Lack of group X secreted phospholipase A₂ increases survival following pandemic H1N1 influenza infection

Alyson A Kelvin; Norbert Degousee; David Banner; Eva Stefanski; Alberto J Leόn; Denis Angoulvant; Stéphane G Paquette; Stephen S H Huang; Ali Danesh; Clinton S Robbins; Hossein Noyan; Mansoor Husain; Gerard Lambeau; Michael Gelb; David J Kelvin; Barry B Rubin

doi:10.1016/j.virol.2014.01.030

Lack of group X secreted phospholipase A₂ increases survival following pandemic H1N1 influenza infection

Virology. 2014 Apr:454-455:78-92. doi: 10.1016/j.virol.2014.01.030. Epub 2014 Feb 25.

Authors

Alyson A Kelvin¹, Norbert Degousee², David Banner³, Eva Stefanski², Alberto J Leόn⁴, Denis Angoulvant⁵, Stéphane G Paquette⁶, Stephen S H Huang⁷, Ali Danesh⁸, Clinton S Robbins³, Hossein Noyan³, Mansoor Husain⁹, Gerard Lambeau¹⁰, Michael Gelb¹¹, David J Kelvin¹², Barry B Rubin²

Affiliations

¹ Immune Diagnostics & Research, Toronto, Ontario, Canada.
² Division of Vascular Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network and the University of Toronto, Toronto, Ontario, Canada.
³ Division of Experimental Therapeutics, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.
⁴ Division of Experimental Therapeutics, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; International Institute of Infection and Immunity, Shantou University Medical College, Shantou, Guangdong, China.
⁵ Division of Cardiology, Trousseau Hospital, Tours University Hospital Center and EA 4245, Francois Rabelais University, Tours, France.
⁶ Division of Experimental Therapeutics, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁷ Division of Experimental Therapeutics, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁸ Blood Systems Research Institute, San Francisco, CA 2-Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
⁹ Division of Experimental Therapeutics, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto, University Health Network, Toronto, Ontario, Canada.
¹⁰ Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS and Université de Nice Sophia Antipolis, IPMC, Sophia Antipolis, 06560 Valbonne, France.
¹¹ Departments of Chemistry and Biochemistry, University of Washington, Seattle, Washington, USA.
¹² Division of Experimental Therapeutics, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; International Institute of Infection and Immunity, Shantou University Medical College, Shantou, Guangdong, China; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Sezione di Microbiologia Sperimentale e Clinica, Dipartimento di Scienze Biomediche, Universita׳ degli Studi di Sassari, Sassari, Italy. Electronic address: dkelvin@uhnresearch.ca.

Abstract

The role of Group X secreted phospholipase A2 (GX-sPLA2) during influenza infection has not been previously investigated. We examined the role of GX-sPLA2 during H1N1 pandemic influenza infection in a GX-sPLA2 gene targeted mouse (GX(-/-)) model and found that survival after infection was significantly greater in GX(-/-) mice than in GX(+/+) mice. Downstream products of GX-sPLA2 activity, PGD2, PGE2, LTB4, cysteinyl leukotrienes and Lipoxin A4 were significantly lower in GX(-/-) mice BAL fluid. Lung microarray analysis identified an earlier and more robust induction of T and B cell associated genes in GX(-/-) mice. Based on the central role of sPLA2 enzymes as key initiators of inflammatory processes, we propose that activation of GX-sPLA2 during H1N1pdm infection is an early step of pulmonary inflammation and its inhibition increases adaptive immunity and improves survival. Our findings suggest that GX-sPLA2 may be a potential therapeutic target during influenza.

Keywords: H1N1 pandemic influenza; Host response; Inflammation; Influenza; Leukotrienes; Lipoxin A(4); Pathogenesis; Phospholipids; Prostaglandins; Secreted phospholipase A(2).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
B-Lymphocytes / immunology
Disease Models, Animal
Gene Expression Profiling
Group X Phospholipases A2 / deficiency*
Group X Phospholipases A2 / genetics
Influenza A Virus, H1N1 Subtype / immunology*
Lung / pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Microarray Analysis
Orthomyxoviridae Infections / pathology*
Orthomyxoviridae Infections / virology*
Survival Analysis
T-Lymphocytes / immunology

Substances

Group X Phospholipases A2

Abstract

Publication types

MeSH terms

Substances

Grants and funding