C. elegans is a powerful model organism for probing many biological processes including host-pathogen interactions. In this project, we defined the transcriptional response of C. elegans and C. briggsae to viral infection by RNA-seq. These studies identified specific responses in each host as well as a core of 59 C. elegans differentially expressed genes whose orthologs were also differentially expressed in C. briggsae infected by Santeuil virus, thereby defining an evolutionarily conserved response to virus infection. Strikingly a subset of these genes were also transcriptionally induced by the microsporidia N. parisii, another intestinal pathogen of C. elegans. Thus, this studies defines a “pan-microbial” transcriptional response to pathogen infection in C. elegans.