{"doi":"10.1093/infdis/jiac369","title":"Fighting the Wrong Enemy: Antibacteriophage Immunity in Phage Therapy","abstract":"Bacteriophages (phages), which are viruses that infect bacteria, have been studied as long as molecular biology itself. Seminal discoveries about DNA and RNA were made by characterizing phage transformation of cultured bacteria, leading to our understanding of central dogmas of biology [1]. They have long been recognized as carriers of genetic factors, particularly virulence factors affecting bacterial pathogens [2]. In recent years, phages have been increasingly implicated as independent drivers of disease processes because of their effects on the intestinal microbiome as well as their ability to prey on disease-relevant bacterial species and strains [3]. Phage therapy is an exciting and reemerging use of bacteriophages to combat bacterial infections. The potential of phages as possible antibacterial agents was recognized soon after their discovery in 1917, and phage therapy was used with some success in the 1920s [4, 5]. Difficulties with strain specificity and purification of phages, combined with the rise of antibiotics, led to the abandonment of phage therapy in the West, though it continued to be studied in the USSR and Poland. In the modern era, however, multidrug-resistant bacteria are being encountered at increasing frequencies that far exceed the rate of new antibiotic development [6]. Phage therapy offers a parallel approach to antibiotic treatment, because the mechanisms of action of bacteriophages are independent of mechanisms of antibiotic resistance, enabling a well-chosen phage or cocktail of phages to combat antibiotic-resistant bacteria [5, 7]. Phage therapy is now used under individual compassionate-use approvals from the Food and Drug Administration, usually in patients whose infections have proved resistant to most conventional antibiotics, such as those caused by Pseudomonas or Acinetobacter [4, 8, 9]. However, the interaction of phages with their bacterial hosts is not the only process of clinical interest. Phages themselves represent foreign protein and DNA or RNA; thus, though they cannot infect eukaryotes, they can directly interact with vertebrate cells and the immune system. Phages can be endocytosed by cultured human cell lines [10–12] and elicit host immune responses through Toll-like receptor 3 and 9 signaling, suggesting a capacity to modulate immunity [13, 14]. However, there has been limited characterization of phage-specific immune responses during administration of phage therapy. Dan et al [15], in this issue of The Journal of Infectious Diseases, characterize immune responses to phage administered to a lung transplant patient to combat a multidrug-resistant Pseudomonas aeruginosa pneumonia. The patient received several courses of 2 different phage cocktails, administered intravenously and inhaled, over several months. The phage therapy was a success, as the patient progressed from intubated to ambulatory status with the first round of therapy, and microbiological cure of the pneumonia was achieved with the second round [9]. The authors tracked CD4 Tcells and antibody formation, as well as serum cytokines. They were able to demonstrate a robust increase in follicular T-helper cells during the first round of phage therapy which waned between courses and peaked again briskly at the second course. They also identified a slight increase in Bcells (likely low because of the patient’s substantial immune suppression and hypogammaglobulinemia) and a late peak in several cytokines, including interleukin 2, interleukin 6, and granulocyte-macrophage colony-stimulating factor, coincident with the maximum CD4 T-cell response. Of particular interest, Dan et al [15] were able to interrogate the target of the immune responses, identifying phage-specific CD4 Tcells proliferating in the patient’s blood as well as development of antiphage immunoglobulin G. The patient did not have any preexisting phage-neutralizing antibodies, but over the course of therapy antibodies developed, which were able to neutralize s","journal":"The Journal of Infectious Diseases","year":2022,"id":292656,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":491707,"name":"Lori R. Holtz","orcid":"0000-0002-5591-7794","position":1,"is_corresponding":false},{"id":976739,"name":"Jerome M. Molleston","orcid":"0000-0003-3702-8317","position":0,"is_corresponding":true}],"reference_count":18,"raw_metadata":null,"created_at":"2026-07-19T00:30:46.209549Z","pmid":"36083993","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}