Bacteriophage-induced tolerant innate memory in macrophage altering host defense responses

The memory characteristics of innate immune responses has been major researched in trained immunity, while the properties and mechanistic advances for tolerant innate memory responses remain limited. Here, we demonstrated the process of diverse of animal phages induced protective state of refractoriness that regulate to subsequent inflammatory challenge referred to as tolerance immunity. We showed phages exposure in vivo render host tolerance defence via generating reprogrammed macrophages that provide significantly better protection against cytokines storm. The bacteriophages dsDNA triger macrophage activiation state, along with M1 like polarization and anti-microbial effector. By transcriptomic and epigenomic approaches, phages pre-activated macrophages upon secondary infections orchestrating gene expression in a gene-specific manner, inhibition of pro-inflammatory functional gene, while upregulation of anti-inflammatory cytokines and defence effector genes. Importantly, the defence genes dependent on IL-10. Together, our findings reveal the role of phages in the regulation of host defense and immune homeostasis.