Giuseppe
Emeritus
[Source: PLoS Pathogens, full text: (LINK). Abstract, edited.]
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Quantitative Subcellular Proteome and Secretome Profiling of Influenza A Virus-Infected Human Primary Macrophages
Niina Lietz?n<SUP>1</SUP>, Tiina ?hman<SUP>1</SUP><SUP>#</SUP>, Johanna Rintahaka<SUP>2</SUP><SUP>#</SUP>, Ilkka Julkunen<SUP>3</SUP>, Tero Aittokallio<SUP>4</SUP>, Sampsa Matikainen<SUP>2</SUP><SUP>?</SUP>, Tuula A. Nyman<SUP>1</SUP><SUP>?</SUP><SUP>*</SUP>
<SUP></SUP>
1 Institute of Biotechnology, University of Helsinki, Helsinki, Finland, 2 Finnish Institute of Occupational Health, Helsinki, Finland, 3 National Institute for Health and Welfare, Helsinki, Finland, 4 Department of Mathematics, University of Turku, Turku, Finland
Abstract
Influenza A viruses are important pathogens that cause acute respiratory diseases and annual epidemics in humans. Macrophages recognize influenza A virus infection with their pattern recognition receptors, and are involved in the activation of proper innate immune response. Here, we have used high-throughput subcellular proteomics combined with bioinformatics to provide a global view of host cellular events that are activated in response to influenza A virus infection in human primary macrophages. We show that viral infection regulates the expression and/or subcellular localization of more than one thousand host proteins at early phases of infection. Our data reveals that there are dramatic changes in mitochondrial and nuclear proteomes in response to infection. We show that a rapid cytoplasmic leakage of lysosomal proteins, including cathepsins, followed by their secretion, contributes to inflammasome activation and apoptosis seen in the infected macrophages. Also, our results demonstrate that P2X<SUB>7</SUB> receptor and src tyrosine kinase activity are essential for inflammasome activation during influenza A virus infection. Finally, we show that influenza A virus infection is associated with robust secretion of different danger-associated molecular patterns (DAMPs) suggesting an important role for DAMPs in host response to influenza A virus infection. In conclusion, our high-throughput quantitative proteomics study provides important new insight into host-response against influenza A virus infection in human primary macrophages.
Author Summary
Influenza A viruses are negative-stranded RNA viruses that are capable of infecting a variety of avian and mammalian species. These viruses are responsible for the annual epidemics that cause severe illnesses in millions of people worldwide. The initial innate immune responses to influenza A viruses have to restrict virus spread before the adaptive immune responses fully develop. Macrophages are the key players of innate immune system and they have a central role in the activation of host response during viral infections. However, the host factors that are involved in the activation of innate immune response during influenza A virus infection are incompletely understood. Here, we have characterized in detail the nuclear, mitochondrial and cytoplasmic proteomes, as well as the secretome from influenza A virus-infected human primary macrophages to get a global view of host factors that are affected by the infection. Our approach allowed us to identify several novel host factors that contribute to innate immune system during influenza A virus infections. These include lysomal proteases cathepsins, P2X<SUB>7</SUB> receptor, src family tyrosine kinases as well as several danger-associated molecular patterns.
Citation: Lietz?n N, ?hman T, Rintahaka J, Julkunen I, Aittokallio T, et al. (2011) Quantitative Subcellular Proteome and Secretome Profiling of Influenza A Virus-Infected Human Primary Macrophages. PLoS Pathog 7(5): e1001340. doi:10.1371/journal.ppat.1001340
Editor: Akiko Iwasaki, Yale University School of Medicine, United States of America
Received: September 23, 2010; Accepted: April 11, 2011;
Published: May 12, 2011
Copyright: ? 2011 Lietz?n 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 work was supported by the Academy of Finland grant 114437, the Sigrid Juselius Foundation, and Helsinki Graduate Program in Biotechnology and Molecular Biology. 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: tuula.nyman@helsinki.fi
# These authors contributed equally to this work.
? These authors also contributed equally to this work.
-Niina Lietz?n<SUP>1</SUP>, Tiina ?hman<SUP>1</SUP><SUP>#</SUP>, Johanna Rintahaka<SUP>2</SUP><SUP>#</SUP>, Ilkka Julkunen<SUP>3</SUP>, Tero Aittokallio<SUP>4</SUP>, Sampsa Matikainen<SUP>2</SUP><SUP>?</SUP>, Tuula A. Nyman<SUP>1</SUP><SUP>?</SUP><SUP>*</SUP>
<SUP></SUP>
1 Institute of Biotechnology, University of Helsinki, Helsinki, Finland, 2 Finnish Institute of Occupational Health, Helsinki, Finland, 3 National Institute for Health and Welfare, Helsinki, Finland, 4 Department of Mathematics, University of Turku, Turku, Finland
Abstract
Influenza A viruses are important pathogens that cause acute respiratory diseases and annual epidemics in humans. Macrophages recognize influenza A virus infection with their pattern recognition receptors, and are involved in the activation of proper innate immune response. Here, we have used high-throughput subcellular proteomics combined with bioinformatics to provide a global view of host cellular events that are activated in response to influenza A virus infection in human primary macrophages. We show that viral infection regulates the expression and/or subcellular localization of more than one thousand host proteins at early phases of infection. Our data reveals that there are dramatic changes in mitochondrial and nuclear proteomes in response to infection. We show that a rapid cytoplasmic leakage of lysosomal proteins, including cathepsins, followed by their secretion, contributes to inflammasome activation and apoptosis seen in the infected macrophages. Also, our results demonstrate that P2X<SUB>7</SUB> receptor and src tyrosine kinase activity are essential for inflammasome activation during influenza A virus infection. Finally, we show that influenza A virus infection is associated with robust secretion of different danger-associated molecular patterns (DAMPs) suggesting an important role for DAMPs in host response to influenza A virus infection. In conclusion, our high-throughput quantitative proteomics study provides important new insight into host-response against influenza A virus infection in human primary macrophages.
Author Summary
Influenza A viruses are negative-stranded RNA viruses that are capable of infecting a variety of avian and mammalian species. These viruses are responsible for the annual epidemics that cause severe illnesses in millions of people worldwide. The initial innate immune responses to influenza A viruses have to restrict virus spread before the adaptive immune responses fully develop. Macrophages are the key players of innate immune system and they have a central role in the activation of host response during viral infections. However, the host factors that are involved in the activation of innate immune response during influenza A virus infection are incompletely understood. Here, we have characterized in detail the nuclear, mitochondrial and cytoplasmic proteomes, as well as the secretome from influenza A virus-infected human primary macrophages to get a global view of host factors that are affected by the infection. Our approach allowed us to identify several novel host factors that contribute to innate immune system during influenza A virus infections. These include lysomal proteases cathepsins, P2X<SUB>7</SUB> receptor, src family tyrosine kinases as well as several danger-associated molecular patterns.
Citation: Lietz?n N, ?hman T, Rintahaka J, Julkunen I, Aittokallio T, et al. (2011) Quantitative Subcellular Proteome and Secretome Profiling of Influenza A Virus-Infected Human Primary Macrophages. PLoS Pathog 7(5): e1001340. doi:10.1371/journal.ppat.1001340
Editor: Akiko Iwasaki, Yale University School of Medicine, United States of America
Received: September 23, 2010; Accepted: April 11, 2011;
Published: May 12, 2011
Copyright: ? 2011 Lietz?n 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 work was supported by the Academy of Finland grant 114437, the Sigrid Juselius Foundation, and Helsinki Graduate Program in Biotechnology and Molecular Biology. 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: tuula.nyman@helsinki.fi
# These authors contributed equally to this work.
? These authors also contributed equally to this work.
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