We present data derived from studies on purified trout and chicken erythrocytes demonstrating that nucleated erythrocytes express a remarkable array of mRNAs in response to different pathogen associated molecular patterns (PAMPs) including pathogen recognition receptors (PRRs), and that PAMPs drive significant transcriptomic remodelling in these cells. RNA-Seq studies highlight a PAMP-specific induced shift in the global trout erythrocyte (tEC) transcript profile and uncovered diverse cohorts of mRNAs related to multiple physiological systems including the endocrine, reproductive and immune systems. Further characterization of erythrocyte responses show a leukocyte-like activation profile and post-transcriptional regulation of induced mRNAs. Conditioned media obtained from poly (I:C) activated tECs contain bioactive, temperature-labile, molecules that modulate the trout macrophage anti-viral response suggesting a functional role for the erythrocyte in the anti-viral immune response in fish. We propose that non-mammalian nucleated erythrocytes play an active role within the immune response and likely contribute to the resolution of infectious states. Our results suggest that there should be a revision in considering the functional organization of the non-mammalian vertebrate immune system. Further, in light of the observed annotated mRNA diversity, we postulate a novel integrative role for the erythrocyte in vertebrate physiology.