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Inflammatory Monocytes Drive Influenza A Virus-Mediated Lung Injury in Juvenile Mice
Bria M Coates1,2, Kelly L Staricha3, Clarissa M Koch4
1Division of Critical Care Medicine, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; b-coates@northwestern.edu.
Insights
Juvenile mice show higher mortality from influenza A virus (IAV) due to exaggerated inflammatory responses, not impaired viral control. Increased monocyte recruitment drives severe lung injury in young IAV infections.
Area of Science:
- Immunology
- Virology
- Pediatric Respiratory Diseases
Background:
- Healthy children face higher mortality from influenza A virus (IAV) than adults.
- Mechanisms driving severe IAV infection in young individuals remain poorly understood.
- IAV infection severity in children necessitates research into age-related immune responses.
Purpose of the Study:
- To investigate the mechanisms underlying severe influenza A virus infection in juvenile mice.
- To compare immune responses and outcomes between juvenile and adult mice infected with IAV.
- To identify key cellular and molecular players contributing to pediatric acute lung injury from IAV.
Main Methods:
- Comparative study of juvenile and adult mice infected with influenza A virus (IAV) at various doses.
- Analysis of type I interferons (IFNs), NLRP3 inflammasome activation, and MCP-1 levels in lung tissue.
- RNA sequencing (RNA-seq) to assess transcriptional signatures of lung monocytes; monocyte depletion using anti-CCR2 antibody.
Main Results:
- Juvenile mice exhibited higher mortality, sustained type I IFN elevation, and persistent NLRP3 inflammasome activation, independent of viral load.
- Elevated MCP-1 levels in juvenile mice correlated with persistent monocyte recruitment and prolonged inflammatory cytokine elevation.
- Juvenile monocytes displayed a proinflammatory transcriptional signature; monocyte depletion reduced inflammation and lung injury in juveniles.
Conclusions:
- Severe IAV infection in juvenile mice is driven by an exaggerated inflammatory response, specifically increased monocyte recruitment, rather than impaired viral clearance.
- Persistent MCP-1 production and subsequent monocyte accumulation are key factors in pediatric IAV-induced acute lung injury.
- Targeting inflammatory monocytes may offer therapeutic strategies for severe influenza in children.
Abstract:
Healthy children are more likely to die of influenza A virus (IAV) infection than healthy adults. However, little is known about the mechanisms underlying the impact of young age on the development of life-threatening IAV infection. We report increased mortality in juvenile mice compared with adult mice at each infectious dose of IAV. Juvenile mice had sustained elevation of type I IFNs and persistent NLRP3 inflammasome activation in the lungs, both of which were independent of viral titer. Juvenile mice, but not adult mice, had increased MCP-1 levels that remained high even after viral clearance. Importantly, continued production of MCP-1 was associated with persistent recruitment of monocytes to the lungs and prolonged elevation of inflammatory cytokines. Transcriptional signatures of recruited monocytes to the juvenile and adult IAV-infected lungs were assessed by RNA-seq. Genes associated with a proinflammatory signature were upregulated in the juvenile monocytes compared with adult monocytes. Depletion of monocytes with anti-CCR2 Ab decreased type I IFN secretion, NLRP3 inflammasome activation, and lung injury in juvenile mice. This suggests an exaggerated inflammatory response mediated by increased recruitment of monocytes to the lung, and not an inability to control viral replication, is responsible for severe IAV infection in juvenile mice. This study provides insight into severe IAV infection in juveniles and identifies key inflammatory monocytes that may be central to pediatric acute lung injury secondary to IAV.
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