The use of bacteriophages to treat antibiotic-resistant infections is becoming increasingly common. Clinical trials of phage therapy for various diseases are ongoing, and there is now evidence of the safety of using bacterial viruses in clinical practice. At the same time, increasing amounts of data are emerging on the interaction of bacteriophages not only with their host bacteria but also with the immune system of the host (human or other mammal). Studying the mechanisms of this interaction may form the basis for the development of new anti-inflammatory and immunomodulatory agents. A. Górski et al., published in September 2019 in the journal Future Microbiology*, devoted a review to the interactions of various bacteriophages with the mammalian immune system.

As early as 2006, the authors of the review hypothesized that phages from the human intestine can migrate into the blood, lymph, and various organs, modulating anti-inflammatory effects and influencing immunological tolerance and immune homeostasis. This hypothesis was later confirmed; moreover, it was discovered that, in a normal person, over 30 billion phage particles pass through intestinal epithelial cells daily (a process called transcytosis) and are distributed throughout the body via the blood and lymph. It was also found that phages can enter other cells of the human body via endocytosis, particularly cells of the immune system. Among the important questions that remain to be explored is whether the effect of phages on the immune system is specific. If phages are highly specific in their interactions with bacteria, then perhaps the immune responses they induce are not universal, but rather specific to different phage species/strains.

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Phage capsid proteins are thought to be responsible for functions unrelated to interactions with bacteria. These proteins vary in immunogenicity and, accordingly, induce the production of different antibodies, which also depends on the route of phage administration. Even different strains of homologous phages specific to a single bacterium can express different proteins, which impart distinct properties to the phage. For example, mutant phage T4 (HAP1) with a nonfunctional Nos protein is more susceptible to destruction by Kupffer cells (liver macrophages) and is cleared from the body more quickly than the wild-type T4 strain.

There is evidence that the effect of phages on the immune system may depend on their specificity. For example, a study of phages specific for Staphylococcus and Pseudomonas revealed that, although they all have similar effects on peripheral blood mononuclear cells (increasing the synthesis of the anti-inflammatory cytokine receptor antagonist IL-1 and cytokine signal suppressor 3), their other effects differ. In particular, all phages specific for Pseudomonas induce the synthesis of the anti-inflammatory cytokine IL-10, whereas this is not characteristic of staphylococcal phages. The filamentous phage Pf, specific for Pseudomonas, inhibits tumor necrosis factor production and phagocytosis, whereas the filamentous phage Fol, specific for Escherichia coli, has no such effect.

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The immunomodulatory and anti-inflammatory effects of phages may also depend on the tissue in which they are located, as has been demonstrated in numerous in vitro experiments on various cell cultures.

As mentioned, phages can penetrate mammalian cells, particularly dendritic cells, monocytes, and B lymphocytes. The authors of this review recently described bacteriophage stimulation of the Hsp72 gene, which encodes one of the most important cellular chaperones, in mammalian cells. This may be a mechanism for protecting cells that the phage penetrates or penetrates from damage it can cause. Hsp72 is also known to reduce T-cell proliferation and cytokine secretion, suggesting that this protein may serve as an immunomodulator. Hsp72 was previously shown to suppress the development of experimental arthritis in mice, and the authors of this review later found that phages have the same effect. Therefore, it can be hypothesized that phage-dependent induction of the Hsp72 chaperone is at least partially responsible for the inhibition of pathological immune responses.

Data on the effects of phages on the mammalian immune system certainly needs to be expanded, but the potential for using these properties of phages for therapeutic purposes is already clear. Perhaps soon, phages for phage therapy will be selected not only based on their specificity for a particular bacterium, but also based on the specific type of immune response they elicit. This is especially relevant for patients with immunodeficiencies, autoimmune diseases, post-allograft patients, and others who require immunostimulation or immunosuppression.

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* Andrzej Górski, Ryszard Międzybrodzki, Ewa Jończyk-Matysiak, Maciej Żaczek, and Jan Borysowski. Phage-specific diverse effects of bacterial viruses on the immune system // Future Microbiol., 2019, 14(14): 1171–1174. doi: 10.2217/fmb-2019-0222