Elucidation of host-pathogen interaction is essential for developing effective strategies to combat bacterial infection. Dual RNA-Seq using cultured cells or tissues/organs as the pathogen host has emerged as a novel strategy to understand the response concurrently from both pathogen and host at cellular level. However, bacterial infection mostly causes systematic responses from the host at organism level where the interplay is urgently to be understood but inevitably being neglected by the current practice. Here, we developed an approach that simultaneously monitor the genome-wide infection-linked transcriptional alterations in both pathogenic Vibrio parahaemolyticus and the infection host nematode Caenorhabditis elegans. Besides the dynamic alterations in both transcriptomes of C. elegans and V. parahaemolyticus during infection, we identify a two-component system, BarA/UvrY, that are essential for host colonization. BarA/UvrY not only controls the virulence factors in V. parahaemolyticus including Type III and Type VI secretion systems, but also represses the MAP kinase mediated signaling cascades to attenuate innate immune responses. Thus, our study exemplifies the use of dual RNA-Seq at organism level to uncover previously unrecognized interplay between host and pathogen. Overall design: Investagation of cross-talk between host and pathogen