residual input Orsay levels, demonstrating the essential roles of these genes. However, Orsay virus replication initiated from an endogenous transgene bypasses the requirements for both SID-3 and B0280.13 suggesting that these two genes function at an early step in the virus lifecycle. Strikingly, the human ortholog of SID-3, activated CDC42 associated kinase (ACK1/TNK2), is capable of phosphorylating human WASP, suggesting that B0280.13 may be a substrate for SID-3 in <em abp="1262">C. elegans</em>. In support of this model, fluorescently tagged SID-3 and B0280.13 co-localized to the apical membrane of C. elegans intestinal cells. Further genetic ablation of TNK2 through CRISPR-Cas9 in two human cell lines, A549 (an adenocarcinomic human alveolar basal epithelial cell line) and Hap1 (a near haploid human cell line derived from myeloid leukemia patients), showed reduced infection by polio virus. Thus, an unbiased genetic screen in <em abp="1263">C. elegans</em> identified critical roles in virus infection for evolutionarily conserved genes in a known human pathway.