scholarly journals SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-κB

2022 ◽  
Vol 5 (1) ◽  
Author(s):  
Christopher J. Neufeldt ◽  
Berati Cerikan ◽  
Mirko Cortese ◽  
Jamie Frankish ◽  
Ji-Young Lee ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Severe Disease ◽  
Significant Proportion ◽  
Lung Damage ◽  
Systemic Complications ◽  
Mild Disease ◽  
Antiviral Responses ◽  
Global Pandemic

AbstractSARS-CoV-2 is a novel virus that has rapidly spread, causing a global pandemic. In the majority of infected patients, SARS-CoV-2 leads to mild disease; however, in a significant proportion of infections, individuals develop severe symptoms that can lead to long-lasting lung damage or death. These severe cases are often associated with high levels of pro-inflammatory cytokines and low antiviral responses, which can cause systemic complications. Here, we have evaluated transcriptional and cytokine secretion profiles and detected a distinct upregulation of inflammatory cytokines in infected cell cultures and samples taken from infected patients. Building on these observations, we found a specific activation of NF-κB and a block of IRF3 nuclear translocation in SARS-CoV-2 infected cells. This NF-κB response was mediated by cGAS-STING activation and could be attenuated through several STING-targeting drugs. Our results show that SARS-CoV-2 directs a cGAS-STING mediated, NF-κB-driven inflammatory immune response in human epithelial cells that likely contributes to inflammatory responses seen in patients and could be therapeutically targeted to suppress severe disease symptoms.

scholarly journals SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-κB

2020 ◽  
Author(s):  
Christopher J. Neufeldt ◽  
Berati Cerikan ◽  
Mirko Cortese ◽  
Jamie Frankish ◽  
Ji-Young Lee ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Severe Disease ◽  
Significant Proportion ◽  
Lung Damage ◽  
Systemic Complications ◽  
Mild Disease ◽  
Antiviral Responses ◽  
Global Pandemic

AbstractSARS-CoV-2 is a novel virus that has rapidly spread, causing a global pandemic. In the majority of infected patients, SARS-CoV-2 leads to mild disease; however, in a significant proportion of infections, individuals develop severe symptoms that can lead to permanent lung damage or death. These severe cases are often associated with high levels of pro-inflammatory cytokines and low antiviral responses which can lead to systemic complications. We have evaluated transcriptional and cytokine secretion profiles from infected cell cultures and detected a distinct upregulation of inflammatory cytokines that parallels samples taken from infected patients. Building on these observations, we found a specific activation of NF-κB and a block of IRF3 nuclear translocation in SARS-CoV-2 infected cells. This NF-κB response is mediated by cGAS-STING activation and could be attenuated through STING targeting drugs. Our results show that SARS-CoV-2 curates a cGAS-STING mediated NF-κB driven inflammatory immune response in epithelial cells that likely contributes to inflammatory responses seen in patients and might be a target to suppress severe disease symptoms.

scholarly journals Retinal microvascular abnormalities in patients after COVID-19 depending on disease severity

2020 ◽  
pp. bjophthalmol-2020-317953
Author(s):  
Miguel Ángel Zapata ◽  
Sandra Banderas García ◽  
Adrián Sánchez ◽  
Anna Falcó ◽  
Susana Otero-Romero ◽  
...  
Keyword(s):  
Respiratory Distress ◽  
Severe Disease ◽  
Control Group ◽  
Vascular Density ◽  
Mild Disease ◽  
Global Pandemic ◽  
Group 3 ◽  
Group 2 ◽  
Group Control Group ◽  
Group 1

BackgroundGlobal pandemic SARS-CoV-2 causes a prothrombotic state without fully elucidated effects. This study aims to analyse and quantify the possible retinal microvascular abnormalities.Materials and methodsCase–control study. Patients between 18 and 55 years old with PCR-confirmed SARS-CoV-2 infection within the last 3 months were included. Risk stratification: group 1—mild disease (asymptomatic/paucisymptomatic); group 2—moderate disease (required hospital admission with no acute respiratory distress) and group 3—severe disease (subjects who developed an acute respiratory distress were admitted in the intensive care unit and presented interleukin 6 values above 40 pg/mL). Age-matched volunteers with negative serology tests were enrolled to control group. A colour photograph, an optical coherence tomography (OCT) and an angiography using OCT centred on the fovea were performed.ResultsControl group included 27 subjects: group 1 included 24 patients, group 2 consisted of 24 patients and 21 participants were recruited for group 3. There were no funduscopic lesions, neither in the colour images nor in the structural OCT. Fovea-centred vascular density (VD) was reduced in group 2 and group 3 compared with group 1 and control group (control group vs group 2; 16.92 vs 13.37; p=0.009) (control group vs group 3; 16.92 vs .13.63; p=0.026) (group 1 vs group 2; 17.16 vs 13.37; p=0.006) (group 1 vs group 3; 17.16 vs 13.63 p=0.017).ConclusionPatients with moderate and severe SARS-CoV-2 pneumonia had decreased central retinal VD as compared with that of asymptomatic/paucisymptomatic cases or control subjects.

scholarly journals Premorbid Echocardiography And Risk of Hospitalization In COVID-19

2022 ◽  
Author(s):  
Harsh Goel ◽  
Kashyap Shah ◽  
Janish Kothari ◽  
Timothy Daly ◽  
Pooja Saraiya ◽  
...  
Keyword(s):  
Risk Factors ◽  
Left Atrial ◽  
Severe Disease ◽  
Vaccine Hesitancy ◽  
Hospital Death ◽  
Rt Pcr ◽  
Mild Disease ◽  
Global Pandemic ◽  
Artery Disease

Abstract Background: COVID-19 has caused an unprecedented global pandemic, with cardiovascular risk factors predicting outcomes. We investigated whether baseline trans-thoracic echocardiography could refine risk beyond clinical risk factors. Methods: Symptomatic COVID-19 positive (RT-PCR) adults across St Luke’s University Health Network between March 1st-October 31st 2021, with trans-thoracic echocardiography (TTE) within 15-180 days preceding COVID-19 positivity were selected. Demographic/clinical/echocardiographic variables were extracted from patients’ EHR and compared between groups stratified by disease severity. Logistic regression was used to identify independent predictors of hospitalization. Results: 192 patients were included. 87 (45.3%) required hospitalization, 34 (17.7%) suffered severe disease (need for ICU care/mechanical ventilation/in-hospital death). Age, co-morbidities, and several echocardiographic abnormalities were more prevalent in moderate-severe versus mild disease. On multivariate analysis, age (OR 1.039, 95% CI 1.011-1.067), coronary artery disease (OR 4.184, 95% CI 1.451-12.063), COPD (OR 6.886, 95% CI 1.396-33.959) and left atrial (LA) diameter ≥4.0cm (OR 2.379, 95% CI 1.031-5.493) predicted need for hospitalization. Model showed excellent discrimination (ROC AUC 0.809, 95% CI 0.746-0.873). Conclusion: Baseline LA enlargement independently predicts risk of hospitalization in COVID-19. When available, baseline LA enlargement could identify patients for 1) closer outpatient follow-up, and 2) counseling vaccine-hesitancy.

scholarly journals C reactive protein as a prognostic indicator of severity in patients with acute pancreatitis

2020 ◽  
Vol 7 (4) ◽  
pp. 1169
Author(s):  
Bharath Nayak Ganesh ◽  
Srinivas Nanjangud Masana Setty
Keyword(s):  
Acute Pancreatitis ◽  
Severe Disease ◽  
Scoring Systems ◽  
Prognostic Indicator ◽  
P Value ◽  
High Morbidity ◽  
C Reactive Protein ◽  
Systemic Complications ◽  
Mild Disease ◽  
Reactive Protein

Background: Acute pancreatitis ranges from a mild illness to a severe disease with high morbidity and mortality. Severity affects the treatment and outcome. The existing scoring systems for assessment of its severity require are time consuming and expensive. This study was an attempt to evaluate the effectiveness of C-reactive protein (CRP) as a prognostic indicator and a marker of severity of acute pancreatitis.Methods: This was a prospective observational study conducted between among 50 patients diagnosed with acute pancreatitis. The Ranson’s score and CTSI was calculated for these patients. CRP levels were measured 48 hours after the onset of symptoms. They were observed for the development of local and systemic complications, and outcome. These were compared with the CRP values. Pearson coefficient was used to study the correlation between the variables. A p value of less than 0.05 was considered to be statistically significant.Results: 30 of the 50 patients had no local complications. 14 patients (28%) had peripancreatic collection and 6 (12%) had pancreatic necrosis. 24 of the 50 patients had systemic complications (48%). 25 patients had mild disease and 25 had severe disease as evidenced by the Ranson’s score. These 25 patients with severe disease also had raised CRP (p<0.05). There was no statistically significant correlation between the CTSI and CRP values. 4 patients with CRP values more than 400 succumbed to the illness.Conclusions: CRP can serve as an inexpensive alternative to the conventional severity assessment methods for the prediction of severity and outcome of patients with acute pancreatitis.

scholarly journals MiR-200c-3p inhibits LPS-induced M1 polarization of BV2 cells by targeting RIP2

2022 ◽  
Author(s):  
Lei Zhao ◽  
Xiaosong Liu ◽  
Jiankai Yang ◽  
Xiaoliang Wang ◽  
Xiaomeng Liu ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
M1 Polarization ◽  
Bv2 Cells ◽  
M1 Phenotype ◽  
Lps Treatment ◽  
Pro Inflammatory Cytokines

Abstract Background Microglia are important immune cells, which can be induced by lipopolysaccharide (LPS) into M1 phenotype that express pro-inflammatory cytokines. Some studies have shown that microRNAs play critical roles in microglial activation. Objective This study was designed to investigate the role of miR-200c-3p in regulating inflammatory responses of LPS-treated BV2 cells. Methods The expression of miR-200c-3p in BV2 cells was detected by real-time PCR. Receptor-interacting protein 2 (RIP2) was predicted as a target gene of miR-200c-3p. Their relationship was verified by dual-luciferase reporter assay. The function of miR-200c-3p and RIP2 in microglial polarization and NF-κB signaling was further evaluated. Results LPS treatment reduced miR-200c-3p expression in a dose-dependent and time-dependent manner in BV2 cells. LPS treatment increased the expression of M1 phenotype markers inducible nitric oxide synthase (iNOS) and major histocompatibility complex class (MHC)-II, promoted the release of pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, and enhanced the nuclear translocation and phosphorylation of nuclear factor-kappaB (NF-κB) p65. Reversely, miR-200c-3p mimics down-regulated the levels of these inflammatory factors. Furthermore, RIP2 was identified to be a direct target of miR-200c-3p. RIP2 knockdown had a similar effect to miR-200c-3p mimics. Overexpression of RIP2 eliminated the inhibitory effect of miR-200c-3p on LPS-induced M1 polarization and NF-κB activation in BV2 cells. Conclusions MiR-200c-3p mimics suppressed LPS-induced microglial M1 polarization and NF-κB activation by targeting RIP2. MiR-200c-3p/RIP2 might be a potential therapeutic target for the treatment of neuroinflammation-associated diseases.

scholarly journals Sectm1a deficiency aggravates inflammation-triggered cardiac dysfunction through disruption of LXRα signalling in macrophages

2020 ◽  
Author(s):  
Yutian Li ◽  
Shan Deng ◽  
Xiaohong Wang ◽  
Wei Huang ◽  
Jing Chen ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Transmembrane Protein ◽  
Bioinformatics Analyses ◽  
Lps Challenge ◽  
Inflammatory Monocytes

Abstract Aims Cardiac dysfunction is a prevalent comorbidity of disrupted inflammatory homeostasis observed in conditions such as sepsis (acute) or obesity (chronic). Secreted and transmembrane protein 1a (Sectm1a) has previously been implicated to regulate inflammatory responses, yet its role in inflammation-associated cardiac dysfunction is virtually unknown. Methods and results Using the CRISPR/Cas9 system, we generated a global Sectm1a-knockout (KO) mouse model and observed significantly increased mortality and cardiac injury after lipopolysaccharide (LPS) injection, when compared with wild-type (WT) control. Further analysis revealed significantly increased accumulation of inflammatory macrophages in hearts of LPS-treated KO mice. Accordingly, ablation of Sectm1a remarkably increased inflammatory cytokines levels both in vitro [from bone marrow-derived macrophages (BMDMs)] and in vivo (in serum and myocardium) after LPS challenge. RNA-sequencing results and bioinformatics analyses showed that the most significantly down-regulated genes in KO-BMDMs were modulated by LXRα, a nuclear receptor with robust anti-inflammatory activity in macrophages. Indeed, we identified that the nuclear translocation of LXRα was disrupted in KO-BMDMs when treated with GW3965 (LXR agonist), resulting in higher levels of inflammatory cytokines, compared to GW3965-treated WT-cells. Furthermore, using chronic inflammation model of high-fat diet (HFD) feeding, we observed that infiltration of inflammatory monocytes/macrophages into KO-hearts were greatly increased and accordingly, worsened cardiac function, compared to WT-HFD controls. Conclusion This study defines Sectm1a as a new regulator of inflammatory-induced cardiac dysfunction through modulation of LXRα signalling in macrophages. Our data suggest that augmenting Sectm1a activity may be a potential therapeutic approach to resolve inflammation and associated cardiac dysfunction.

scholarly journals COVID-19 and the kidney; mechanisms of tubular injury by SARS-CoV-2

2020 ◽  
Vol 10 (1) ◽  
pp. e08-e08
Author(s):  
Rojin Chegini ◽  
Zahra Mojtahedi ◽  
Bhaskar VKS Lakkakula ◽  
Aiyoub Pezeshgi ◽  
Saniya Niazi ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Impairment ◽  
Inflammatory Cytokines ◽  
Severe Disease ◽  
Significant Proportion ◽  
Kidney Injury ◽  
Blood Stream ◽  
Full Understanding ◽  
Tubular Injury ◽  
Pro Inflammatory Cytokines

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic, reported to cause asymptomatic to severe disease and eventually death. Multi-organ failure and death in patients with severe COVID-19 is associated with increased release of pro-inflammatory cytokines into the blood stream. Renal impairment is reported in a significant proportion of COVID-19 patients and is associated with high mortality. Acute kidney injury (AKI) is multifactorial and involving overlapping pathogenic mechanisms. This review updates the reader of recent publications dealing with the mechanisms underlying AKI in patients with COVID-19. A full understanding of all the possible ways in which the system plays its role in AKI is still a matter of research. Further studies are warranted to better understand the causes of AKI in COVID-19 patients.

scholarly journals Mitochondrial DNA leakage induces odontoblast inflammation via the cGAS-STING pathway

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lu Zhou ◽  
Yi-Fei Zhang ◽  
Fu-Hua Yang ◽  
Han-Qing Mao ◽  
Zhi Chen ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Real Time ◽  
Inflammatory Cytokines ◽  
Real Time Pcr ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Immunofluorescent Staining ◽  
Bacterial Invasion ◽  
Sting Pathway ◽  
Pro Inflammatory Cytokines

Abstract Background Mitochondrial DNA (mtDNA) is a vital driver of inflammation when it leaks from damaged mitochondria into the cytosol. mtDNA stress may contribute to cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway activation in infectious diseases. Odontoblasts are the first cells challenged by cariogenic bacteria and involved in maintenance of the pulp immune and inflammatory responses to dentine-invading pathogens. In this study, we investigated that mtDNA as an important inflammatory driver participated in defending against bacterial invasion via cGAS-STING pathway in odontoblasts. Methods The normal tissues, caries tissues and pulpitis tissues were measured by western blotting and immunohistochemical staining. Pulpitis model was built in vitro to evaluated the effect of the cGAS-STING pathway in odontoblast-like cell line (mDPC6T) under inflammation. Western blot and real-time PCR were performed to detect the expression of cGAS-STING pathway and pro-inflammatory cytokines. The mitochondrial function was evaluated reactive oxygen species (ROS) generated by mitochondria using MitoSOX Red dye staining. Cytosolic DNA was assessed by immunofluorescent staining and real-time PCR in mDPC6T cells after LPS stimulation. Furthermore, mDPC6T cells were treated with ethidium bromide (EtBr) to deplete mtDNA or transfected with isolated mtDNA. The expression of cGAS-STING pathway and pro-inflammatory cytokines were measured. Results The high expression of cGAS and STING in caries and pulpitis tissues in patients, which was associated with inflammatory progression. The cGAS-STING pathway was activated in inflamed mDPC6T. STING knockdown inhibited the nuclear import of p65 and IRF3 and restricted the secretion of the inflammatory cytokines CXCL10 and IL-6 induced by LPS. LPS caused mitochondrial damage in mDPC6T, which promoted mtDNA leakage into the cytosol. Depletion of mtDNA inhibited the cGAS-STING pathway and nuclear translocation of p65 and IRF3. Moreover, repletion of mtDNA rescued the inflammatory response, which was inhibited by STING knockdown. Conclusion Our study systematically identified a novel mechanism of LPS-induced odontoblast inflammation, which involved mtDNA leakage from damaged mitochondria into the cytosol stimulating the cGAS-STING pathway and the inflammatory cytokines IL-6 and CXCL10 secretion. The mtDNA-cGAS-STING axis could be a potent therapeutic target to prevent severe bacterial inflammation in pulpitis. Graphic abstract

Suppressive Effects of Britanin, a Sesquiterpene Compound Isolated from Inulae Flos, on Mast Cell-Mediated Inflammatory Responses

2014 ◽  
Vol 42 (04) ◽  
pp. 935-947 ◽  
Author(s):  
Hyo-Hyun Park ◽  
Sun-Gun Kim ◽  
Young Na Park ◽  
Jiean Lee ◽  
Youn Ju Lee ◽  
...  
Keyword(s):  
Mast Cell ◽  
Inflammatory Cytokines ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Human Mast Cell ◽  
Ionophore A23187 ◽  
Dependent Manner ◽  
Vitro Assay ◽  
Dose Dependent ◽  
Pro Inflammatory Cytokines

Mast cells are central players in immediate-type hypersensitvity and inflammatory responses. In the present study, the effects of britanin on the passive cutaneous anaphylaxis (PCA) reaction in mice and on the phorbol 12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-induced production of pro-inflammatory cytokines in human mast cell line (HMC-1) were evaluated. The oral administration of britanin (10–20 mg/kg) decreased the mast cell-mediated PCA reaction in IgE-sensitized mice. In the activity and mechanism of britanin in vitro assay, britanin suppressed the gene expression and secretion of pro-inflammatory cytokines in a dose-dependent manner in HMC-1. In addition, britanin attenuated PMACI-induced activation of NF-κB as indicated by the inhibition of the degradation of IκBα, nuclear translocation of NF-κB, NF-κB/DNA binding activity assay, and blocked the phosphorylation of p38 MAP kinase, in a dose-dependent manner. We conclude that britanin may have potential as a treatment for allergic-inflammatory diseases.

scholarly journals Mesenchymal Stem Cells Impact on COVID-19 Patients Immune System, an Ex Vivo Study

2021 ◽  
Author(s):  
Raedeh Saraei ◽  
kosar malekpour ◽  
Ali Hazrati ◽  
Hamed Valizadeh ◽  
Behnam Hashemi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Methylation Status ◽  
Lung Damage ◽  
Th2 Cells ◽  
Regulatory Function ◽  
Anti Inflammatory

Abstract Current clinical management approaches for COVID-19 patients are generally based on supportive treatment, which mainly includes respiratory support and restricted fluid input, which is currently a subject of much debate. Systemic Inflammation caused by SARS-CoV-2 may be related to various extrapulmonary comorbidities such as cytokine-mediated neuroinflammation leading to both non-neuronal and neurological consequences in COVID-19. Mesenchymal stem cells (MSCs) are adult stem cells with multipotent properties suitable for medical applications that have been reported as potential therapies in the setting of lung diseases. The immunosuppressive properties of MSCs provide a strong rationale to explore their potential beneficial effects on immune events in COVID-19. Multiple in vivo studies have demonstrated the capability of MSCs to prevent inflammatory responses and reduce lung damage. Recently, the use of MSCs in treating COVID-19 disease has improved long-term pulmonary function, but the specific mechanisms by which MSCs inhibit the severe inflammatory response induced by SARS-CoV-2 have not been elucidated. To the best of our knowledge, this is the first work describing the regulatory effects of MSCs on peripheral blood mononuclear cells (PBMCs) derived from patients with COVID-19 by measuring the pro-inflammatory and anti-inflammatory cytokines expression and secretion. We also examined the effects on the methylation of genes normally suppressed by DNA methylation in PBMCs. Our result showed that MSCs exerted an immune regulatory function on PBMCs in culture, skewing toward a type-2 response. This occurs by a mechanism consistent with a reduction in inflammatory factors (TNF-α, IL-1β, IL-6, IL-18, and IFNγ) protein and mRNA expression levels. In contrast, the anti-inflammatory cytokines (IL-4 and IL-10) increased following co-culture with MSCs. Consistent with these findings, the DNA methylation status of these immune genes seemed relevant to their expression pattern, except for GATA3, IL-1β, and IFNγ genes which showed no significant differences in methylation level between PBMCs with and without MSC exposure. Moreover, in co-culture interaction, MSCs modulated the Th1/Th2 cells in PBMCs compared to unstimulated PBMCs. These data demonstrate that MSCs can exert important immunomodulatory functions that affect virus-associated cytokine storms in pulmonary tissue during the severe respiratory stage.

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