title: M1-like monocytes are a major immunological determinant of severity in previously healthy adults with life-threatening influenza.
abstract: 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 ofn= 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.
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Cole
authors.affiliation: National Heart and Lung Division, Imperial College London, St. Mary's Campus, London, United Kingdom.
authors.forename: Jake
authors.initials: J
authors.lastname: Dunning
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Wai Ling
authors.initials: WL
authors.lastname: Kok
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Kambez Hajipouran
authors.initials: KH
authors.lastname: Benam
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Adel
authors.initials: A
authors.lastname: Benlahrech
authors.affiliation: Computational Biology Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Emmanouela
authors.initials: E
authors.lastname: Repapi
authors.affiliation: School of Biosciences and Medicine, University of Surrey, Guildford, United Kingdom.
authors.forename: Fernando O
authors.initials: FO
authors.lastname: Martinez
authors.affiliation: National Heart and Lung Division, Imperial College London, St. Mary's Campus, London, United Kingdom.
authors.forename: Lydia
authors.initials: L
authors.lastname: Drumright
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Powell
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Bennett
authors.affiliation: Section of Virology, Faculty of Medicine, Wright Fleming Institute, Imperial College London, London, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Elderfield
authors.affiliation: National Infection Service, Public Health England, Colindale, London, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Thomas
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Tao
authors.initials: T
authors.lastname: Dong
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: McCauley
authors.affiliation: Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, United Kingdom.|School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
authors.affiliation: Computational Biology Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Taylor
authors.affiliation: National Infection Service, Public Health England, Colindale, London, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Zambon
authors.affiliation: Section of Virology, Faculty of Medicine, Wright Fleming Institute, Imperial College London, London, United Kingdom.
authors.forename: Wendy
authors.initials: W
authors.lastname: Barclay
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
authors.affiliation: National Heart and Lung Division, Imperial College London, St. Mary's Campus, London, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Openshaw
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Ling-Pei
authors.initials: LP
authors.lastname: Ho
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype; D007251:Influenza, Human / Q000276:immunology* / Q000473:pathology; D008168:Lung / Q000473:pathology / Q000821:virology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D010641:Phenotype; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019562:Viral Load; D055815:Young Adult
chemical_list: D014409:Tumor Necrosis Factor-alpha