Journal
JCI INSIGHT
Volume 2, Issue 7, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.91868
Keywords
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Categories
Funding
- Wellcome Trust
- Medical Research Council (MRC) [U117585868, U117512723, G0600371]
- Higher Education Funding Council for England Senior Fellow
- SLC
- MOSAIC [090382/Z/09/Z]
- Imperial College's Comprehensive Biomedical Research Centre
- Asthma UK [MRC-Asthma UK Centre, MRC-AsthmaUKCentre] Funding Source: researchfish
- Medical Research Council [G1000758B, MC_G1001212, MC_UU_00008/1, G1000758, MR/R502121/1, G0600371, MC_UU_12010/1, G0600520, MC_U117585868, G1001046, MC_U117512723, MR/L018942/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10150] Funding Source: researchfish
- The Francis Crick Institute [10030] Funding Source: researchfish
- MRC [MC_UU_12010/1, MC_UU_00008/1, MC_U117512723, G0600371, MC_G1001212, G1001046, G0600520, MR/L018942/1, MC_U117585868, MR/R502121/1] Funding Source: UKRI
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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-alpha 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.
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