Phage Therapy of Pneumonia Is Not Associated with an Overstimulation of the Inflammatory Response Compared to Antibiotic Treatment in Mice

Abstract

Supported by years of clinical use in some countries and more recently by literature on experimental models, as well as its compassionate use in Europe and in the United States, bacteriophage (phage) therapy is providing a solution for difficult-to-treat bacterial infections. However, studies of the impact of such treatments on the host remain scarce. Murine acute pneumonia initiated by intranasal instillation of two pathogenic strains of Escherichia coli (536 and LM33) was treated by two specific bacteriophages (536_P1 and LM33_P1; intranasal) or antibiotics (ceftriaxone, cefoxitin, or imipenem-cilastatin; intraperitoneal). Healthy mice also received phages alone. The severity of pulmonary edema, acute inflammatory cytokine concentration (blood and lung homogenates), complete blood counts, and bacterial and bacteriophage counts were determined at early (Յ12 h) and late (Ն20 h) time points. The efficacy of bacteriophage to decrease bacterial load was faster than with antibiotics, but the two displayed similar endpoints. Bacteriophage treatment was not associated with overinflammation but in contrast tended to lower inflammation and provided a faster correction of blood cell count abnormalities than did antibiotics. In the absence of bacterial infection, bacteriophage 536_P1 promoted a weak increase in the production of antiviral cytokines (gamma interferon [IFN-␥] and interleukin-12 ) and chemokines in the lungs but not in the blood. However, such variations were no longer observed when bacteriophage 536_P1 was administered to treat infected animals. The rapid lysis of bacteria by bacteriophages in vivo does not increase the innate inflammatory response compared to that with antibiotic treatment.

Bacteriophage Interactions With Epithelial Cells: Therapeutic Implications

“…Pincus et al ( 2015 ) showed that a staphylococcal phage induces interferon gamma in primary human keratinocyte cultures but not in blood MNC. Likewise, E. coli phages elicited marked production of IFN gamma and IL-12 by lung cells but not MNC (Dufour et al, 2019 ).…”

Phage-Specific Diverse Effects of Bacterial Viruses on the Immune System

“…The intranasal administration of 536_P1 (but not LM33-P1) coliphage in mice with experimental pneumonia caused an increase in lung antiviral cytokines and chemokines. Neither phage evoked changes in blood cytokine/chemokine levels, which also suggests that phage effects on the immune system may have various manifestations in different compartments of the body [16]. Phage ability to mediate tissue-specific activity is confirmed by Pincus et al [17], where staphylococcal phage did not induce proinflammatory cytokines in human peripheral blood mononuclear cells but may have induced IFN-γ in human keratinocytes.…”

Animal Models of Phage Therapy

“…Phages also do not induce significant amounts of inflammation. Dufour et al (2019) found that phages could elicit cytokine production above baseline, but this was localized, phage dependent, and had no observable clinical consequences. Other work has shown that when uninfected mice were given inhalational or intraperitoneal phages, no appreciable levels of either TNF-α or MIP-2 were observed in the lungs ( Carmody et al, 2010 ).…”