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 7

Lungs from high-pathogenicity H5N1 infection are enriched for monocytes and M1 genes, with downregulation of M2 genes.

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Lungs from high-pathogenicity H5N1 infection are enriched for monocytes ...
(A) Quantitative spider plot representation of the degree of enrichment of gene ontology (GO) terms for major immune cell subsets using the GOrilla online tool. Numbers represent enrichment scores. Granulocyte, regulation of granulocyte chemotaxis; Monocyte, regulation of monocyte chemotaxis; Macrophage, regulation of macrophage chemotaxis; B cell, regulation of B cell–mediated immunity; NK cell, regulation of NK cell–mediated immunity; T cell, positive regulation of α-β T cell activation. Days 3 and 5 refer to days after infection. (B and C) Expression of differentially regulated monocyte-attracting chemokines in lungs on days 3 and 5 after infection with H5N1 (black) or X179A (gray) relative to uninfected mice. (D and E) GSEA enrichment plots of M1 macrophage or M2 macrophage genes in lungs from H5N1- or X179A-infected mice on day 3, showing M1 enrichment of upregulated genes on day 3 for both H5N1 and X179A. This indicates an overrepresentation of M1 genes in both infections on day 3. In contrast, there was an underrepresentation of M2 genes in H5N1 but not X179A. This is one of 4 gene sets used to interrogate M1 and M2 gene enrichment (GSE51466) (all 4 are shown in Supplemental Figure 8). Enrichment score refers to the degree to which the gene set is overrepresented at the top or bottom of the ranked input list of genes. n = 3 mice per group for gene arrays. NES, normalized enrichment score (adjusted for gene set size or multiple hypothesis testing). Red bold or blue text indicates statistically significant enrichment of genes on day 3 after infection or in uninfected lungs, respectively.