Complement C5 Activation during Influenza A Infection in Mice Contributes to Neutrophil Recruitment and Lung Injury
Identifieur interne : 000B62 ( Pmc/Curation ); précédent : 000B61; suivant : 000B63Complement C5 Activation during Influenza A Infection in Mice Contributes to Neutrophil Recruitment and Lung Injury
Auteurs : Cristiana C. Garcia [Brésil] ; Wynne Weston-Davies [Royaume-Uni] ; Remo C. Russo [Brésil] ; Luciana P. Tavares [Brésil] ; Milene A. Rachid [Brésil] ; José C. Alves-Filho [Brésil] ; Alexandre V. Machado [Brésil] ; Bernhard Ryffel [Afrique du Sud] ; Miles A. Nunn [Royaume-Uni] ; Mauro M. Teixeira [Brésil]Source :
- PLoS ONE [ 1932-6203 ] ; 2013.
Abstract
Influenza virus A (IAV) causes annual epidemics and intermittent pandemics that affect millions of people worldwide. Potent inflammatory responses are commonly associated with severe cases of IAV infection. The complement system, an important mechanism of innate and humoral immune responses to infections, is activated during primary IAV infection and mediates, in association with natural IgM, viral neutralization by virion aggregation and coating of viral hemmagglutinin. Increased levels of the anaphylatoxin C5a were found in patients fatally infected with the most recent H1N1 pandemic virus. In this study, our aim was to evaluate whether targeting C5 activation alters inflammatory lung injury and viral load in a murine model of IAV infection. To address this question C57Bl/6j mice were infected intranasally with 104 PFU of the mouse adapted Influenza A virus A/WSN/33 (H1N1) or inoculated with PBS (Mock). We demonstrated that C5a is increased in bronchoalveolar lavage fluid (BALF) upon experimental IAV infection. To evaluate the role of C5, we used OmCI, a potent arthropod-derived inhibitor of C5 activation that binds to C5 and prevents release of C5a by complement. OmCI was given daily by intraperitoneal injection from the day of IAV infection until day 5. Treatment with OmCI only partially reduced C5a levels in BALF. However, there was significant inhibition of neutrophil and macrophage infiltration in the airways, Neutrophil Extracellular Traps (NETs) formation, death of leukocytes, lung epithelial injury and overall lung damage induced by the infection. There was no effect on viral load. Taken together, these data suggest that targeting C5 activation with OmCI during IAV infection could be a promising approach to reduce excessive inflammatory reactions associated with the severe forms of IAV infections.
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DOI: 10.1371/journal.pone.0064443
PubMed: 23696894
PubMed Central: 3655967
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Tavares</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil</addr-line></nlm:aff><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais</wicri:regionArea></affiliation></author><author><name sortKey="Rachid, Milene A" sort="Rachid, Milene A" uniqKey="Rachid M" first="Milene A." last="Rachid">Milene A. Rachid</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil</addr-line></nlm:aff><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Departamento de Patologia Geral, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil</addr-line></nlm:aff><country xml:lang="fr">Brésil</country><wicri:regionArea>Departamento de Patologia Geral, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais</wicri:regionArea></affiliation></author><author><name sortKey="Alves Filho, Jose C" sort="Alves Filho, Jose C" uniqKey="Alves Filho J" first="José C." last="Alves-Filho">José C. Alves-Filho</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil</addr-line></nlm:aff><country xml:lang="fr">Brésil</country><wicri:regionArea>Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo</wicri:regionArea></affiliation></author><author><name sortKey="Machado, Alexandre V" sort="Machado, Alexandre V" uniqKey="Machado A" first="Alexandre V." last="Machado">Alexandre V. Machado</name><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil</addr-line></nlm:aff><country xml:lang="fr">Brésil</country><wicri:regionArea>Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais</wicri:regionArea></affiliation></author><author><name sortKey="Ryffel, Bernhard" sort="Ryffel, Bernhard" uniqKey="Ryffel B" first="Bernhard" last="Ryffel">Bernhard Ryffel</name><affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>CNRS UMR7355, CNRS and University Orleans, France and IIDMM, University of Cape Town, Cape Town, South Africa</addr-line></nlm:aff><country xml:lang="fr">Afrique du Sud</country><wicri:regionArea>CNRS UMR7355, CNRS and University Orleans, France and IIDMM, University of Cape Town, Cape Town</wicri:regionArea></affiliation></author><author><name sortKey="Nunn, Miles A" sort="Nunn, Miles A" uniqKey="Nunn M" first="Miles A." last="Nunn">Miles A. Nunn</name><affiliation wicri:level="1"><nlm:aff id="aff8"><addr-line>Centre for Ecology and Hydrology, Wallingford, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Ecology and Hydrology, Wallingford</wicri:regionArea></affiliation></author><author><name sortKey="Teixeira, Mauro M" sort="Teixeira, Mauro M" uniqKey="Teixeira M" first="Mauro M." last="Teixeira">Mauro M. Teixeira</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil</addr-line></nlm:aff><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Influenza virus A (IAV) causes annual epidemics and intermittent pandemics that affect millions of people worldwide. Potent inflammatory responses are commonly associated with severe cases of IAV infection. The complement system, an important mechanism of innate and humoral immune responses to infections, is activated during primary IAV infection and mediates, in association with natural IgM, viral neutralization by virion aggregation and coating of viral hemmagglutinin. Increased levels of the anaphylatoxin C5a were found in patients fatally infected with the most recent H1N1 pandemic virus. In this study, our aim was to evaluate whether targeting C5 activation alters inflammatory lung injury and viral load in a murine model of IAV infection. To address this question C57Bl/6j mice were infected intranasally with 10<sup>4</sup> PFU of the mouse adapted Influenza A virus A/WSN/33 (H1N1) or inoculated with PBS (Mock). We demonstrated that C5a is increased in bronchoalveolar lavage fluid (BALF) upon experimental IAV infection. To evaluate the role of C5, we used OmCI, a potent arthropod-derived inhibitor of C5 activation that binds to C5 and prevents release of C5a by complement. OmCI was given daily by intraperitoneal injection from the day of IAV infection until day 5. Treatment with OmCI only partially reduced C5a levels in BALF. However, there was significant inhibition of neutrophil and macrophage infiltration in the airways, Neutrophil Extracellular Traps (NETs) formation, death of leukocytes, lung epithelial injury and overall lung damage induced by the infection. There was no effect on viral load. Taken together, these data suggest that targeting C5 activation with OmCI during IAV infection could be a promising approach to reduce excessive inflammatory reactions associated with the severe forms of IAV infections.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Nascimento, Ej" uniqKey="Nascimento E">EJ Nascimento</name></author><author><name sortKey="Silva, Am" uniqKey="Silva A">AM Silva</name></author><author><name sortKey="Cordeiro, Mt" uniqKey="Cordeiro M">MT Cordeiro</name></author><author><name sortKey="Brito, Ca" uniqKey="Brito C">CA Brito</name></author><author><name sortKey="Gil, Lh" uniqKey="Gil L">LH Gil</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kanmura, S" uniqKey="Kanmura S">S Kanmura</name></author><author><name sortKey="Uto, H" uniqKey="Uto H">H Uto</name></author><author><name sortKey="Sato, Y" uniqKey="Sato Y">Y 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">23696894</article-id><article-id pub-id-type="pmc">3655967</article-id><article-id pub-id-type="publisher-id">PONE-D-12-29332</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0064443</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune System</subject><subj-group><subject>Complement System</subject></subj-group></subj-group><subj-group><subject>Immunopathology</subject></subj-group></subj-group><subj-group><subject>Microbiology</subject><subj-group><subject>Immunity</subject><subj-group><subject>Inflammation</subject><subject>Innate Immunity</subject></subj-group></subj-group><subj-group><subject>Virology</subject><subj-group><subject>Animal Models of Infection</subject></subj-group></subj-group><subj-group><subject>Host-Pathogen Interaction</subject><subject>Pathogenesis</subject></subj-group></subj-group><subj-group><subject>Model Organisms</subject><subj-group><subject>Animal Models</subject><subj-group><subject>Mouse</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Medicine</subject><subj-group><subject>Infectious Diseases</subject><subj-group><subject>Viral Diseases</subject><subj-group><subject>Influenza</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Complement C5 Activation during Influenza A Infection in Mice Contributes to Neutrophil Recruitment and Lung Injury</article-title><alt-title alt-title-type="running-head">The Role of C5 Activation in Influenza A Infection</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Garcia</surname><given-names>Cristiana C.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Weston-Davies</surname><given-names>Wynne</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Russo</surname><given-names>Remo C.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tavares</surname><given-names>Luciana P.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rachid</surname><given-names>Milene A.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Alves-Filho</surname><given-names>José C.</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Machado</surname><given-names>Alexandre V.</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ryffel</surname><given-names>Bernhard</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nunn</surname><given-names>Miles A.</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Teixeira</surname><given-names>Mauro M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Varleigh Ltd, London, United Kingdom</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Departamento de Fisiologia e Biofísica, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Departamento de Patologia Geral, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil</addr-line></aff><aff id="aff5"><label>5</label><addr-line>Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil</addr-line></aff><aff id="aff7"><label>7</label><addr-line>CNRS UMR7355, CNRS and University Orleans, France and IIDMM, University of Cape Town, Cape Town, South Africa</addr-line></aff><aff id="aff8"><label>8</label><addr-line>Centre for Ecology and Hydrology, Wallingford, United Kingdom</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Chan</surname><given-names>Michael C. W.</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Centre of Influenza Research, The University of Hong Kong, Hong Kong</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>mmtex@icb.ufmg.br</email></corresp><fn fn-type="COI-statement"><p><bold>Competing Interests: </bold>The authors have the following interests. The author Dr. Wynne Weston-Davies is the Medical Director of Varleigh Ltd, the company that developed and supplied the C5a inhibitor, OmCI or coversin, used in this study. Co-authors Jose Carlos Alves-Filho and Bernhard Ryffel are PLOS ONE Editorial Board members. There are no further patents, products in development, or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.</p></fn><fn fn-type="con"><p>Conceived and designed the experiments: CCG WW RCR BR MN MMT. Performed the experiments: CCG RCR LPT MAR AVM JCAF. Analyzed the data: CCG RCR LPT MAR. Contributed reagents/materials/analysis tools: WW AVM MN BR JCAF. Wrote the paper: CCG WW MN MMT.</p></fn></author-notes><pub-date pub-type="collection"><year>2013</year></pub-date><pub-date pub-type="epub"><day>16</day><month>5</month><year>2013</year></pub-date><volume>8</volume><issue>5</issue><elocation-id>e64443</elocation-id><history><date date-type="received"><day>24</day><month>9</month><year>2012</year></date><date date-type="accepted"><day>15</day><month>4</month><year>2013</year></date></history><permissions><copyright-statement>© 2013 Garcia et al</copyright-statement><copyright-year>2013</copyright-year><copyright-holder>Garcia et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>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 properly credited.</license-p></license></permissions><abstract><p>Influenza virus A (IAV) causes annual epidemics and intermittent pandemics that affect millions of people worldwide. Potent inflammatory responses are commonly associated with severe cases of IAV infection. The complement system, an important mechanism of innate and humoral immune responses to infections, is activated during primary IAV infection and mediates, in association with natural IgM, viral neutralization by virion aggregation and coating of viral hemmagglutinin. Increased levels of the anaphylatoxin C5a were found in patients fatally infected with the most recent H1N1 pandemic virus. In this study, our aim was to evaluate whether targeting C5 activation alters inflammatory lung injury and viral load in a murine model of IAV infection. To address this question C57Bl/6j mice were infected intranasally with 10<sup>4</sup> PFU of the mouse adapted Influenza A virus A/WSN/33 (H1N1) or inoculated with PBS (Mock). We demonstrated that C5a is increased in bronchoalveolar lavage fluid (BALF) upon experimental IAV infection. To evaluate the role of C5, we used OmCI, a potent arthropod-derived inhibitor of C5 activation that binds to C5 and prevents release of C5a by complement. OmCI was given daily by intraperitoneal injection from the day of IAV infection until day 5. Treatment with OmCI only partially reduced C5a levels in BALF. However, there was significant inhibition of neutrophil and macrophage infiltration in the airways, Neutrophil Extracellular Traps (NETs) formation, death of leukocytes, lung epithelial injury and overall lung damage induced by the infection. There was no effect on viral load. Taken together, these data suggest that targeting C5 activation with OmCI during IAV infection could be a promising approach to reduce excessive inflammatory reactions associated with the severe forms of IAV infections.</p></abstract><funding-group><funding-statement>The authors were funded by the National Institute of Science and Technology in Dengue (INCT Dengue) and the National Institute of Science and Technology in Vaccines (INCTV) from CNPq/Fapemig. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><page-count count="11"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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