Intranasal phage therapy overcomes antibody neutralization challenges in pulmonary Pseudomonas aeruginosa infections

Dhammika Leshan Wannigama^{1

2

3

4

5

6}, Jingping Shao^#⁷, Hongya Sun^#⁸, Yangzhong Wang^#^{9

10}, Cameron Hurst^{11

12

13

14}, Peter N Monk¹⁵, Mohan Amarasiri^{11

16}, Phatthranit Phattharapornjaroen^{17

18}, William Graham Fox Ditcham¹⁹, Thin Sandi Htun²⁰, Sirirat Luk-In²¹, Yoshitaka Shimotai²², Natharin Ngamwongsatit²³, Hitoshi Ishikawa²⁴, Naveen Kumar Devanga Ragupathi^{25

26}, Daniel Pletzer²⁷, Talerngsak Kanjanabuch^{28

29

30

31}, Aisha Khatib³², Kazuhiko Miyanaga³³, Longzhu Cui³³, Kenji Shibuya³⁴, Paul G Higgins^{35

36

37}, Anthony Kicic^{38

39

40

41}, Parichart Hongsing^{42

43}, Jinxin Zhao⁴⁴, Shuichi Abe^{45

46}, Hiroshi Hamamoto⁴⁷

Affiliations

¹ Department of Infectious Diseases, Faculty of Medicine, Yamagata University, Yamagata, Japan. leshanwannigama@med.id.yamagata-u.ac.jp.
² Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan. leshanwannigama@med.id.yamagata-u.ac.jp.
³ Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan. leshanwannigama@med.id.yamagata-u.ac.jp.
⁴ School of Medicine, Faculty of Health and Medical Sciences, The University of Western Australia, Nedlands, WA, Australia. leshanwannigama@med.id.yamagata-u.ac.jp.
⁵ Yamagata Prefectural University of Health Sciences, Kamiyanagi, Yamagata, 990-2212, Japan. leshanwannigama@med.id.yamagata-u.ac.jp.
⁶ Biofilms and Antimicrobial Resistance Consortium of ODA receiving countries, The University of Sheffield, Sheffield, UK. leshanwannigama@med.id.yamagata-u.ac.jp.
⁷ Faculty of Pharmacy, Zhejiang Pharmaceutical University, Ningbo, 315100, People's Republic of China.
⁸ Department of Pharmacy, The Affiliated People's Hospital of Ningbo University, Ningbo, 315100, People's Republic of China.
⁹ Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan. 632551432@qq.com.
¹⁰ Division of Respiratory and Critical Care Medicine, Affiliated Fuling hospital of Chongqing University, Chongqing, China. 632551432@qq.com.
¹¹ Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan.
¹² Department of Clinical Epidemiology, Faculty of Medicine, Thammasat University, Rangsit, 10120, Thailand.
¹³ Center of Excellence in Applied Epidemiology, Thammasat University, Rangsit, 10120, Thailand.
¹⁴ Mater Research Institute, University of Queensland, Queensland, Australia.
¹⁵ Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, UK.
¹⁶ Department of Civil and Environmental Engineering, Graduate School of Engineering, Tohoku University, Sendai, Miyagi, Japan.
¹⁷ Faculty of Health Science Technology, Chulabhorn Royal Academy, Bangkok, 10210, Thailand.
¹⁸ HRH Princess Chulabhorn Disaster and Emergency Medicine Center, Chulabhorn Royal Academy, Bangkok, 10210, Thailand.
¹⁹ School of Medicine, Faculty of Health and Medical Sciences, The University of Western Australia, Nedlands, WA, Australia.
²⁰ Laboratory of Host Defense, World Premier Institute-Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Osaka, 565-0871, Japan.
²¹ Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
²² Department of Infectious Diseases, Faculty of Medicine, Yamagata University, Yamagata, Japan.
²³ Department of Clinical Sciences and Public Health, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom, Thailand.
²⁴ Yamagata Prefectural University of Health Sciences, Kamiyanagi, Yamagata, 990-2212, Japan.
²⁵ Biofilms and Antimicrobial Resistance Consortium of ODA receiving countries, The University of Sheffield, Sheffield, UK.
²⁶ Division of Microbial Interactions, Department of Research and Development, Bioberrys Healthcare and Research Centre, Vellore, 632009, India.
²⁷ Department of Microbiology and Immunology, University of Otago, 720 Cumberland St., Dunedin, 9054, New Zealand.
²⁸ Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
²⁹ Center of Excellence in Kidney Metabolic Disorders, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
³⁰ Dialysis Policy and Practice Program (DiP3), School of Global Health, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
³¹ Peritoneal Dialysis Excellence Center, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
³² Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada.
³³ Division of Bacteriology, School of Medicine, Jichi Medical University, Tochigi, Japan.
³⁴ Tokyo Foundation for Policy Research, Minato-ku, Tokyo, Japan.
³⁵ Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
³⁶ German Centre for Infection Research, Partner site Bonn-Cologne, Cologne, Germany.
³⁷ Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50935, Cologne, Germany.
³⁸ Telethon Kids Institute, University of Western Australia, Nedlands, WA, 6009, Australia.
³⁹ Centre for Cell Therapy and Regenerative Medicine, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia.
⁴⁰ Department of Respiratory and Sleep Medicine, Perth Children's Hospital, Nedlands, WA, 6009, Australia.
⁴¹ School of Public Health, Curtin University, Bentley, WA, 6102, Australia.
⁴² Department of Infectious Diseases, Faculty of Medicine, Yamagata University, Yamagata, Japan. parichart.hon@mfu.ac.th.
⁴³ Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan. parichart.hon@mfu.ac.th.
⁴⁴ Department of Microbiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
⁴⁵ Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan. abeshu@icloud.com.
⁴⁶ Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan. abeshu@icloud.com.
⁴⁷ Department of Infectious Diseases, Faculty of Medicine, Yamagata University, Yamagata, Japan. hamamoto@med.id.yamagata-u.ac.jp.

^# Contributed equally.

PMID: 41108387
DOI: 10.1007/s00203-025-04526-6

Intranasal phage therapy overcomes antibody neutralization challenges in pulmonary Pseudomonas aeruginosa infections

Dhammika Leshan Wannigama et al. Arch Microbiol. 2025.

. 2025 Oct 18;207(12):310.

doi: 10.1007/s00203-025-04526-6.

Authors

Affiliations

¹ Department of Infectious Diseases, Faculty of Medicine, Yamagata University, Yamagata, Japan. leshanwannigama@med.id.yamagata-u.ac.jp.
² Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan. leshanwannigama@med.id.yamagata-u.ac.jp.
³ Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan. leshanwannigama@med.id.yamagata-u.ac.jp.
⁴ School of Medicine, Faculty of Health and Medical Sciences, The University of Western Australia, Nedlands, WA, Australia. leshanwannigama@med.id.yamagata-u.ac.jp.
⁵ Yamagata Prefectural University of Health Sciences, Kamiyanagi, Yamagata, 990-2212, Japan. leshanwannigama@med.id.yamagata-u.ac.jp.
⁶ Biofilms and Antimicrobial Resistance Consortium of ODA receiving countries, The University of Sheffield, Sheffield, UK. leshanwannigama@med.id.yamagata-u.ac.jp.
⁷ Faculty of Pharmacy, Zhejiang Pharmaceutical University, Ningbo, 315100, People's Republic of China.
⁸ Department of Pharmacy, The Affiliated People's Hospital of Ningbo University, Ningbo, 315100, People's Republic of China.
⁹ Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan. 632551432@qq.com.
¹⁰ Division of Respiratory and Critical Care Medicine, Affiliated Fuling hospital of Chongqing University, Chongqing, China. 632551432@qq.com.
¹¹ Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan.
¹² Department of Clinical Epidemiology, Faculty of Medicine, Thammasat University, Rangsit, 10120, Thailand.
¹³ Center of Excellence in Applied Epidemiology, Thammasat University, Rangsit, 10120, Thailand.
¹⁴ Mater Research Institute, University of Queensland, Queensland, Australia.
¹⁵ Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, UK.
¹⁶ Department of Civil and Environmental Engineering, Graduate School of Engineering, Tohoku University, Sendai, Miyagi, Japan.
¹⁷ Faculty of Health Science Technology, Chulabhorn Royal Academy, Bangkok, 10210, Thailand.
¹⁸ HRH Princess Chulabhorn Disaster and Emergency Medicine Center, Chulabhorn Royal Academy, Bangkok, 10210, Thailand.
¹⁹ School of Medicine, Faculty of Health and Medical Sciences, The University of Western Australia, Nedlands, WA, Australia.
²⁰ Laboratory of Host Defense, World Premier Institute-Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Osaka, 565-0871, Japan.
²¹ Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
²² Department of Infectious Diseases, Faculty of Medicine, Yamagata University, Yamagata, Japan.
²³ Department of Clinical Sciences and Public Health, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom, Thailand.
²⁴ Yamagata Prefectural University of Health Sciences, Kamiyanagi, Yamagata, 990-2212, Japan.
²⁵ Biofilms and Antimicrobial Resistance Consortium of ODA receiving countries, The University of Sheffield, Sheffield, UK.
²⁶ Division of Microbial Interactions, Department of Research and Development, Bioberrys Healthcare and Research Centre, Vellore, 632009, India.
²⁷ Department of Microbiology and Immunology, University of Otago, 720 Cumberland St., Dunedin, 9054, New Zealand.
²⁸ Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
²⁹ Center of Excellence in Kidney Metabolic Disorders, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
³⁰ Dialysis Policy and Practice Program (DiP3), School of Global Health, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
³¹ Peritoneal Dialysis Excellence Center, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
³² Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada.
³³ Division of Bacteriology, School of Medicine, Jichi Medical University, Tochigi, Japan.
³⁴ Tokyo Foundation for Policy Research, Minato-ku, Tokyo, Japan.
³⁵ Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
³⁶ German Centre for Infection Research, Partner site Bonn-Cologne, Cologne, Germany.
³⁷ Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50935, Cologne, Germany.
³⁸ Telethon Kids Institute, University of Western Australia, Nedlands, WA, 6009, Australia.
³⁹ Centre for Cell Therapy and Regenerative Medicine, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia.
⁴⁰ Department of Respiratory and Sleep Medicine, Perth Children's Hospital, Nedlands, WA, 6009, Australia.
⁴¹ School of Public Health, Curtin University, Bentley, WA, 6102, Australia.
⁴² Department of Infectious Diseases, Faculty of Medicine, Yamagata University, Yamagata, Japan. parichart.hon@mfu.ac.th.
⁴³ Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan. parichart.hon@mfu.ac.th.
⁴⁴ Department of Microbiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
⁴⁵ Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan. abeshu@icloud.com.
⁴⁶ Pathogen Hunter's Research Team, Department of Infectious Diseases and Infection Control, Yamagata Prefectural Central Hospital, Yamagata, Japan. abeshu@icloud.com.
⁴⁷ Department of Infectious Diseases, Faculty of Medicine, Yamagata University, Yamagata, Japan. hamamoto@med.id.yamagata-u.ac.jp.

^# Contributed equally.

PMID: 41108387
DOI: 10.1007/s00203-025-04526-6

Abstract

Phage therapy is a promising approach against multidrug-resistant infections, yet systemic administration can lead to incomplete cures. We investigated the distribution, immune responses, and efficacy of the therapeutic phage KPP10 delivered via intranasal or intraperitoneal (IP) routes in murine Pseudomonas aeruginosa lung infection models. Intranasal pre-treatment achieved markedly higher localization of KPP10 in the lungs and bronchoalveolar compartment compared to IP delivery. Intranasal administration elicited minimal systemic antibody responses, whereas IP injection triggered significant IgG, IgM, and IgA production. Antibody responses did not differ significantly between doses. In acute and chronic infection models, intranasal KPP10 significantly improved survival (p < 0.01) and reduced lung bacterial loads relative to IP injection. Importantly, IP treatment was associated with bacterial rebound after day 14 in chronic infection, whereas intranasal dosing sustained bacterial clearance. These findings demonstrate that intranasal delivery enhances pulmonary localization, minimizes antibody-mediated neutralization, and provides superior therapeutic efficacy, highlighting its potential as a more effective route for phage therapy against P. aeruginosa lung infections.

Keywords: Antibody-mediated neutralization; Chronic pulmonary Pseudomonas aeruginosa infections; Intranasal phage treatment.

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Conflict of interest statement

Declarations. Conflict of Interest: The authors declare no competing interests. Ethical approval: The study protocol was approved by the Institutional Review Board (IRB) of the Yamagata Prefectural Central Hospital, Yamagata, Japan (07/2022). The present article was prepared in compliance with the ARRIVE 2.0 guidelines for reporting animal research. Inclusion and diversity: We, the authors of this paper, embrace inclusive, diverse, and equitable conduct of research. Our team comprises individuals who self-identify as underrepresented ethnic minorities, gender minorities, members of the LGBTQIA+ community, and individuals living with disabilities. We actively promote gender balance in our reference list while maintaining scientific relevance.

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Intranasal phage therapy overcomes antibody neutralization challenges in pulmonary Pseudomonas aeruginosa infections

Affiliations

Intranasal phage therapy overcomes antibody neutralization challenges in pulmonary Pseudomonas aeruginosa infections

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Miscellaneous