Deficiency of melanoma differentiation-associated protein 5 results in exacerbated chronic postviral lung inflammation

Won Keun Kim, Deepika Jain, Melissa D. Sánchez, Cynthia J. Koziol-White, Krystal Matthews, Moyar Q. Ge, Angela Franciska Haczku, Reynold A. Panettieri, Matthew B. Frieman, Carolina B. López

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Rationale: Respiratory viral infections can result in the establishment of chronic lung diseases. Understanding the early innate immune mechanisms that participate in the development of chronic postviral lung disease may reveal new targets for therapeutic intervention. The intracellular viral sensor protein melanoma differentiation-associated protein 5 (MDA5) sustains the acute immune response to Sendai virus, a mouse pathogen that causes chronic lung inflammation, but its role in the development of postviral chronic lung disease is unknown. Objectives: To establish the role of MDA5 in the development of chronic lung disease. Methods: MDA5-deficient or control mice were infected with Sendai virus. The acute inflammatory response was evaluated by profiling chemokine and cytokine expression and by characterizing the composition of the cellular infiltrate. The impact of MDA5 on chronic lung pathology and functionwas evaluated through histological studies, degree of oxygen saturation, and responsiveness to carbachol. Measurements and Main Results: MDA5 deficiency resulted in normal virus replication and in a distinct profile of chemokines and cytokines that associated with acute lung neutropenia and enhanced accumulation of alternatively activated macrophages. Diminished expression of neutrophil-recruiting chemokines was also observed in cells infected with influenza virus, suggesting a key role of MDA5 in driving the early accumulation of neutrophils at the infection site. The biased acute inflammatory response ofMDA5-deficientmice led to an enhanced chronic lung inflammation, epithelial cell hyperplasia, airway hyperreactivity, and diminished blood oxygen saturation. Conclusions: MDA5 modulates the development of chronic lung inflammation by regulating the early inflammatory response in the lung.

Original languageEnglish (US)
Pages (from-to)437-448
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume189
Issue number4
DOIs
StatePublished - Feb 15 2014
Externally publishedYes

Keywords

  • Chronic lung disease
  • Innate immunity
  • Paramyxovirus
  • Respiratory virus

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Kim, W. K., Jain, D., Sánchez, M. D., Koziol-White, C. J., Matthews, K., Ge, M. Q., Haczku, A. F., Panettieri, R. A., Frieman, M. B., & López, C. B. (2014). Deficiency of melanoma differentiation-associated protein 5 results in exacerbated chronic postviral lung inflammation. American Journal of Respiratory and Critical Care Medicine, 189(4), 437-448. https://doi.org/10.1164/rccm.201307-1338OC