M1-like monocytes are a major immunological determinant of severity in previously healthy adults with life-threatening influenza

In each influenza season, a distinct group of young, otherwise healthy individuals with no risk factors succumbs to life-threatening infection. To better understand the cause for this, we analyzed a broad range of immune responses in blood from a unique cohort of patients, comprising previously healthy individuals hospitalized with and without respiratory failure during one influenza season, and infected with one specific influenza A strain. This analysis was compared with similarly hospitalized influenza patients with known risk factors (total of n = 60 patients recruited). We found a sustained increase in a specific subset of proinflammatory monocytes, with high TNF-α expression and an M1-like phenotype (independent of viral titers), in these previously healthy patients with severe disease. The relationship between M1-like monocytes and immunopathology was strengthened using murine models of influenza, in which severe infection generated using different models (including the high-pathogenicity H5N1 strain) was also accompanied by high levels of circulating M1-like monocytes. Additionally, a raised M1/M2 macrophage ratio in the lungs was observed. These studies identify a specific subtype of monocytes as a modifiable immunological determinant of disease severity in this subgroup of severely ill, previously healthy patients, offering potential novel therapeutic avenues.

[1]  K. Benam,et al.  How the Respiratory Epithelium Senses and Reacts to Influenza Virus , 2019, American journal of respiratory cell and molecular biology.

[2]  H. Rosenberg,et al.  Critical Adverse Impact of IL-6 in Acute Pneumovirus Infection , 2019, The Journal of Immunology.

[3]  L. Ho,et al.  Contribution of innate immune cells to pathogenesis of severe influenza virus infection. , 2017, Clinical science.

[4]  P. Thomas,et al.  Balancing Immune Protection and Immune Pathology by CD8+ T-Cell Responses to Influenza Infection , 2016, Front. Immunol..

[5]  J. Mejía-Aranguré,et al.  TNF, IL6, and IL1B Polymorphisms Are Associated with Severe Influenza A (H1N1) Virus Infection in the Mexican Population , 2015, PloS one.

[6]  A. Till,et al.  Lipoxin A4 Attenuates Obesity-Induced Adipose Inflammation and Associated Liver and Kidney Disease. , 2015, Cell metabolism.

[7]  Paul Kellam,et al.  Accumulation of Human-Adapting Mutations during Circulation of A(H1N1)pdm09 Influenza Virus in Humans in the United Kingdom , 2014, Journal of Virology.

[8]  S. Goerdt,et al.  Macrophage activation and polarization: nomenclature and experimental guidelines. , 2014, Immunity.

[9]  Akiko Iwasaki,et al.  Innate immunity to influenza virus infection , 2014, Nature Reviews Immunology.

[10]  S. Gordon,et al.  The M1 and M2 paradigm of macrophage activation: time for reassessment , 2014, F1000prime reports.

[11]  P. Goepfert,et al.  Immune Suppression by Neutrophils in HIV-1 Infection: Role of PD-L1/PD-1 Pathway , 2014, PLoS pathogens.

[12]  R. Webby,et al.  Mucosal immune responses predict clinical outcomes during influenza infection independently of age and viral load. , 2014, American journal of respiratory and critical care medicine.

[13]  T. Hussell,et al.  Alveolar macrophages: plasticity in a tissue-specific context , 2014, Nature Reviews Immunology.

[14]  L. Beckers,et al.  Reprogramming macrophages to an anti‐inflammatory phenotype by helminth antigens reduces murine atherosclerosis , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  H. Perlman,et al.  Flow cytometric analysis of macrophages and dendritic cell subsets in the mouse lung. , 2013, American journal of respiratory cell and molecular biology.

[16]  C. Karp,et al.  Role of the Lipoxygenase Pathway in RSV-induced Alternatively Activated Macrophages Leading to Resolution of Lung Pathology , 2013, Mucosal Immunology.

[17]  P. Thomas,et al.  Depletion of Alveolar Macrophages during Influenza Infection Facilitates Bacterial Superinfections , 2013, The Journal of Immunology.

[18]  Xiang Gao,et al.  Bacterial colonization dampens influenza-mediated acute lung injury via induction of M2 alveolar macrophages , 2013, Nature Communications.

[19]  Tao Dong,et al.  Examination of Influenza Specific T Cell Responses after Influenza Virus Challenge in Individuals Vaccinated with MVA-NP+M1 Vaccine , 2013, PloS one.

[20]  C. Carmona-Rivera,et al.  Low-density granulocytes: a distinct class of neutrophils in systemic autoimmunity , 2013, Seminars in Immunopathology.

[21]  S. Gordon,et al.  Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages: similarities and differences. , 2013, Blood.

[22]  Dayan Wang,et al.  Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals , 2013, Nature Communications.

[23]  I. Müller,et al.  Characterization of a Novel Population of Low-Density Granulocytes Associated with Disease Severity in HIV-1 Infection , 2012, PloS one.

[24]  J. Knight,et al.  Lupus neutrophils: ‘NET’ gain in understanding lupus pathogenesis , 2012, Current opinion in rheumatology.

[25]  M. Jordana,et al.  Critical role of natural killer cells in lung immunopathology during influenza infection in mice. , 2012, The Journal of infectious diseases.

[26]  Jean H. Chang,et al.  Implication of Inflammatory Macrophages, Nuclear Receptors, and Interferon Regulatory Factors in Increased Virulence of Pandemic 2009 H1N1 Influenza A Virus after Host Adaptation , 2012, Journal of Virology.

[27]  Paul Kellam,et al.  IFITM3 restricts the morbidity and mortality associated with influenza , 2012, Nature.

[28]  A. McMichael,et al.  Pivotal Advance: Invariant NKT cells reduce accumulation of inflammatory monocytes in the lungs and decrease immune‐pathology during severe influenza A virus infection , 2012, Journal of leukocyte biology.

[29]  D. Hume,et al.  Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. , 2012, Blood.

[30]  E. Pamer,et al.  Monocyte recruitment during infection and inflammation , 2011, Nature Reviews Immunology.

[31]  J. Rello,et al.  Imbalanced pro- and anti-Th17 responses (IL-17/granulocyte colony-stimulating factor) predict fatal outcome in 2009 pandemic influenza , 2011, Critical care.

[32]  P. Zabel,et al.  Myeloid‐derived suppressor cells in the peripheral blood of cancer patients contain a subset of immature neutrophils with impaired migratory properties , 2011, Journal of leukocyte biology.

[33]  Michael R. Elliott,et al.  Identification of a Novel Macrophage Phenotype That Develops in Response to Atherogenic Phospholipids via Nrf2 , 2010, Circulation research.

[34]  Tao Dong,et al.  Reduction of Natural Killer but Not Effector CD8 T Lymphoyctes in Three Consecutive Cases of Severe/Lethal H1N1/09 Influenza A Virus Infection , 2010, PloS one.

[35]  J. M. Bernal-Blanco,et al.  Severe Pneumonia Associated with Pandemic (H1N1) 2009 Outbreak, San Luis Potosí, Mexico , 2010, Emerging infectious diseases.

[36]  Robert Schechter,et al.  Factors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in California. , 2009, JAMA.

[37]  Jessica K. Alexander,et al.  Identification of Two Distinct Macrophage Subsets with Divergent Effects Causing either Neurotoxicity or Regeneration in the Injured Mouse Spinal Cord , 2009, The Journal of Neuroscience.

[38]  L. Becker,et al.  Single Nucleotide Polymorphisms in Monocyte Chemoattractant Protein-1 and Its Receptor Act Synergistically to Increase the Risk of Carotid Atherosclerosis , 2009, Cerebrovascular Diseases.

[39]  Scott A. Brown,et al.  TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection , 2009, Proceedings of the National Academy of Sciences.

[40]  Israel Steinfeld,et al.  BMC Bioinformatics BioMed Central , 2008 .

[41]  Matthias Mack,et al.  Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand , 2008, The Journal of experimental medicine.

[42]  Anneliese O. Speak,et al.  Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans. , 2008, The Journal of clinical investigation.

[43]  Lucy A. Perrone,et al.  H5N1 and 1918 Pandemic Influenza Virus Infection Results in Early and Excessive Infiltration of Macrophages and Neutrophils in the Lungs of Mice , 2008, PLoS pathogens.

[44]  E. Ramsburg,et al.  CCR2+ Monocyte-Derived Dendritic Cells and Exudate Macrophages Produce Influenza-Induced Pulmonary Immune Pathology and Mortality1 , 2008, The Journal of Immunology.

[45]  R. Webster,et al.  Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection , 2007, Proceedings of the National Academy of Sciences.

[46]  P. Doherty,et al.  A question of self‐preservation: immunopathology in influenza virus infection , 2007, Immunology and cell biology.

[47]  Yi Guan,et al.  Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia , 2006, Nature Medicine.

[48]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Angus Nicoll,et al.  Avian influenza A (H5N1) infection in humans. , 2005, The New England journal of medicine.

[50]  Silvano Sozzani,et al.  The chemokine system in diverse forms of macrophage activation and polarization. , 2004, Trends in immunology.

[51]  Z. Makita,et al.  Interferon-γ-induced apoptosis and activation of THP-1 macrophages , 2002 .

[52]  Roger E Bumgarner,et al.  Cellular transcriptional profiling in influenza A virus-infected lung epithelial cells: The role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[53]  N. Maeda,et al.  Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus. , 2000, The American journal of pathology.

[54]  K. Reeth Cytokines in the pathogenesis of influenza. , 2000 .

[55]  A. Kumar,et al.  Emergence of a Novel Swine-Origin Influenza A (H1N1) Virus in Humans , 2010 .

[56]  Z. Makita,et al.  Interferon-gamma-induced apoptosis and activation of THP-1 macrophages. , 2002, Life sciences.