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MBio. 2019 Jun 4;10(3). pii: e02469-18. doi: 10.1128/mBio.02469-18.

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

Author information

1
Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Nanshan, Shenzhen, China liang.li@siat.ac.cn nstan@ntu.edu.sg.
2
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
3
Department of Respiratory Medicine, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
4
INSERM LNC, UMR1231, Dijon, France.
5
University Bourgogne Franche-Comté, LNC UMR1231, Dijon, France.
6
LipSTIC LabEx, Fondation de Coopération Scientifique Bourgogne Franche-Comté, Dijon, France.
7
University Hospital of Dijon, Dijon, France.
8
Intensive Care Unit, University Hospital of Dijon, Dijon, France.
9
Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Interdisciplinary Graduate School, Nanyang Technological University, Singapore, Singapore.
10
Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University, Singapore, Singapore.
11
Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
12
Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore.
13
Department of Pathology, National University Hospital, Singapore, Singapore.
14
School of Medicine, Southern University of Science and Technology, Shenzhen, China.
15
Institute of Preventive Veterinary Medicine, and Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China.
16
Host and Pathogen Interactivity Laboratory, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
17
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore liang.li@siat.ac.cn nstan@ntu.edu.sg.
18
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.

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.

KEYWORDS:

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

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