M1-like monocytes are a major immunological determinant of severity in previously healthy adults with life-threatening influenza
Suzanne L. Cole, Jake Dunning, Wai Ling Kok, Kambez Hajipouran Benam, Adel Benlahrech, Emmanouela Repapi, Fernando O. Martinez, Lydia Drumright, Timothy J. Powell, Michael Bennett, Ruth Elderfield, Catherine Thomas, MOSAIC investigators, Tao Dong, John McCauley, Foo Y. Liew, Stephen Taylor, Maria Zambon, Wendy Barclay, Vincenzo Cerundolo, Peter J. Openshaw, Andrew J. McMichael, Ling-Pei Ho
Suzanne L. Cole, Jake Dunning, Wai Ling Kok, Kambez Hajipouran Benam, Adel Benlahrech, Emmanouela Repapi, Fernando O. Martinez, Lydia Drumright, Timothy J. Powell, Michael Bennett, Ruth Elderfield, Catherine Thomas, MOSAIC investigators, Tao Dong, John McCauley, Foo Y. Liew, Stephen Taylor, Maria Zambon, Wendy Barclay, Vincenzo Cerundolo, Peter J. Openshaw, Andrew J. McMichael, Ling-Pei Ho
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Research Article Immunology Infectious disease

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 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.

Authors

Suzanne L. Cole, Jake Dunning, Wai Ling Kok, Kambez Hajipouran Benam, Adel Benlahrech, Emmanouela Repapi, Fernando O. Martinez, Lydia Drumright, Timothy J. Powell, Michael Bennett, Ruth Elderfield, Catherine Thomas, MOSAIC investigators, Tao Dong, John McCauley, Foo Y. Liew, Stephen Taylor, Maria Zambon, Wendy Barclay, Vincenzo Cerundolo, Peter J. Openshaw, Andrew J. McMichael, Ling-Pei Ho

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Figure 3

Monocytes in severe NRF patients are M1 like.

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Monocytes in severe NRF patients are M1 like. (A–C) Classical, inflammat...
(A–C) Classical, inflammatory, and patrolling monocytes in blood of mild and severe NRF and WRF patients. (D) Pie chart representation of classical, inflammatory, and patrolling monocyte frequencies in blood of NRF or WRF patients and healthy controls (HC) observed in A–C. Values refer to % of total monocytes. (E) Ex vivo expression of genes associated with M1 and M2 macrophage differentiation in CD14+ monocytes isolated from n = 10 NRF and n = 5 WRF patients with severe disease. Each gene is normalized to β-actin in the sample and then compared with the mean of the gene/β-actin of healthy controls (n = 9) (Mann-Whitney test with Bonferroni correction for multiple testing; ** adjusted P = 0.01). (F) TNF-α gene expression normalized to CD14 gene expression for each of the severe NRF and WRF patients and healthy controls. (E and F) Asterisks refer to statistically different genes comparing NRF severe and WRF sever. (G) TNF-α/IL-10 gene expression. (H) Ratio of TNF-α/IL-10 protein expression by intracellular cytokine staining. TNF-α and IL-10 expression (as cytokine-positive cells, as proportion of CD14+ monocytes) was measured following 6 hours of LPS stimulation of PBMCs. (I and J) Expression of M1 (CCR7 surface staining) and M2 (CD163 surface staining) markers on monocytes, measured by flow cytometry. P values were calculated using Kruskal-Wallis test and Dunn’s multiple comparison test for F–G and Student’s t test if data were normally distributed and Mann-Whitney test if not for A–D and H–J. *P < 0.05; **P < 0.01. NRF, no risk factors; WRF, with risk factors.