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

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 second...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	ANGPTL4 secondary bacterial pneumonia antibiotic resistance host-directed immunotherapeutics vascular permeability Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1bf0767f133a40f4a35769c99d508b56
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spelling	oai:doaj.org-article:1bf0767f133a40f4a35769c99d508b562021-11-15T15:55:24ZAntibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia10.1128/mBio.02469-182150-7511https://doaj.org/article/1bf0767f133a40f4a35769c99d508b562019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02469-18https://doaj.org/toc/2150-7511ABSTRACT 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.Liang LiBenjamin Jie Wei FooKa Wai KwokNoriho SakamotoHiroshi MukaeKoichi IzumikawaStéphane MandardJean-Pierre QuenotLaurent LagrostWooi Keong TehGurjeet Singh KohliPengcheng ZhuHyungwon ChoiMartin Lindsay BuistJu Ee SeetLiang YangFang HeVincent Tak Kwong ChowNguan Soon TanAmerican Society for MicrobiologyarticleANGPTL4secondary bacterial pneumoniaantibiotic resistancehost-directed immunotherapeuticsvascular permeabilityMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	ANGPTL4 secondary bacterial pneumonia antibiotic resistance host-directed immunotherapeutics vascular permeability Microbiology QR1-502
spellingShingle	ANGPTL4 secondary bacterial pneumonia antibiotic resistance host-directed immunotherapeutics vascular permeability Microbiology QR1-502 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 Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia
description	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.
format	article
author	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
author_facet	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
author_sort	Liang Li
title	Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia
title_short	Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia
title_full	Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia
title_fullStr	Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia
title_full_unstemmed	Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia
title_sort	antibody treatment against angiopoietin-like 4 reduces pulmonary edema and injury in secondary pneumococcal pneumonia
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/1bf0767f133a40f4a35769c99d508b56
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Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia

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