Interaction Among Phage, Bacteria, and Health

What are the effects of bacteriophages on the body's immune system?
Bacteriophages cannot infect eukaryotic cells, but more and more studies have shown that phages can regulate the immune response of mammals. Especially when the phage and the host bacteria (https://phagenbio.creative-biolabs.com/discovery-of-phage-targeting-bacteria.htm) are in a symbiotic relationship, the bacteria even use the prophage to change the innate immune response of mammals and promote the survival of the bacteria in the body. Recent studies showed that Pseudomonas aeruginosa strains containing the "Pf" prophage are more likely to cause chronic and difficult-to-heal wounds. Further research found that after Pf phage is swallowed by leukocytes, phage RNA activates the antiviral Toll-like receptor 3 (TLR-3) mediated interferon γ (IFN-γ) response, thereby inhibiting the tumor necrosis factor TNF-α in the wound environment, leading to the weakening of the phagocytosis of white blood cells, which makes it difficult to remove Pseudomonas aeruginosa from the wound, and thereby induces a long-lasting and chronic wound infection. Another study found that a bacteriophage encoding Ankyrin protein can down-regulate the level of TNF-α in macrophages by inducing Escherichia coli to secrete ANK protein, thereby reducing the phagocytosis of Escherichia coli.

When bacteriophages are used to treat diseases (https://phagenbio.creative-biolabs.com/phage-based-therapy.htm), sometimes excessive use can cause inflammation. In a mouse model study of phage treatment of adherent invasive Escherichia coli (AIEC)-related colon cancer, scientists found that continuous oral administration of phage cocktail in mice can reduce the AIEC load in the intestines and down-regulate the expression of genes related to tumor growth and metastasis, thereby effectively preventing colon cancer caused by AIEC. However, when phage is used excessively, a large amount of phage DNA accumulated in the intestine can activate IFN-γ through the TLR-9-related molecular pathway, thereby aggravating the symptoms of colitis.

What effect does the immune system have on bacteria and phage?
Bacteriophages and their host bacteria will affect the body's immune system, and vice versa, the body's immune response will also affect bacteria and phages.

The genome of Salmonella typhimurium usually contains prophage, some of which encode toxic genes that can enhance the host bacteria's invasion of intestinal epithelial cells and aggravate the body's intestinal inflammation. The researchers mixed the same amount of Salmonella with and without the prophage SpoEø to infect mice, and found that the number of lysogens containing SpoEø steadily increased after co-infection. Further studies have shown that by-products of Salmonella typhimurium causing intestinal inflammation can trigger bacterial stress responses, leading to increased bacteriophage SpoEø and lysogenic transformation in the intestine. To this end, the researchers developed an oral vaccine. After the mice were vaccinated, the immune response mediated by antibody IgA was induced, thereby effectively preventing the invasion of Salmonella and the lysogenic transformation of Salmonella SpoEø, and reducing the occurrence and development of diseases.

As mentioned above, Pseudomonas aeruginosa containing Pf phage is more likely to cause chronic and difficult-to-heal wounds. Scientists used the major capsid protein of Pf phage to immunize mice to stimulate the mice to produce a humoral immune response. As a result, the incidence of Pseudomonas aeruginosa wound infection was reduced by half. The researchers then isolated monoclonal antibodies (mAbs) against the Pf phage major capsid protein and treated the mice, which also significantly relieved the symptoms. This indicates that by revealing the key factors of the pathogenic effect of bacteriophages in some bacterial disease, an immune strategy developed with its epitope as a target can effectively prevent the occurrence of this diseases.

Recent studies found that Enterococcus hirae, a commensal bacterium in the intestine, contains a prophage, a major epitope of the TMP protein encoded by which is highly similar to the tumor peptide epitope PSMB4, so the bacteria can upregulate the anti-tumor immune response of CD8+ T cells after infecting mice. Whether it is to stimulate dendritic cells with the phage TMP epitope or express the epitope on the surface of Escherichia coli, it can limit the growth of tumors and improve the effect of immunotherapy. Further studies showed that the phage can also be integrated into another symbiotic bacteria in the intestine, Enterococcus gallinarum, suggesting that it can be widely spread in the intestine. Given the diversity of the gut microbiota, there may be many similar mechanisms that affect human health.