DUSP10 Negatively Regulates the Inflammatory Response to Rhinovirus through Interleukin-1β Signaling

Manley, Grace C A; Stokes, Clare; Marsh, Elizabeth K.; Sabroe, Ian; Parker, Lisa C.

doi:10.1128/jvi.01659-18

Cited by 25 publications

(28 citation statements)

References 63 publications

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“…As mitochondria plays important role in cellular respiration and lung diseases 85 , aberrant expression of these genes might also lead to lung-related complications. DUSP10 can regulate unusual inflammatory responses upon viral infections 86 , but in SARS-CoV-2-infected lung this gene was found downregulated, possibly through NSP12-TCF12 interactions (Fig. 7A).…”

Section: Discussionmentioning

confidence: 99%

Lung transcriptome of a COVID-19 patient and systems biology predictions suggest impaired surfactant production which may be druggable by surfactant therapy

Islam

Khan

2020

Sci Rep

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An incomplete understanding of the molecular mechanisms behind impairment of lung pathobiology by COVID-19 complicates its clinical management. In this study, we analyzed the gene expression pattern of cells obtained from biopsies of COVID-19-affected patient and compared to the effects observed in typical SARS-CoV-2 and SARS-CoV-infected cell-lines. We then compared gene expression patterns of COVID-19-affected lung tissues and SARS-CoV-2-infected cell-lines and mapped those to known lung-related molecular networks, including hypoxia induced responses, lung development, respiratory processes, cholesterol biosynthesis and surfactant metabolism; all of which are suspected to be downregulated following SARS-CoV-2 infection based on the observed symptomatic impairments. Network analyses suggest that SARS-CoV-2 infection might lead to acute lung injury in COVID-19 by affecting surfactant proteins and their regulators SPD, SPC, and TTF1 through NSP5 and NSP12; thrombosis regulators PLAT, and EGR1 by ORF8 and NSP12; and mitochondrial NDUFA10, NDUFAF5, and SAMM50 through NSP12. Furthermore, hypoxia response through HIF-1 signaling might also be targeted by SARS-CoV-2 proteins. Drug enrichment analysis of dysregulated genes has allowed us to propose novel therapies, including lung surfactants, respiratory stimulants, sargramostim, and oseltamivir. Our study presents a distinct mechanism of probable virus induced lung damage apart from cytokine storm.

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Section: Discussionmentioning

confidence: 99%

Lung transcriptome of a COVID-19 patient and systems biology predictions suggest impaired surfactant production which may be druggable by surfactant therapy

Islam

Khan

2020

Sci Rep

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“…Indeed, airway epithelial JNK activation was found critical in initiation of allergic in ammation, especially house dust mite, fungi or OVA induced TLR2/JNK activation [56]. Rhinoviruses infection of airway epithelial cell frequently produced higher levels of in ammatory cytokines via TLR4/JNK pathway and exacerbated in ammation in asthma, causing worse airway obstruction and symptoms [62]. In clinical, systemic glucocorticoid (GC) inhibited phosphorylation of JNK in bronchial mucosal cells in GC responsiveness asthma, while the phenomenon was not observed in GC-resistant asthmatic subjects [63].…”

Section: Discussionmentioning

confidence: 99%

Mas Receptor Activation Attenuates Allergic Airway Inflammation via Inhibiting JNK/CCL2-induced Macrophage Recruitment

Hong

Chen

Shi

et al. 2020

Preprint

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Background: Defective absorption of acute allergic airway inflammation is involved in the initiation and development of chronic asthma. After allergen exposure, there is a rapid recruitment of macrophages around the airways, which promote acute inflammatory responses. The Ang-(1-7)/Mas receptor axis reportedly plays protective roles in various tissue inflammation and remodeling processes in vivo. However, the exact role of Mas receptor and their underlying mechanisms during the pathology of acute allergic airway inflammation remains unclear. Methods: Mas receptor expression was assessed in ovalbumin-induced acute asthmatic murine model. Then we estimated the anti-inflammatory role of Mas receptor in vivo and explored expressions of several known inflammatory cytokines as well as phosphorylation levels of MAPK pathways. Mas receptor functions and underlying mechanisms were studied further in the human bronchial epithelial cell line (16HBE).Results: Mas receptor expression decreased in acute allergic airway inflammation. Multiplex immunofluorescence co-localized Mas receptor and EpCAM, indicated that Mas receptor may function in the bronchial epithelium. Activating Mas receptor through AVE0991 significantly alleviated macrophage infiltration in airway inflammation, accompanied with down-regulation of CCL2 and phosphorylation levels of MAPK pathways. Further studies in 16HBE showed that AVE0991 pre-treatment inhibited LPS-induced or anisomycin-induced CCL2 increase and THP-1 macrophages migration via JNK pathways.Conclusion: Our findings suggested that Mas receptor activation significantly attenuated CCL2 dependent macrophage recruitments in acute allergic airway inflammation through JNK pathways, which indicated that Mas receptor, CCL2 and phospho-JNK could be potential targets against allergic airway inflammation.

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“…Several mitochondrial genes like-NDUFA10, NDUFAF5, SAMM50 are found downregulated in COVID-19 affected lung (Figure 7); as mitochondria plays important role in cellular respiration and lung diseases [102], aberration of these might also lead to lung related complicacies. DUSP10 can regulate aberrant inflammatory response upon viral infections [103], but in SARS-CoV-2 infected lung this gene is downregulated which might have occurred through the interaction of NSP12-TCF12 interactions (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

Lung biopsy cells transcriptional landscape from COVID-19 patient stratified lung injury in SARS-CoV-2 infection through impaired pulmonary surfactant metabolism

Islam

Khan

2020

Preprint

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Clinical management of COVID-19 is still complicated due to the lack of therapeutic interventions to reduce the breathing problems, respiratory complications and acute lung injury -which are the major complications of most of the mild to critically affected patients and the molecular mechanisms behind these clinical features are still largely unknown. In this study, we have used the RNA-seq gene expression pattern in the COVID-19 affected lung biopsy cells and compared it with the effects observed in typical cell lines infected with SARS-CoV-2 and SARS-CoV. We performed functional overrepresentation analyses using these differentially expressed genes to signify the processes/pathways which could be deregulated during SARS-CoV-2 infection resulting in the symptomatic impairments observed in COVID-19. Our results showed that the significantly altered processes include inflammatory responses, antiviral cytokine signaling, interferon responses, and interleukin signaling etc. along with downmodulated processes related to lung's functionality likeresponses to hypoxia, lung development, respiratory processes, cholesterol biosynthesis and surfactant metabolism. We also found that the viral protein interacting host's proteins involved in similar pathways like: respiratory failure, lung diseases, asthma, and hypoxia responses etc., suggesting viral proteins might be deregulating the processes related to acute lung injury/breathing complications in COVID-19 patients. Protein-protein interaction networks of these processes and map of gene expression of deregulated genes revealed that several viral proteins can directly or indirectly modulate the host genes/proteins of those lung related processes along with several host transcription factors and miRNAs. Surfactant proteins and their regulators SPD, SPC, TTF1 etc. which maintains the stability of the pulmonary tissue are found to be downregulated through viral NSP5, NSP12 that could lead to deficient gaseous exchange by the surface films. Mitochondrial dysfunction owing to the aberration of NDUFA10, NDUFAF5, SAMM50 etc. by NSP12; abnormal thrombosis in lungs through atypical PLAT, EGR1 functions by viral ORF8, NSP12; dulled hypoxia responses due to unusual shift in HIF-1 downstream signaling might be the causative elements behind the acute lung injury in COVID-19 patients. Our study put forward a distinct mechanism of probable virus induced lung damage apart from cytokine storm and advocate the need of further research for alternate therapy in this direction.

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DUSP10 Negatively Regulates the Inflammatory Response to Rhinovirus through Interleukin-1β Signaling

Cited by 25 publications

References 63 publications

Lung transcriptome of a COVID-19 patient and systems biology predictions suggest impaired surfactant production which may be druggable by surfactant therapy

Lung transcriptome of a COVID-19 patient and systems biology predictions suggest impaired surfactant production which may be druggable by surfactant therapy

Mas Receptor Activation Attenuates Allergic Airway Inflammation via Inhibiting JNK/CCL2-induced Macrophage Recruitment

Lung biopsy cells transcriptional landscape from COVID-19 patient stratified lung injury in SARS-CoV-2 infection through impaired pulmonary surfactant metabolism

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