Phages trump bacteria in immune interactions

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Science Translational Medicine  27 Feb 2019:
Vol. 11, Issue 481, eaaw5331
DOI: 10.1126/scitranslmed.aaw5331


Bacteriophages modulate mouse cancer and colitis models through unexpected immune interactions.

Human microbiome studies often focus on bacteria despite the larger number of viruses, especially bacteriophages. Interest in bacteriophages has grown due to associations between phage ecology and diseases, such as inflammatory bowel disease (IBD), as well the potential use of phages to specifically target pathogens. Unfortunately, it is still unknown how phages shape microbiome functions. Gogokhia et al. validate phages as a modality to treat colon cancer and uncover unexpected direct immune interactions. To explore phage therapy for colon cancer, the authors isolated strains of Caudovirales that target adherent invasive Escherchia coli (AIEC), a bacteria which in mice that spontaneously develop cancer (APCmin) increases tumor size and mortality. In APCmin mice colonized with AIEC, phage administration decreased tumor size and improved survival. RNAseq analysis of the mucosa confirmed changes in cancer pathways and immune pathways. Analysis of immune cell populations confirmed phage-dependent increases in CD4+ and CD8+ T cells in mesenteric lymph nodes. To understand if this effect was mediated directly by the phage or through AIEC, the authors infected germfree mice with phage and again demonstrated T cell changes. In vitro it was then determined that the phage did not act on T cells but through dendritic cells in a TLR9-dependent manner. As the observed phage-immune interactions polarized T cells to proinflammatory interferon-γ (IFN-γ) secretion and Caudovirales have been negatively associated with IBD, the authors tested whether phages worsen mouse models of colitis. In a DSS colitis model, phage administration increased inflammation in a TLR9-dependent fashion. Translating this work into humans, an increase in Caudovirales phage DNA in stool samples correlated with a lack of response to fecal transplant in patients with IBD. Similarly, viral particles isolated only from patients with active IBD compared with inactive IBD or healthy controls were capable of stimulating IFN-γ production from T cells. This article demonstrates a direct interaction between bacteriophages and the immune system. While this study suggests phages targeting AIEC would exacerbate colitis, companies are using exactly this strategy in IBD in ongoing phase I/II trials. It is clear that further research will be needed to understand how these observations in mice extend to the human immune system and its unique microbiome, which unlike mice natively contains E. coli and may be commonly exposed to E. coli phages, altering the baseline immune response. Similarly, the applications of this therapy to cancer will need to be carefully explored especially in conjunction with traditional chemotherapeutics.

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