Respiratory Syncytial Virus Infection Upregulates NLRC5 and Major Histocompatibility Complex Class I Expression through RIG-I Induction in Airway Epithelial Cells

Guo, Xuancheng; Liu, Taixiang; Shi, Hengfei; Wang, Jingjing; Ji, Ping; Wang, Hongwei; Hou, Yayi; Tan, Ren Xiang; Li, Erguang

doi:10.1128/jvi.00349-15

Cited by 37 publications

(38 citation statements)

References 69 publications

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“…IFN stimulation upregulates TLR-3 and -4 expression and cause them to redistribute from sequestered endosomal compartments to the cell surface [21]. In a similar manner, IFN induces LRR-, and CARD-containing 5 (NLRC5), priming RSV infected cells to respond to additional PAMPs [31]. Through these effects, IFN auto-amplification primes neighboring epithelial cells to elicit a protective anti-viral state and commitment to apoptosis [32].…”

Section: Activation and Cross-talk Of The Nfκb And Irf3 Pathways In Rmentioning

confidence: 99%

RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling

Brasier

2020

Viruses

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Respiratory syncytial virus infection is responsible for seasonal upper and lower respiratory tract infections worldwide, causing substantial morbidity. Self-inoculation of the virus into the nasopharynx results in epithelial replication and distal spread into the lower respiratory tract. Here, respiratory syncytial virus (RSV) activates sentinel cells important in the host inflammatory response, resulting in epithelial-derived cytokine and interferon (IFN) expression resulting in neutrophilia, whose intensity is associated with disease severity. I will synthesize key findings describing how RSV replication activates intracellular NFκB and IRF signaling cascades controlling the innate immune response (IIR). Recent studies have implicated a central role for Scg1a1 + expressing progenitor cells in IIR, a cell type uniquely primed to induce neutrophilic-, T helper 2 (Th2)-polarizing-, and fibrogenic cytokines that play distinct roles in disease pathogenesis. Molecular studies have linked the positive transcriptional elongation factor-b (P-TEFb), a pleiotrophic chromatin remodeling complex in immediate-early IIR gene expression. Through intrinsic kinase activity of cyclin dependent kinase (CDK) 9 and atypical histone acetyl transferase activity of bromodomain containing protein 4 (BRD4), P-TEFb mediates transcriptional elongation of IIR genes. Unbiased proteomic studies show that the CDK9•BRD4 complex is dynamically reconfigured by the innate response and targets TGFβ-dependent fibrogenic gene networks. Chronic activation of CDK9•BRD4 mediates chromatin remodeling fibrogenic gene networks that cause epithelial mesenchymal transition (EMT). Mesenchymal transitioned epithelial cells elaborate TGFβ and IL6 that function in a paracrine manner to expand the population of subepithelial myofibroblasts. These findings may account for the long-term reduction in pulmonary function in children with severe lower respiratory tract infection (LRTI). Modifying chromatin remodeling properties of the CDK9•BRD4 coactivators may provide a mechanism for reducing post-infectious airway remodeling that are a consequence of severe RSV LRTIs.Viruses 2020, 12, 472 2 of 17 spread into the lower airways produces lower respiratory tract infection (LRTI), whose clinical features include bronchiolitis and pneumonia. Pathologically, LRTI is associated with epithelial giant cell formation, necrosis, sloughing, producing mucous plugging, ventilation-perfusion mismatching, and acute hypoxic respiratory failure [2][3][4]. The findings that the initial clinical manifestations of hypoxia are correlated with high viral titers and epithelial-derived cytokines [5,6] indicates that RSV activation of the IIR plays an important component of early disease manifestations.Observational studies of naturally occurring RSV infections in humans suggest that acute infection produces an initial neutrophilic airway inflammation [7], followed by a CD8+ T-cell response important in viral clearance (reviewed in [8]). Because protective IgA antibodies wane six months after...

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Section: Activation and Cross-talk Of The Nfκb And Irf3 Pathways In Rmentioning

confidence: 99%

RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling

Brasier

2020

Viruses

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“…The expression of NLRC5 is observed in various tissues in human and mouse, predominantly in hematopoeitic cells [20,53,55,57,59]. While NLRC5 expression levels are low in nonhematopoietic cells compared to hematopoietic cells, nonhematopoietic cells have the capacity to upregulate the expression upon poly (I:C) stimulation or infection with viruses including influenza virus, respiratory syncytial virus or Sendai virus [19,[58][59][60].…”

Section: Nlrc5: Identification Of Mhc Class I Transactivatormentioning

confidence: 99%

CITA/NLRC5: A critical transcriptional regulator of MHC class I gene expression

et al. 2016

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Major histocompatibility complex (MHC) class I and class II molecules play essential roles in the development and activation of the human adaptive immune system. An NLR protein, CIITA (MHC class II transactivator) has been recognized as a master regulator of MHC class II gene expression, albeit knowledge about the regulatory mechanism of MHC class I gene expression had been limited. Recently identified MHC class I transactivator (CITA), or NLRC5, also belongs to the NLR protein family and constitutes a critical regulator for the transcriptional activation of MHC class I genes. In addition to MHC class I genes, CITA/NLRC5 induces the expression of β2 -microglobulin, TAP1 and LMP2, essential components of the MHC class I antigen presentation pathway. Therefore, CITA/NLRC5 and CIITA are transcriptional regulators that orchestrate the concerted expression of critical components in the MHC class I and class II pathways, respectively. © 2016 BioFactors, 42(4):349-357, 2016.

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“…The cells were routinely screened for Mycoplasma contamination. RSV was a type A strain and was propagated in A549 cells as we previously described (51). It is known that ultracentrifugation tends to result in significant loss of virus infectivity.…”

Section: Methodsmentioning

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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Respiratory Syncytial Virus Infection Upregulates NLRC5 and Major Histocompatibility Complex Class I Expression through RIG-I Induction in Airway Epithelial Cells

Cited by 37 publications

References 69 publications

RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling

RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling

CITA/NLRC5: A critical transcriptional regulator of MHC class I gene expression

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

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