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.
Highlights
Seasonal influenza epidemics can affect 5%–10% of adults, causing up to 0.5 million deaths annually worldwide [1]
During the 2009 pandemic, most individuals infected with pH1N1 influenza A virus (IAV) had mild or uncomplicated illness, there was a discrete prevalence of severe disease in otherwise healthy persons
Since macrophages can be classified as M1 or M2 according to specific surface markers secondary to IFN-γ/LPS or IL-4/IL-13 activation respectively [19], and since we have previously shown that some M1 and M2 features are conserved between circulating monocytes and tissue macrophages [20], we explored the use of M1 and M2 markers as a method of characterizing monocytes before they differentiate into macrophages
Summary
Seasonal influenza epidemics can affect 5%–10% of adults, causing up to 0.5 million deaths annually worldwide [1]. The most severe disease occurs in those with diverse factors associated with a suboptimal immune response, for example, children under 5 years of age, the elderly, those who are pregnant or on immunosuppressants, or those with haematological malignancies. During the 2009 pandemic (pH1N1), most individuals infected with pH1N1 influenza A virus (IAV) had mild or uncomplicated illness, there was a discrete prevalence of severe disease in otherwise healthy persons. 90% of all deaths in the pandemic occurred in those under 65 years of age [2,3,4]. An “immune storm” has been suggested to underlie these severe cases, but the critical cellular immune cause remains unclear
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