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 2

Sustained increase in monocyte levels in NRF patients with severe IAV infection.

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Sustained increase in monocyte levels in NRF patients with severe IAV in...
(A) Typical flow cytometry size-granularity plots from a severe pH1N1 and an ILI patient demonstrating excess of large, granular immune cell populations (gates “a” and “b”) for IAV-infected patients. ILI, influenza-like illness but PCR negative for influenza virus. (B) Gate “a” from A was identified as CD15+CD14– low density granulocytes (LDG) and gate “b” comprised CD14+ (CD14mid–hi) monocytes. Gate “b” can further be divided into CD14hiCD16– classical monocytes: “i”; CD14hiCD16+ intermediate or inflammatory monocytes, “ii”; and CD14midCD16+ nonclassical or patrolling monocytes, “iii.” These gates were CD3–. (C and D) Circulating CD14+ (i.e., CD14mid–hi) monocytes and CD15+ LDG expressed as absolute numbers of cells per ml of blood for all pH1N1 patients (n = 43; n = 17 mild, n = 26 severe) and healthy controls (n = 12). (E and F) Relationship between viral load at TP0 (see Table 1) and circulating monocytes and LDG for 41 of 43 pH1N1 patients (viral load unavailable for 2 patients). Viral load relative to each patient was expressed as “relative PFU equivalents” (see Methods). (G and H) Number of circulating CD14+ monocytes and CD15+ LDG for NRF (no risk factors; n = 18) and WRF (with risk factors; n = 14) patients. (I and J) Monocyte and LDG numbers for n = 5 severe and n = 5 mild NRF patients normalized for time from the first symptoms. These patients were sampled between 8 and 18 days from the first symptoms. (K) Monocyte and LDG numbers at TP1 (admission) and 4–6 weeks later (TP2) for n = 9 patients from the NRF severe group. Filled symbols refer to patients still hospitalized at TP2. r values and significance were calculated using Spearman’s rank test. All values are mean ± SEM for normally distributed sets and median ± interquartile range for nonnormal distribution. P values were calculated using Kruskal-Wallis test and Dunn’s multiple comparison test (C, D, G, and H); Mann-Whitney (I and J); and Wilcoxon matched-pairs signed rank test for TP1 versus TP2 (K). *P < 0.05; **P < 0.01; ****P < 0.0001. TP, time point; HC, healthy control.