Platelet-activating factor receptor plays a role in lung injury and death caused by Influenza A in mice

• Published in: PLoS pathogens Vol. 6; no. 11; p. e1001171
• Main Authors: Garcia, Cristiana C, Russo, Remo C, Guabiraba, Rodrigo, Fagundes, Caio T, Polidoro, Rafael B, Tavares, Luciana P, Salgado, Ana Paula C, Cassali, Geovanni D, Sousa, Lirlândia P, Machado, Alexandre V, Teixeira, Mauro M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-11-2010; Public Library of Science (PLoS)
• Subjects: Animal experimentation; Animals; Antiviral agents; Apoptosis; Blotting, Western; Chemokines; Chickens; Complications and side effects; Cytokines; Demographic aspects; Dihydropyridines - pharmacology; Disease Models, Animal; Health aspects; Immunology; Immunology/Immunity to Infections; Infections; Infectious Diseases/Respiratory Infections; Infectious Diseases/Viral Infections; Inflammation Mediators - metabolism; Influenza; Influenza A virus; Influenza A Virus, H1N1 Subtype - genetics; Influenza A Virus, H1N1 Subtype - pathogenicity; Life Sciences; Lung diseases; Lung Injury - metabolism; Lung Injury - prevention & control; Lung Injury - virology; Lungs; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Orthomyxoviridae Infections - metabolism; Orthomyxoviridae Infections - prevention & control; Orthomyxoviridae Infections - virology; Pandemics; Pathology; Physiological aspects; Platelet activating factor; Platelet Activating Factor - genetics; Platelet Activating Factor - metabolism; Platelet Membrane Glycoproteins - antagonists & inhibitors; Platelet Membrane Glycoproteins - physiology; Prevention; Proteins; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - physiology; Recruitment; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; RNA, Messenger - genetics; Rodents; Survival Rate; Swine influenza; Toll-Like Receptors - genetics; Toll-Like Receptors - metabolism; Viral infections; Viral Load; Virology/Animal Models of Infection; Brazil
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1001171

Influenza A virus causes annual epidemics which affect millions of people worldwide. A recent Influenza pandemic brought new awareness over the health impact of the disease. It is thought that a severe inflammatory response against the virus contributes to disease severity and death. Therefore, modulating the effects of inflammatory mediators may represent a new therapy against Influenza infection. Platelet activating factor (PAF) receptor (PAFR) deficient mice were used to evaluate the role of the gene in a model of experimental infection with Influenza A/WSN/33 H1N1 or a reassortant Influenza A H3N1 subtype. The following parameters were evaluated: lethality, cell recruitment to the airways, lung pathology, viral titers and cytokine levels in lungs. The PAFR antagonist PCA4248 was also used after the onset of flu symptoms. Absence or antagonism of PAFR caused significant protection against flu-associated lethality and lung injury. Protection was correlated with decreased neutrophil recruitment, lung edema, vascular permeability and injury. There was no increase of viral load and greater recruitment of NK1.1(+) cells. Antibody responses were similar in WT and PAFR-deficient mice and animals were protected from re-infection. Influenza infection induces the enzyme that synthesizes PAF, lyso-PAF acetyltransferase, an effect linked to activation of TLR7/8. Therefore, it is suggested that PAFR is a disease-associated gene and plays an important role in driving neutrophil influx and lung damage after infection of mice with two subtypes of Influenza A. Further studies should investigate whether targeting PAFR may be useful to reduce lung pathology associated with Influenza A virus infection in humans.