Antibodies targeting phage fiber and nozzle proteins impair Acinetobacter baumannii phage therapy by blocking infection and promoting immune clearance
6 affiliations
- 1State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
- 2University of Chinese Academy of Sciences, Beijing, China
- 3Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
- 4Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
- 5Faculty of Medicine, Wroclaw University of Science and Technology, Wrocław, Poland
- 6Hubei Jiangxia Laboratory, Wuhan, China
Abstract
Phage therapy represents a promising strategy to tackle the growing threat of antimicrobial resistance. Increasing evidence has demonstrated that phage-specific antibodies may compromise the efficacy of phage therapy. Nevertheless, little is known about how phage protein specificity of antibodies modulates phage therapeutic outcomes. Herein, we utilized AbP20, a podovirus against Acinetobacter baumannii, to explore the effects of antibodies elicited by each structural protein on phage therapy efficacy in a mouse infection model. Intraperitoneal administration of AbP20 once a day for 7 consecutive days induced robust phage-specific antibody responses that impaired phage therapy. Genome-guided antigen screening identified that antibodies elicited by the nozzle and fiber proteins of AbP20, rather than those targeting the portal, capsid, or adaptor proteins, are the dominant drivers of phage therapy failure. Specifically, fiber-specific and nozzle-specific antibodies block bacterial adsorption and genomic injection of AbP20, respectively. Meanwhile, both antibody subsets efficiently induce large phage aggregates and potentiate macrophage phagocytosis via an Fc receptor-independent pathway. An evolved AbP20 variant with improved neutralization escape capacity exhibited comparable antibody-accelerated phagocytosis and host immune clearance, yet partially rescued therapeutic failure caused by neutralizing antibodies. Collectively, this study elucidates that nozzle- and fiber-elicited neutralizing antibodies impair phage therapy via dual synergistic mechanisms, which offers novel insights into the multifaceted modulation of phage-specific antibodies against phage therapeutic efficacy.
Phage therapy can fail when the immune system makes antibodies against therapeutic viruses. This study shows that fiber- and nozzle-specific antibodies block phage infection and promote aggregation-driven, Fc receptor-independent phagocytosis.
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BibTeX
@article{xue2026antibodies,
title = {{Antibodies targeting phage fiber and nozzle proteins impair Acinetobacter baumannii phage therapy by blocking infection and promoting immune clearance}},
author = {Heng Xue and Xinfeng Li and Guibo Rao and Fen Hu and Mingyue Zhong and Paulina Miernikiewicz and Rui Qiu and Sheng Cao and Krystyna Dąbrowska and Hang Yang},
journal = {PLOS Biology},
year = {2026},
month = sep,
doi = {10.1371/journal.pbio.3004009},
url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004009},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Antibodies targeting phage fiber and nozzle proteins impair Acinetobacter baumannii phage therapy by blocking infection and promoting immune clearance
AU - Heng Xue
AU - Xinfeng Li
AU - Guibo Rao
AU - Fen Hu
AU - Mingyue Zhong
AU - Paulina Miernikiewicz
AU - Rui Qiu
AU - Sheng Cao
AU - Krystyna Dąbrowska
AU - Hang Yang
PY - 2026
DA - 2026/09/22
JO - PLOS Biology
DO - 10.1371/journal.pbio.3004009
UR - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004009
AB - Phage therapy represents a promising strategy to tackle the growing threat of antimicrobial resistance. Increasing evidence has demonstrated that phage-specific antibodies may compromise the efficacy of phage therapy. Nevertheless, little is known about how phage protein specificity of antibodies modulates phage therapeutic outcomes. Herein, we utilized AbP20, a podovirus against Acinetobacter baumannii, to explore the effects of antibodies elicited by each structural protein on phage therapy efficacy in a mouse infection model. Intraperitoneal administration of AbP20 once a day for 7 consecutive days induced robust phage-specific antibody responses that impaired phage therapy. Genome-guided antigen screening identified that antibodies elicited by the nozzle and fiber proteins of AbP20, rather than those targeting the portal, capsid, or adaptor proteins, are the dominant drivers of phage therapy failure. Specifically, fiber-specific and nozzle-specific antibodies block bacterial adsorption and genomic injection of AbP20, respectively. Meanwhile, both antibody subsets efficiently induce large phage aggregates and potentiate macrophage phagocytosis via an Fc receptor-independent pathway. An evolved AbP20 variant with improved neutralization escape capacity exhibited comparable antibody-accelerated phagocytosis and host immune clearance, yet partially rescued therapeutic failure caused by neutralizing antibodies. Collectively, this study elucidates that nozzle- and fiber-elicited neutralizing antibodies impair phage therapy via dual synergistic mechanisms, which offers novel insights into the multifaceted modulation of phage-specific antibodies against phage therapeutic efficacy. Phage therapy can fail when the immune system makes antibodies against therapeutic viruses. This study shows that fiber- and nozzle-specific antibodies block phage infection and promote aggregation-driven, Fc receptor-independent phagocytosis.
SN - 1545-7885
ER -