An emerging pathotype of Aeromonas hydrophila (vAh) has been responsible for widespread farm losses in the US catfish industry over the last decade. While our genetic and biochemical understanding of vAh has been greatly enhanced in this time frame, our ability to reliably induce the disease in the laboratory has remained limited. Taking cues from observed farm conditions associated with outbreaks, here we perturbed iron scavenging dynamics and catfish feeding status. Addition of a xenosiderophore, deferoxamine mesylate (DFO), to vAh cultures prior to immersion challenge significantly increased virulence in several vAh isolates but not in a non-epidemic strain. DFO addition did not impact vAh growth dynamics or perturb iron-sensitive gene pathways, but did significantly enhance hemolysis of catfish blood. Furthermore, hours between last feeding and immersion challenge (postprandial status), was observed to be a critical determinant of catfish susceptibility. Fish with a full gastrointestinal tract had significantly lower survival than those in a fasted state, and this effect was cumulative with that of DFO-enhanced vAh virulence. Taken together, our results not only provide a more robust challenge model, they offer actionable insights into pond level host-pathogen-environmental interactions potentially underlying vAh pathogenesis. Utilizing these more robust challenge models, we are currently examining the practical efficacy of varying protective strategies for the industry including diet modification, vaccination, genetic selection, and modulation of the pond environment. Our latest results in this vein will also be presented.