Bacterial lysis, autophagy and innate immune responses during adjunctive phage therapy in a child. Issue 9 (9th August 2021)

• Record Type: Journal Article
• Authors: Khatami, Ameneh; Lin, Ruby C Y; Petrovic‐Fabijan, Aleksandra; Alkalay‐Oren, Sivan; Almuzam, Sulaiman; Britton, Philip N; Brownstein, Michael J; Dao, Quang; Fackler, Joe; Hazan, Ronen; Horne, Bri'Anna; Nir‐Paz, Ran; Iredell, Jonathan R
• Is Part Of: EMBO molecular medicine. Volume 13:Issue 9(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-08-09
• Subjects: bacteriophage -- child -- immune response -- osteoarticular infection -- Pseudomonas aeruginosa; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202113936
• Languages: English
• ISSNs: 1757-4676

Abstract

Abstract: Adjunctive phage therapy was used in an attempt to avoid catastrophic outcomes from extensive chronic Pseudomonas aeruginosa osteoarticular infection in a 7‐year‐old child. Monitoring of phage and bacterial kinetics allowed real‐time phage dose adjustment, and along with markers of the human host response, indicated a significant therapeutic effect within two weeks of starting adjunctive phage therapy. These findings strongly suggested the release of bacterial cells or cell fragments into the bloodstream from deep bony infection sites early in treatment. This was associated with transient fever and local pain and with evidence of marked upregulation of innate immunity genes in the host transcriptome. Adaptive immune responses appeared to develop after a week of therapy and some immunomodulatory elements were also observed to be upregulated. SYNOPSIS: Successful phage therapy for extensive chronic osteoarticular infection in a child resulted in an initial flush of bacterial contents into the bloodstream with an inflammatory response marked by fever, local pain and upregulation of genes associated with autophagy and innate immunity. Pain‐free weight bearing on the affected leg was achieved for the first time since the initial injury, seven weeks after completion of adjunctive phage therapy, and long‐term follow‐up demonstrated radiological improvement. Viable phage was recovered from pre‐dose blood samples up until day 5, consistent with productive infection of the target bacteria throughout the dosing interval. Strong upregulation of several genes linked to the innate immune response coincided with first phage administration, subsequent Pseudomonas DNAemia spike and rise in key inflammatory markers. Hierarchical clustering analysis further confirmed the enrichment of innate immune response‐associated genes on day 2, which appeared to subside over a few days so that by day 29 the gene profile was similar to that of pre‐therapy. Abstract : Monitoring of phage and bacterial kinetics during adjunctive phage therapy for extensive chronic osteoarticular infection in a child demonstrated an initial flush of bacterial contents into the bloodstream associated with an inflammatory response marked by fever, local pain and upregulation of genes linked to autophagy and innate immunity.