Alveolar macrophage–derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes

Goritzka, Michelle; Makris, Spyridon; Kausar, Fahima; Durant, Lydia; Pereira, Catherine; Kumagai, Yutaro; Culley, Fiona J.; Mack, Matthias; Akira, Shizuo; Johansson, Cecilia

doi:10.1084/jem.20140825

Cited by 229 publications

(360 citation statements)

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“…NLRP3 signaling is also regulated by the mitochondrial RLR signaling protein MAVS. RLR signaling resulting in the production of type I IFNs and other proinflammatory cytokines that promote adaptive antiviral immunity is regulated by mtDNA and a number of mitochondrial proteins (84,118). AMs detect respiratory syncytial virus (RSV) via MAVS, and loss of MAVS may underlie the development of RSV-induced severe lung inflammation (118).…”

Section: Resultsmentioning

confidence: 99%

“…RLR signaling resulting in the production of type I IFNs and other proinflammatory cytokines that promote adaptive antiviral immunity is regulated by mtDNA and a number of mitochondrial proteins (84,118). AMs detect respiratory syncytial virus (RSV) via MAVS, and loss of MAVS may underlie the development of RSV-induced severe lung inflammation (118). MAVS also regulates the response of lung mast cells to influenza A virus (IAV) (119) and may be responsible for CS enhancement of virus-induced pulmonary innate immune and remodeling responses in mice (120).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondria in lung disease

Cloonan¹,

Choi²

2016

Journal of Clinical Investigation

209

182

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Mitochondria in lung disease

Cloonan¹,

Choi²

2016

Journal of Clinical Investigation

209

182

View full text Add to dashboard Cite

“…TLR4 expression also sensitizes airway epithelial cells to endotoxin and mediates RSV bronchiolitis (20,21). Although proinflammatory cytokine production and dysregulation of IFN production have been identified as a primary cause of RSV disease (2,9,10,14,22), accumulating evidence suggests that reactive oxygen species (ROS) have a critical role in RSV disease (23)(24)(25). RSV infection induces rapid ROS production that leads to chemokine induction and IRF pathway activation (26)(27)(28)(29).…”

mentioning

confidence: 99%

Suppression of IRG-1 Reduces Inflammatory Cell Infiltration and Lung Injury in Respiratory Syncytial Virus Infection by Reducing Production of Reactive Oxygen Species

Ren

Zhuo

et al. 2016

J Virol

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Respiratory syncytial virus (RSV) infection is a common cause of lower respiratory tract illness in infants and children. RSV is a negative-sense, single-strand RNA (ssRNA) virus that mainly infects airway epithelial cells. Accumulating evidence indicates that reactive oxygen species (ROS) production is a major factor for pulmonary inflammation and tissue damage of RSV disease. We investigated immune-responsive gene-1 (IRG1) expression during RSV infection, since IRG1 has been shown to mediate innate immune response to intracellular bacterial pathogens by modulating ROS and itaconic acid production. We found that RSV infection induced IRG1 expression in human A549 cells and in the lung tissues of RSV-infected mice. RSV infection or IRG1 overexpression promoted ROS production. Accordingly, knockdown of IRG1 induction blocked RSV-induced ROS production and proinflammatory cytokine gene expression. Finally, we showed that suppression of IRG1 induction reduced immune cell infiltration and prevented lung injury in RSV-infected mice. These results therefore link IRG1 induction to ROS production and immune lung injury after RSV infection. IMPORTANCERSV infection is among the most common causes of childhood diseases. Recent studies identify ROS production as a factor contributing to RSV disease. We investigated the cause of ROS production and identified IRG1 as a critical factor linking ROS production to immune lung injury after RSV infection. We found that IRG1 was induced in A549 alveolar epithelial cells and in mouse lungs after RSV infection. Importantly, suppression of IRG1 induction reduced inflammatory cell infiltration and lung injury in mice. This study links IRG1 induction to oxidative damage and RSV disease. It also uncovers a potential therapeutic target in reducing RSV-caused lung injury. Human infection with respiratory syncytial virus (RSV) is a major cause of childhood disease of lower respiratory tract infection with common cold-like symptoms. The infection is frequently associated with the development of bronchospasm and bronchiolitis, particularly in children less than 1 year old. Globally, RSV is responsible for over 33 million new episodes of acute lower respiratory tract infection in children, with at least 3.4 million severe cases that require hospital admissions each year (1, 2). A growing body of evidence shows that RSV infection has become a significant burden in the elderly in industrialized countries (3-6). In addition, RSV infection may contribute to the onset of development of type 2 diabetes (7). Proinflammatory response in the lung is thought to play a fundamental role in RSV disease, but the mechanisms regulating RSV disease and long-term consequences are incompletely defined (8-13).RSV is a negative-sense, single-strand RNA virus of the family Paramyxoviridae, which also includes common respiratory viruses such as those causing measles and mumps. Human RSV infects polarized epithelial cells in the airway and, to lesser degrees, macrophages and dendritic cells (14,15). RSV stimul...

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“…The primary source of type I IFN after RSV infection has been shown to be alveolar macrophages, which help to recruit inflammatory monocytes to the lungs to mount an antiviral defense, although alveolar macrophages are unable to support replication of RSV (43). It is possible that alveolar macrophages and infiltrating monocytes in the absence of functional CX3CR1 are more prone to producing IL-1β in virus-infected lungs.…”

Section: Discussionmentioning

confidence: 99%