Abstract a) Background Tenacibaculum maritimum is a fish pathogen known for causing serious damage to a broad range of wild and farmed marine fish populations worldwide. The recently sequenced genome of T. maritimum strain NCIMB 2154 T provided unprecedented information on the possible molecular mechanisms involved in the virulence of this species. However, little is known about the dynamic of infection in vivo, and information is lacking on both the intrinsic host response (gene expression) and its associated microbiome community. Here, we applied complementary omic approaches, including dual RNAseq and 16S rRNA gene metabarcoding sequencing using Nanopore and short-read Illumina technologies to unravel the host–pathogen interplay in an experimental infection system using the tropical fish Platax orbicularis as model. b) Results We showed that the T. maritimum transcriptomic landscape during infection is characterised by an enhancement of antibiotic catalytic and glucan catalytic functions but a decrease in the sulfate assimilation process, compared with in vitro cultures. The fish host concurrently displays a large panel of immune effectors, notably involving innate response and triggering acute inflammatory response. In addition, our results suggest that fish activate an adaptive immune response visible through the stimulation of T-helper cells, Th17, with congruent reduction of Th2 and T-regulatory cells. Fish were, however, largely sensitive to infection, and less than 25% survived after 96 hpi. These surviving fish showed no evidence of stress (cortisol levels) or significant difference in microbiome diversity compared with controls at the same sampling time. The presence of Tenacibaculum in resistant fish skin and the total absence of any skin lesions suggest that these fish did not escape contact with the pathogen, but rather that they prevented pathogen entry. In these individuals, we detected up-regulation of specific immune-related genes differentiating resistant individuals from controls at 96 hpi, which suggests a possible genomic basis of resistance, although no genetic variation in coding regions were found. c) Conclusion Here we focus in detail on the interplay between common fish pathogens and host immune response during experimental infection. We further highlight key actors of defence response, pathogenicity and possible genomic bases of fish resistance to T. maritimum .