Targeting of Mammalian Glycans Enhances Phage Predation in the Gastrointestinal Tract

Abstract

The human mucosal surface is a complex ecosystem comprised of a eukaryotic epithelium, a prokaryotic microbiota, and a carbohydrate-rich interface that separates them. A less characterized, third entity, that of bacteriophage (phage), parasitizes prokaryotes but generally do not interact with eukaryotic cells. In the gastrointestinal tract, the interaction of these two domains of life influences the health status of the host, especially if there is colonization with invasive pathobionts. If the pathobiont causes a symptomatic infection, treatment with antibiotics is necessary. However, antibiotics act broadly thereby killing many protective commensals and they lack the physio-chemical properties to be optimally active in the mucosa, and may have associated adverse effects, including toxicities. Here, we report a novel C3 type phage of the genus Kuravirus whose lytic cycle is enhanced in intestinal environments. The enhanced activity is encoded in the viral tail fiber gene, whose protein product binds human heparan sulfated proteoglycans and localizes the phage to the epithelial cell surface, thereby positioning it near the location of its bacterial host. This finding offers the prospect of developing epithelial-targeting phage to selectively remove invasive pathobiont species from mucosal surfaces.

Interactions between bacterial and phage communities in natural environments

“…Interestingly, some lytic phages can adhere on mucosal surfaces, which may benefit both the phage -by providing a better access to bacteria -and the host -by limiting bacterial proliferation in mucus 186,187 . In addition, phages may promote the expression of innate immunity genes 188 , prevent activation and proliferation of immune cells 189 , disturb phagocytosis by dendritic cells 190,191 or affect bacterial antigen expression, which might alter recognition of pathogens by the immune system 192 .…”

Gut bacteriophages and the pinball challenge

“…However, in our study, we only tested a handful of phages, and it would be presumptuous to believe that their interactions with their hosts can be generalisable to the billions of particles present in an intestine. Indeed, a few months after we showed that our phages were weak mucus colonisers, Green et al published the characterisation of phages with a strong affinity for mucin and intestinal glycan and capable of targeting pathogenic E. coli embedded in the mucus layer (Green et al, 2021). On the one hand, this is a reminder of how phage-specific these mechanisms can be and that an unprecedented diversity of such mechanisms could be hidden in the microbiota community.…”

Phage resistance accompanies reduced fitness of uropathogenicE. coliin the urinary environment

“…UTI89 and CFT073 are well-characterized UPEC cystitis and pyelonephritis isolates respectively, while DS515 and DS566 are recently isolates from patients with neurogenic bladders from spinal cord injury. HP3 and ES17 are phages with demonstrated efficacy against extraintestinal pathogenic E. coli (ExPEC) including UPEC(24, 31, 35, 46, 61).…”