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PLoS Pathog. Platelet-Activating Factor Receptor Plays a Role in Lung Injury and Death Caused by Influenza A in Mice
Platelet-Activating Factor Receptor Plays a Role in Lung Injury and Death Caused by Influenza A in Mice (PLoS Pathogens, abstract, edited)
[Source: PLoS Pathogens, full text: <cite cite="http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1001171?utm_so urce=feedburner&utm_medium=feed&utm_campaign=Feed% 3A+plospathogens%2FNewArticles+%28Ambra+-+Pathogens+New+Articles%29">PLoS Pathogens: Platelet-Activating Factor Receptor Plays a Role in Lung Injury and Death Caused by Influenza A in Mice</cite>. Abstract, edited.]
Platelet-Activating Factor Receptor Plays a Role in Lung Injury and Death Caused by Influenza A in Mice
Cristiana C. Garcia 1, Remo C. Russo 1, Rodrigo Guabiraba 1, Caio T. Fagundes 1, Rafael B. Polidoro 1, Luciana P. Tavares 1, Ana Paula C. Salgado 2, Geovanni D. Cassali 3, Lirl?ndia P. Sousa 4, Alexandre V. Machado 2, Mauro M. Teixeira 1*
1 Departamento de Bioqu?mica e Imunologia, Instituto de Ci?ncias Biol?gicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil,
2 Centro de Pesquisas Ren? Rachou, Funda??o Oswaldo Cruz, Belo Horizonte, MG, Brazil,
3 Departamento de Patologia, Instituto de Ci?ncias Biol?gicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil,
4 Departamento de An?lises Cl?nicas e Toxicol?gicas, Faculdade de Farm?cia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
Abstract
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.
Author Summary
Influenza virus causes disease that affects people from different age, gender or social conditions. The illness spreads easily and affects millions of people every year. Vaccines are effective preventive approaches, but the high degree of viral antigenic drift requires annual formulation. Anti-viral drugs are used as therapy, but are only effective at the very early stages of disease. The main symptoms that lead to hospitalizations and deaths are associated with the severe inflammatory host immune response triggered by the virus infection. Our approach was to decrease the inflammatory events associated with the viral infection by targeting a molecule, Platelet Activating Factor receptor (PAFR), known to induce several inflammatory events, including leukocyte recruitment and leakage. We found that PAFR deficient mice or wild type mice treated with a PAFR antagonist had less pulmonary inflammation, pulmonary injury and lethality rates when infected by two subtypes of Influenza A virus. In contrast, the immune response against the virus, as assessed by viral loads and specific antibodies, were not decreased. Our findings concur with the idea that severe inflammation plays an important role in flu morbidity and mortality and show that PAFR is a major driver of the exacerbated inflammation in mice infected with Influenza A virus.
Citation: Garcia CC, Russo RC, Guabiraba R, Fagundes CT, Polidoro RB, et al. (2010) Platelet-Activating Factor Receptor Plays a Role in Lung Injury and Death Caused by Influenza A in Mice. PLoS Pathog 6(11): e1001171. doi:10.1371/journal.ppat.1001171
Editor: Ron A. M. Fouchier, Erasmus Medical Center, Netherlands
Received: April 19, 2010; Accepted: September 29, 2010; Published: November 4, 2010
Copyright: ? 2010 Garcia et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This investigation received financial support from Coordenacao de Aperfeicoamento de Pessoal de Ni*vel Superior (CAPES/Brazil), Conselho Nacional de Desenvolvimento Cienti*fico e Tecnologico (CNPq/Brazil), Instituto Nacional de Ciencia e Tecnologia em Dengue (ICNT em Dengue/Brazil) and Fundacao do Amparo a Pesquisas do Estado de Minas Gerais (FAPEMIG/Brazil). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: mmtex@icb.ufmg.br
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[Source: PLoS Pathogens, full text: <cite cite="http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1001171?utm_so urce=feedburner&utm_medium=feed&utm_campaign=Feed% 3A+plospathogens%2FNewArticles+%28Ambra+-+Pathogens+New+Articles%29">PLoS Pathogens: Platelet-Activating Factor Receptor Plays a Role in Lung Injury and Death Caused by Influenza A in Mice</cite>. Abstract, edited.]
Platelet-Activating Factor Receptor Plays a Role in Lung Injury and Death Caused by Influenza A in Mice
Cristiana C. Garcia 1, Remo C. Russo 1, Rodrigo Guabiraba 1, Caio T. Fagundes 1, Rafael B. Polidoro 1, Luciana P. Tavares 1, Ana Paula C. Salgado 2, Geovanni D. Cassali 3, Lirl?ndia P. Sousa 4, Alexandre V. Machado 2, Mauro M. Teixeira 1*
1 Departamento de Bioqu?mica e Imunologia, Instituto de Ci?ncias Biol?gicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil,
2 Centro de Pesquisas Ren? Rachou, Funda??o Oswaldo Cruz, Belo Horizonte, MG, Brazil,
3 Departamento de Patologia, Instituto de Ci?ncias Biol?gicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil,
4 Departamento de An?lises Cl?nicas e Toxicol?gicas, Faculdade de Farm?cia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
Abstract
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.
Author Summary
Influenza virus causes disease that affects people from different age, gender or social conditions. The illness spreads easily and affects millions of people every year. Vaccines are effective preventive approaches, but the high degree of viral antigenic drift requires annual formulation. Anti-viral drugs are used as therapy, but are only effective at the very early stages of disease. The main symptoms that lead to hospitalizations and deaths are associated with the severe inflammatory host immune response triggered by the virus infection. Our approach was to decrease the inflammatory events associated with the viral infection by targeting a molecule, Platelet Activating Factor receptor (PAFR), known to induce several inflammatory events, including leukocyte recruitment and leakage. We found that PAFR deficient mice or wild type mice treated with a PAFR antagonist had less pulmonary inflammation, pulmonary injury and lethality rates when infected by two subtypes of Influenza A virus. In contrast, the immune response against the virus, as assessed by viral loads and specific antibodies, were not decreased. Our findings concur with the idea that severe inflammation plays an important role in flu morbidity and mortality and show that PAFR is a major driver of the exacerbated inflammation in mice infected with Influenza A virus.
Citation: Garcia CC, Russo RC, Guabiraba R, Fagundes CT, Polidoro RB, et al. (2010) Platelet-Activating Factor Receptor Plays a Role in Lung Injury and Death Caused by Influenza A in Mice. PLoS Pathog 6(11): e1001171. doi:10.1371/journal.ppat.1001171
Editor: Ron A. M. Fouchier, Erasmus Medical Center, Netherlands
Received: April 19, 2010; Accepted: September 29, 2010; Published: November 4, 2010
Copyright: ? 2010 Garcia et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This investigation received financial support from Coordenacao de Aperfeicoamento de Pessoal de Ni*vel Superior (CAPES/Brazil), Conselho Nacional de Desenvolvimento Cienti*fico e Tecnologico (CNPq/Brazil), Instituto Nacional de Ciencia e Tecnologia em Dengue (ICNT em Dengue/Brazil) and Fundacao do Amparo a Pesquisas do Estado de Minas Gerais (FAPEMIG/Brazil). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: mmtex@icb.ufmg.br
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