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Research Article | Host-Microbe Biology

Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia

Liang Li, Benjamin Jie Wei Foo, Ka Wai Kwok, Noriho Sakamoto, Hiroshi Mukae, Koichi Izumikawa, Stéphane Mandard, Jean-Pierre Quenot, Laurent Lagrost, Wooi Keong Teh, Gurjeet Singh Kohli, Pengcheng Zhu, Hyungwon Choi, Martin Lindsay Buist, Ju Ee Seet, Liang Yang, Fang He, Vincent Tak Kwong Chow, Nguan Soon Tan
Liise-anne Pirofski, Editor
Liang Li
Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Nanshan, Shenzhen, ChinaSchool of Biological Sciences, Nanyang Technological University, Singapore, Singapore
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Benjamin Jie Wei Foo
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
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Ka Wai Kwok
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
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Noriho Sakamoto
Department of Respiratory Medicine, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Hiroshi Mukae
Department of Respiratory Medicine, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Koichi Izumikawa
Department of Respiratory Medicine, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Stéphane Mandard
INSERM LNC, UMR1231, Dijon, FranceUniversity Bourgogne Franche-Comté, LNC UMR1231, Dijon, FranceLipSTIC LabEx, Fondation de Coopération Scientifique Bourgogne Franche-Comté, Dijon, France
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Jean-Pierre Quenot
INSERM LNC, UMR1231, Dijon, FranceLipSTIC LabEx, Fondation de Coopération Scientifique Bourgogne Franche-Comté, Dijon, FranceUniversity Hospital of Dijon, Dijon, FranceIntensive Care Unit, University Hospital of Dijon, Dijon, France
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Laurent Lagrost
INSERM LNC, UMR1231, Dijon, FranceUniversity Bourgogne Franche-Comté, LNC UMR1231, Dijon, FranceLipSTIC LabEx, Fondation de Coopération Scientifique Bourgogne Franche-Comté, Dijon, FranceUniversity Hospital of Dijon, Dijon, France
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Wooi Keong Teh
Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Interdisciplinary Graduate School, Nanyang Technological University, Singapore, Singapore
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  • ORCID record for Wooi Keong Teh
Gurjeet Singh Kohli
Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University, Singapore, Singapore
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Pengcheng Zhu
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
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Hyungwon Choi
Saw Swee Hock School of Public Health, National University of Singapore, Singapore
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Martin Lindsay Buist
Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore
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Ju Ee Seet
Department of Pathology, National University Hospital, Singapore, Singapore
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Liang Yang
School of Medicine, Southern University of Science and Technology, Shenzhen, ChinaSingapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University, Singapore, SingaporeSchool of Biological Sciences, Nanyang Technological University, Singapore, Singapore
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Fang He
Institute of Preventive Veterinary Medicine, and Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
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Vincent Tak Kwong Chow
Host and Pathogen Interactivity Laboratory, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Nguan Soon Tan
School of Biological Sciences, Nanyang Technological University, Singapore, SingaporeLee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
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Liise-anne Pirofski
Albert Einstein College of Medicine
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DOI: 10.1128/mBio.02469-18
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ABSTRACT

Secondary bacterial lung infection by Streptococcus pneumoniae (S. pneumoniae) poses a serious health concern, especially in developing countries. We posit that the emergence of multiantibiotic-resistant strains will jeopardize current treatments in these regions. Deaths arising from secondary infections are more often associated with acute lung injury, a common consequence of hypercytokinemia, than with the infection per se. Given that secondary bacterial pneumonia often has a poor prognosis, newer approaches to improve treatment outcomes are urgently needed to reduce the high levels of morbidity and mortality. Using a sequential dual-infection mouse model of secondary bacterial lung infection, we show that host-directed therapy via immunoneutralization of the angiopoietin-like 4 c-isoform (cANGPTL4) reduced pulmonary edema and damage in infected mice. RNA sequencing analysis revealed that anti-cANGPTL4 treatment improved immune and coagulation functions and reduced internal bleeding and edema. Importantly, anti-cANGPTL4 antibody, when used concurrently with either conventional antibiotics or antipneumolysin antibody, prolonged the median survival of mice compared to monotherapy. Anti-cANGPTL4 treatment enhanced immune cell phagocytosis of bacteria while restricting excessive inflammation. This modification of immune responses improved the disease outcomes of secondary pneumococcal pneumonia. Taken together, our study emphasizes that host-directed therapeutic strategies are viable adjuncts to standard antimicrobial treatments.

IMPORTANCE Despite extensive global efforts, secondary bacterial pneumonia still represents a major cause of death in developing countries and is an important cause of long-term functional disability arising from lung tissue damage. Newer approaches to improving treatment outcomes are needed to reduce the significant morbidity and mortality caused by infectious diseases. Our study, using an experimental mouse model of secondary S. pneumoniae infection, shows that a multimodal treatment that concurrently targets host and pathogen factors improved lung tissue integrity and extended the median survival time of infected mice. The immunoneutralization of host protein cANGPTL4 reduced the severity of pulmonary edema and damage. We show that host-directed therapeutic strategies as well as neutralizing antibodies against pathogen virulence factors are viable adjuncts to standard antimicrobial treatments such as antibiotics. In view of their different modes of action compared to antibiotics, concurrent immunotherapies using antibodies are potentially efficacious against secondary pneumococcal pneumonia caused by antibiotic-resistant pathogens.

  • Copyright © 2019 Li et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia
Liang Li, Benjamin Jie Wei Foo, Ka Wai Kwok, Noriho Sakamoto, Hiroshi Mukae, Koichi Izumikawa, Stéphane Mandard, Jean-Pierre Quenot, Laurent Lagrost, Wooi Keong Teh, Gurjeet Singh Kohli, Pengcheng Zhu, Hyungwon Choi, Martin Lindsay Buist, Ju Ee Seet, Liang Yang, Fang He, Vincent Tak Kwong Chow, Nguan Soon Tan
mBio Jun 2019, 10 (3) e02469-18; DOI: 10.1128/mBio.02469-18

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Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia
Liang Li, Benjamin Jie Wei Foo, Ka Wai Kwok, Noriho Sakamoto, Hiroshi Mukae, Koichi Izumikawa, Stéphane Mandard, Jean-Pierre Quenot, Laurent Lagrost, Wooi Keong Teh, Gurjeet Singh Kohli, Pengcheng Zhu, Hyungwon Choi, Martin Lindsay Buist, Ju Ee Seet, Liang Yang, Fang He, Vincent Tak Kwong Chow, Nguan Soon Tan
mBio Jun 2019, 10 (3) e02469-18; DOI: 10.1128/mBio.02469-18
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KEYWORDS

ANGPTL4
secondary bacterial pneumonia
antibiotic resistance
host-directed immunotherapeutics
vascular permeability

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