Repetitive Exposure to Bacteriophage Cocktails against <i>Pseudomonas aeruginosa</i> or <i>Escherichia coli</i> Provokes Marginal Humoral Immunity in Naïve Mice
Chantal Weissfuss,
Sandra-Maria Wienhold,
Magdalena Bürkle,
Baptiste Gaborieau,
Judith Bushe,
Ulrike Behrendt,
Romina Bischoff,
Imke H. E. Korf,
Sarah Wienecke,
Antonia Dannheim,
Holger Ziehr,
Christine Rohde,
Achim D. Gruber,
Jean-Damien Ricard,
Laurent Debarbieux,
Martin Witzenrath,
Geraldine Nouailles
Affiliations
Chantal Weissfuss
Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases, Respiratory Medicine and Critical Care, 10117 Berlin, Germany
Sandra-Maria Wienhold
Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases, Respiratory Medicine and Critical Care, 10117 Berlin, Germany
Magdalena Bürkle
Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases, Respiratory Medicine and Critical Care, 10117 Berlin, Germany
Baptiste Gaborieau
Institut Pasteur, Université Paris Cité, CNRS UMR6047, Department of Microbiology, Bacteriophage Bacteria Host, 75015 Paris, France
Judith Bushe
Department of Veterinary Pathology, Freie Universität Berlin, 14163 Berlin, Germany
Ulrike Behrendt
Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases, Respiratory Medicine and Critical Care, 10117 Berlin, Germany
Romina Bischoff
Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases, Respiratory Medicine and Critical Care, 10117 Berlin, Germany
Imke H. E. Korf
Department of Pharmaceutical Biotechnology, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), 38124 Braunschweig, Germany
Sarah Wienecke
Department of Pharmaceutical Biotechnology, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), 38124 Braunschweig, Germany
Antonia Dannheim
Department of Pharmaceutical Biotechnology, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), 38124 Braunschweig, Germany
Holger Ziehr
Department of Pharmaceutical Biotechnology, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), 38124 Braunschweig, Germany
Christine Rohde
Department of Microorganisms, Leibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures GmbH, 38124 Braunschweig, Germany
Achim D. Gruber
Department of Veterinary Pathology, Freie Universität Berlin, 14163 Berlin, Germany
Jean-Damien Ricard
Université Paris Cité, INSERM UMR1137, IAME, 75018 Paris, France
Laurent Debarbieux
Institut Pasteur, Université Paris Cité, CNRS UMR6047, Department of Microbiology, Bacteriophage Bacteria Host, 75015 Paris, France
Martin Witzenrath
Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases, Respiratory Medicine and Critical Care, 10117 Berlin, Germany
Geraldine Nouailles
Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases, Respiratory Medicine and Critical Care, 10117 Berlin, Germany
Phage therapy of ventilator-associated pneumonia (VAP) is of great interest due to the rising incidence of multidrug-resistant bacterial pathogens. However, natural or therapy-induced immunity against therapeutic phages remains a potential concern. In this study, we investigated the innate and adaptive immune responses to two different phage cocktails targeting either Pseudomonas aeruginosa or Escherichia coli—two VAP-associated pathogens—in naïve mice without the confounding effects of a bacterial infection. Active or UV-inactivated phage cocktails or buffers were injected intraperitoneally daily for 7 days in C57BL/6J wild-type mice. Blood cell analysis, flow cytometry analysis, assessment of phage distribution and histopathological analysis of spleens were performed at 6 h, 10 days and 21 days after treatment start. Phages reached the lungs and although the phage cocktails were slightly immunogenic, phage injections were well tolerated without obvious adverse effects. No signs of activation of innate or adaptive immune cells were observed; however, both active phage cocktails elicited a minimal humoral response with secretion of phage-specific antibodies. Our findings show that even repetitive injections lead only to a minimal innate and adaptive immune response in naïve mice and suggest that systemic phage treatment is thus potentially suitable for treating bacterial lung infections.
