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 6

M2 macrophage transfer to lungs of infected mice improves disease outcome.

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M2 macrophage transfer to lungs of infected mice improves disease outcom...
(A) M1 and M2 markers on bone marrow–derived macrophages (MØ) used for adoptive transfer. Graphs show mean ± SEM from n = 3 preparations of bone marrow pooled from 4–6 mice per preparation. (B and C) Number of transferred cells (identifiable as CD45.1+ cells) in BAL and lung digests of mice 6 and 24 hours after administration of M1 BMDMs (+M1) or M2 BMDMs (+M2). n = 6 mice per group; 2 separate experiments. (Absolute values are given in Supplemental Figure 6, D and E.) (D) Numbers of resident alveolar macrophages in host mice after M1 BMDM or M2 BMDM transfer. 2 experiments, total of 4–6 mice at each time point for B–D. (E–G) Weight loss, clinical scores, and percentage of mice culled after adoptive transfer of M1, M2 BMDMs, or PBS. Clinical course was best in the M2-transferred group compared with PBS or M1 groups, with statistically significant findings on days 3 and 4. On day 4, mice that received M1 showed significantly worse clinical scores compared with those that received PBS and M2: clinical score 0, healthy; 1, calm but still exploring; 2, slow and exploring less; 3, hunched and shivery; 4, inactive; and 5, inactive even with handling. Total of n = 6 mice per group, 2 experiments. Differences among the 3 groups were analyzed using 2-way ANOVA with repeated measures. Comparisons were performed up to day 4 when all 3 groups still had equal numbers of mice. All P values for multiple comparisons were <0.001 except for clinical score on day 3, where the P value for M2 compared with M1 and PBS P < 0.05. For A and D, statistical significance was measured using 1-way ANOVA with Tukey test. *P < 0.05; **P < 0.01; ***P < 0.001. BMDM, bone marrow–derived macrophage.