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.

Reduced Nasal Viral Load and IFN Responses in Infants with Respiratory Syncytial Virus Bronchiolitis and Respiratory Failure

“…Alveolar macrophages have been reported to generate type-I IFNs in the early response to RSV infection, thereby limiting disease (44). Additionally, M1-monocytes are a major determinant of severity in life-threatening influenza (45). Given our observation of lower type-I IFN expression in severe disease we speculate that alveolar macrophages and/or neutrophils may mediate these differences between moderate and severe infants.…”

Type-1 IFN primed monocytes in pathogenesis of idiopathic pulmonary fibrosis

“…Similarly in the liver, monocyte presence is associated with pathological inflammation (51). We have also shown previously that very high levels of circulating monocytes are associated with severe respiratory impairment in influenza (52). Reduced rate of differentiation to macrophages can also have other negative impact on fibrosis.…”

“…Cultured cells were incubated with Zombie Aqua fixable viability stain (Biolegend) to enable exclusion of dead cells from subsequent analysis. Cells were incubated with antibodies against surface antigens for 20 minutes at 4 o C and fixed with Stabilising Fixative (BD) prior to acquisition (52).…”

Nanoparticle delivery of microRNA-146a regulates mechanotransduction in lung macrophages and mitigates lung injury during mechanical ventilation

“…50uL of BMDM suspension (1 × 10 6 total cells) was intratracheally instilled into mice 6-8 hours prior to ventilation. (42)…”