Bacteriophages – viruses that infect bacteria exclusively – have long appeared to serve a singular purpose: to hunt down and eliminate their bacterial prey. Researchers at the HUN-REN Biological Research Centre, Szeged have now presented a more nuanced picture in a study published in Nature Communications. They have shown that certain phages in our gut can attach to human cells through specific proteins. The discovery could contribute to the development of new therapeutic approaches.
Researchers at the Translational Microbiology Laboratory of the Institute of Biochemistry at the HUN-REN Biological Research Centre in Szeged set out to determine how bacteriophages – viruses that infect bacteria – are able to attach to the surface of human cells. First, the researchers exposed human intestinal epithelial cells to several thousand phages, collected from volunteers with either healthy or disrupted gut microbiota, and observed which phages adhered to the cells. This enabled them to study what identify several surface proteins that act as a kind of molecular glue. However, these results were bioinformatic prediction, so next the researchers sought to confirm the supposed role of the identified proteins experimentally. They transferred the genes encoding such proteins into phages that does not normally attach to human cells at all. The thus engineered phages readily latched onto human cells and was taken up by them. When fed to mice, the modified phages also remained in the animals’ intestinal tract for much longer than the original, non-adhering one. The team also found that even miniscule differences in the structure of the adhesive protein mattered: two modified phages bearing almost identical adhesive proteins attached in slightly different ways and with different strengths, suggesting that nature can fine-tune this ability with considerable precision.
They do not infect humans
It is important to emphasise that this does not mean phages are becoming “human viruses”. They remain incompatible with human cells and so cannot infect them. Instead, they can carry proteins to attachment to the cell surface, after which the cell’s own uptake machinery encloses the phages in a vesicle and internalises them. Once inside such phages can also reach the endoplasmic reticulum – the cell’s internal transport and processing system. The variants that reach it are precisely those that enter the cells most efficiently. “For a long time, we regarded phages purely as bacteria-hunting viruses, but they appear to be more complex players than that: they can also attach directly to the surface of human cells. They are not becoming human viruses; rather, they use molecular anchors that may later prove important in designing more targeted phage therapies,” said Gábor Apjok, co-first and co-corresponding author of the study.
A more comprehensive understanding of the microbiome
The findings also add nuance to our understanding of the microbiome. The researchers screened two large databases containing nearly 75,000 viral genomes in total and found that the protein domains responsible for adhesion are far from rare in viral communities found in the human gut. Adhesion-competent phages were more common in gut samples from healthy people than in samples from people with inflammatory bowel disease. According to the researchers, this suggests that these phages may persist more stably in the environment of a healthy, intact intestinal mucosa. Their presence is therefore more likely to be a sign of a healthy gut lining than its cause. “In our digestive tract, phages do not move through empty space: they must persist among layers of mucus, bacteria and epithelial cells. Certain surface proteins may also help them attach within this environment,” said Tóbiás Sári, co-first author of the study.
A possible precursor to future therapies
The discovery may also have important implications for phage therapy – the use of bacteriophages to treat bacterial infections, an approach that is becoming increasingly valuable in the era of antibiotic resistance. The researchers suggest that incorporating the newly identified adhesion proteins into engineered phages could make it possible to target therapeutic phages more precisely and retain them at the desired site for longer. A bolder idea – currently only a theoretical possibility – is that they could also serve as intracellular delivery vehicles, carrying therapeutic agents for diseases associated with the endoplasmic reticulum, such as cystic fibrosis. “To achieve this, we need to understand how phages reach the right location, how they remain there and what kind of relationship they can establish with human tissues,” said Bálint Kintses, head of the research group and co-corresponding author of the study.
Source: Hun-Ren
