Bacteriophage DNA induces an interrupted immune response during phage therapy in a chicken model

Magdalena Podlacha, Lidia Gaffke, Łukasz Grabowski, Jagoda Mantej, Michał Grabski, Małgorzata Pierzchalska, Karolina Pierzynowska, Grzegorz Węgrzyn () and Alicja Węgrzyn ()
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Magdalena Podlacha: University of Gdansk
Lidia Gaffke: University of Gdansk
Łukasz Grabowski: University of Gdansk
Jagoda Mantej: Univentum Labs
Michał Grabski: University of Gdansk
Małgorzata Pierzchalska: University of Agriculture
Karolina Pierzynowska: University of Gdansk
Grzegorz Węgrzyn: University of Gdansk
Alicja Węgrzyn: University of Gdansk

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract One of the hopes for overcoming the antibiotic resistance crisis is the use of bacteriophages to combat bacterial infections, the so-called phage therapy. This therapeutic approach is generally believed to be safe for humans and animals as phages should infect only prokaryotic cells. Nevertheless, recent studies suggested that bacteriophages might be recognized by eukaryotic cells, inducing specific cellular responses. Here we show that in chickens infected with Salmonella enterica and treated with a phage cocktail, bacteriophages are initially recognized by animal cells as viruses, however, the cGAS-STING pathway (one of two major pathways of the innate antiviral response) is blocked at the stage of the IRF3 transcription factor phosphorylation. This inhibition is due to the inability of RNA polymerase III to recognize phage DNA and to produce dsRNA molecules which are necessary to stimulate a large protein complex indispensable for IRF3 phosphorylation, indicating the mechanism of the antiviral response impairment.

Date: 2024
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DOI: 10.1038/s41467-024-46555-7

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