Immunogenicity of bacteriophages

Phages are key modulators of bacterial interactions and ecosystems within microbiomes. Though phages do not infect human cells, they bear substantial similarities to eukaryotic viruses. Increasing evidence suggests that phages directly influence the physiology of host tissues and activate antiviral immune programs; thus, phages appear to share a double-edged sword relationship with their human host. Despite significant medical importance, the immunological influence of commensal and therapeutic phages on the human host remains sparsely understood. Hundreds of trillions of diverse bacteriophages (phages) peacefully thrive within and on the human body. However, whether and how phages influence their mammalian hosts is poorly understood. In this review, we explore current knowledge and present growing evidence that direct interactions between phages and mammalian cells often induce host inflammatory and antiviral immune responses. We show evidence that, like viruses of the eukaryotic host, phages are actively internalized by host cells and activate conserved viral detection receptors. This interaction often generates proinflammatory cytokine secretion and recruitment of adaptive immune programs. However, significant variability exists in phage–immune interactions, suggesting an important role for structural phage characteristics. The factors leading to the differential immunogenicity of phages remain largely unknown but are highly influenced by their human and bacterial hosts. Hundreds of trillions of diverse bacteriophages (phages) peacefully thrive within and on the human body. However, whether and how phages influence their mammalian hosts is poorly understood. In this review, we explore current knowledge and present growing evidence that direct interactions between phages and mammalian cells often induce host inflammatory and antiviral immune responses. We show evidence that, like viruses of the eukaryotic host, phages are actively internalized by host cells and activate conserved viral detection receptors. This interaction often generates proinflammatory cytokine secretion and recruitment of adaptive immune programs. However, significant variability exists in phage–immune interactions, suggesting an important role for structural phage characteristics. The factors leading to the differential immunogenicity of phages remain largely unknown but are highly influenced by their human and bacterial hosts. white blood cells (lymphocytes) that respond to specific and unique antigens; differ from innate immunity, which recognizes broadly conserved molecular patterns. a molecular structure that can be recognized by an adaptive immune cell receptor. innate immune cells that capture antigens and present them to lymphocytes to enable antigen-specific immune responses. a mixture of phages from two or more phage strains given as a single treatment. small secreted proteins that mediate intercellular signaling. a cellular process whereby cells alter membrane shape or composition to internalize extracellular material, such as molecules, nanoparticles, or other agents. viruses that infect and replicate within cells of eukaryotic organisms. tending to promote accumulation of immune cells (inflammation). cells that respond nonspecifically to microbial molecules via pattern recognition receptors (e.g., macrophages) or that are involved in protecting from microbial incursions (e.g., epithelial cells). a common microbe-associated molecular pattern found on the outer membranes of many Gram-negative bacteria. the process of a bacterium acquiring a prophage. Often, the phage inserts specific characteristics that improve bacterial survival. a community of microorganisms that are present in or on multicellular organisms. Often used synonymously with 'microbiome.' a bacteriophage morphology consisting of a nonenveloped icosahedral head and a long contractile tail. a mélange of cells collected from animal or human blood. Comprise primarily lymphocytes, with a smaller proportion of monocytes and dendritic cells. cellular process of whereby cells ingest larger particles (>0.5 μm). uptake of extracellular fluids and smaller particles into a cell by the budding of small vesicles from the cell membrane. a bacteriophage morphology consisting of a nonenveloped icosahedral head and a very short noncontractile tail. innate immune receptors that recognize conserved molecular structures such as pathogen-associated molecular patterns, microbe-associated molecular patterns, damage-associated molecular patterns, and others. process by which cell receptors are activated, invaginate, and form vesicles containing the activating substance. a bacteriophage morphology consisting of a nonenveloped icosahedral head and a long noncontractile tail. the most well-studied dsDNA phage. It is a strictly virulent phage that infects E. coli. phage cycle wherein the phage genome is integrated into the bacterial genome as a symbiotic prophage. Prophages replicate alongside the bacterial chromosome during bacterial cell division. the transport of macromolecules from one side of a polarized cell to the other. communities of viruses present in or on multicellular organisms. A subset of a microbiota. phage cycle wherein the phage infects, replicates within, and bursts the bacterial cell to release its progeny.