Inflammatory monocytes drive influenza A virus-mediated lung injury in juvenile mice

Bria M. Coates*, Kelly L. Staricha, Clarissa M. Koch, Yuan Cheng, Dale K. Shumaker, G. R.Scott Budinger, Harris Perlman, Alexander V. Misharin, Karen M. Ridge

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Healthy children are more likely to die of influenza Avirus (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.

Original languageEnglish (US)
Pages (from-to)2391-2404
Number of pages14
JournalJournal of Immunology
Volume200
Issue number7
DOIs
StatePublished - Apr 1 2018

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Influenza A virus
Lung Injury
Human Influenza
Monocytes
Inflammasomes
Lung
Infection
Acute Lung Injury
RNA
Pediatrics
Cytokines
Mortality
Genes

ASJC Scopus subject areas

  • Immunology

Cite this

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title = "Inflammatory monocytes drive influenza A virus-mediated lung injury in juvenile mice",
abstract = "Healthy children are more likely to die of influenza Avirus (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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Inflammatory monocytes drive influenza A virus-mediated lung injury in juvenile mice. / Coates, Bria M.; Staricha, Kelly L.; Koch, Clarissa M.; Cheng, Yuan; Shumaker, Dale K.; Budinger, G. R.Scott; Perlman, Harris; Misharin, Alexander V.; Ridge, Karen M.

In: Journal of Immunology, Vol. 200, No. 7, 01.04.2018, p. 2391-2404.

Research output: Contribution to journalArticle

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AU - Coates, Bria M.

AU - Staricha, Kelly L.

AU - Koch, Clarissa M.

AU - Cheng, Yuan

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AU - Budinger, G. R.Scott

AU - Perlman, Harris

AU - Misharin, Alexander V.

AU - Ridge, Karen M.

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