Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 17 de 17
Filter
1.
Front Immunol ; 13: 821681, 2022.
Article in English | MEDLINE | ID: covidwho-1708117

ABSTRACT

Peritoneal dialysis (PD) is a valuable 'home treatment' option, even more so during the ongoing Coronavirus pandemic. However, the long-term use of PD is limited by unfavourable tissue remodelling in the peritoneal membrane, which is associated with inflammation-induced angiogenesis. This appears to be driven primarily through vascular endothelial growth factor (VEGF), while the involvement of other angiogenic signaling pathways is still poorly understood. Here, we have identified the crucial contribution of mesothelial cell-derived angiogenic CXC chemokine ligand 1 (CXCL1) to peritoneal angiogenesis in PD. CXCL1 expression and peritoneal microvessel density were analysed in biopsies obtained by the International Peritoneal Biobank (NCT01893710 at www.clinicaltrials.gov), comparing 13 children with end-stage kidney disease before initiating PD to 43 children on chronic PD. The angiogenic potential of mesothelial cell-derived CXCL1 was assessed in vitro by measuring endothelial tube formation of human microvascular endothelial cells (HMECs) treated with conditioned medium from human peritoneal mesothelial cells (HPMCs) stimulated to release CXCL1 by treatment with either recombinant IL-17 or PD effluent. We found that the capillary density in the human peritoneum correlated with local CXCL1 expression. Both CXCL1 expression and microvessel density were higher in PD patients than in the age-matched patients prior to initiation of PD. Exposure of HMECs to recombinant CXCL1 or conditioned medium from IL-17-stimulated HPMCs resulted in increased endothelial tube formation, while selective inhibition of mesothelial CXCL1 production by specific antibodies or through silencing of relevant transcription factors abolished the proangiogenic effect of HPMC-conditioned medium. In conclusion, peritoneal mesothelium-derived CXCL1 promotes endothelial tube formation in vitro and associates with peritoneal microvessel density in uremic patients undergoing PD, thus providing novel targets for therapeutic intervention to prolong PD therapy.


Subject(s)
Chemokine CXCL1/metabolism , Neovascularization, Pathologic/pathology , Peritoneal Dialysis/methods , Peritoneum/blood supply , Renal Replacement Therapy/methods , COVID-19/pathology , Cells, Cultured , Child , Child, Preschool , Epithelium/metabolism , Humans , Infant , Interleukin-17/metabolism , Kidney Failure, Chronic/therapy , Peritoneum/pathology , Vascular Endothelial Growth Factor A/metabolism , Vascular Remodeling/physiology
2.
Pharmacol Res ; 176: 106083, 2022 02.
Article in English | MEDLINE | ID: covidwho-1638968

ABSTRACT

The pathogenic hyper-inflammatory response has been revealed as the major cause of the severity and death of the Corona Virus Disease 2019 (COVID-19). Xuanfei Baidu Decoction (XFBD) as one of the "three medicines and three prescriptions" for the clinically effective treatment of COVID-19 in China, shows unique advantages in the control of symptomatic transition from moderate to severe disease states. However, the roles of XFBD to against hyper-inflammatory response and its mechanism remain unclear. Here, we established acute lung injury (ALI) model induced by lipopolysaccharide (LPS), presenting a hyperinflammatory process to explore the pharmacodynamic effect and molecular mechanism of XFBD on ALI. The in vitro experiments demonstrated that XFBD inhibited the secretion of IL-6 and TNF-α and iNOS activity in LPS-stimulated RAW264.7 macrophages. In vivo, we confirmed that XFBD improved pulmonary injury via down-regulating the expression of proinflammatory cytokines such as IL-6, TNF-α and IL1-ß as well as macrophages and neutrophils infiltration in LPS-induced ALI mice. Mechanically, we revealed that XFBD treated LPS-induced acute lung injury through PD-1/IL17A pathway which regulates the infiltration of neutrophils and macrophages. Additionally, one major compound from XFBD, i.e. glycyrrhizic acid, shows a high binding affinity with IL17A. In conclusion, we demonstrated the therapeutic effects of XFBD, which provides the immune foundations of XFBD and fatherly support its clinical applications.


Subject(s)
Acute Lung Injury/drug therapy , Drugs, Chinese Herbal/pharmacology , Interleukin-17/metabolism , Macrophages/drug effects , Neutrophils/drug effects , Programmed Cell Death 1 Receptor/metabolism , Signal Transduction/drug effects , Acute Lung Injury/metabolism , Animals , COVID-19/drug therapy , COVID-19/metabolism , Cell Line , China , Cytokines/metabolism , Leukocyte Count/methods , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Neutrophils/metabolism , RAW 264.7 Cells
3.
Eur Cytokine Netw ; 32(1): 8-14, 2021 Mar 01.
Article in English | MEDLINE | ID: covidwho-1477642

ABSTRACT

Cytokine release syndrome is a serious complication of the new coronavirus infection (COVID-19). The aim of the study was to assess effectiveness and safety of the IL-17 antagonist nekatimab for its treatment. The retrospective study included COVID-19 patients with C-reactive protein levels >60 mg/L. Patients received either netakimab (group NET), IL-6 antagonist tocilizumab (group TOC) or no anti-cytokine treatment (group CON). Forty-four patients were enrolled in the NET group, 27 patients in the TOC group, and 47 patients in the CON group. Mortality was lower in the NET group than in TOC and CON groups (2.3% vs. 14.8% and 31.9%; p = 0.018 and p < 0.001). NET group patients required intensive care unit admission (6.8% vs. 25.9% and 46.3%; p = 0.025 and p < 0.001) and mechanical ventilation (4.6% vs. 22.2% and 31.9%; p = 0.022 and p = 0.002) less frequently than patients of the TOC and CON groups. After 7-10 days of anti-cytokine drug administration, a reduction in lung lesion volume (p = 0.016) and an increase in the proportion of patients who did not need oxygen support (p = 0.005) or stayed in prone position (p = 0.044) was observed in the NET group only group; C-reactive protein levels were the same in the TOC and NET groups (p = 0.136) and lower in the CON group (p < 0.001 and p = 0.005). IL-6 levels decreased in the NET group (p = 0.005) and did not change in the TOC group (p = 0.953). There was no difference in the incidence of side effects between groups. The IL-17 antagonist netakimab is effective and safe in the treatment of cytokine release syndrome in COVID-19.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Interleukin-17/antagonists & inhibitors , C-Reactive Protein/metabolism , COVID-19/blood , COVID-19/virology , Case-Control Studies , Humans , Interleukin-17/metabolism , Interleukin-6/blood , Lung/pathology , Lung/virology , SARS-CoV-2/physiology , Treatment Outcome
4.
mBio ; 12(5): e0159921, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1398577

ABSTRACT

Cellular immunity may be involved in organ damage and rehabilitation in patients with coronavirus disease 2019 (COVID-19). We aimed to delineate immunological features of COVID-19 patients with pulmonary sequelae (PS) 1 year after discharge. Fifty COVID-19 survivors were recruited and classified according to radiological characteristics, including 24 patients with PS and 26 patients without PS. Phenotypic and functional characteristics of immune cells were evaluated by multiparametric flow cytometry. Patients with PS had an increased proportion of natural killer (NK) cells and a lower percentage of B cells than patients without PS. Phenotypic and functional features of T cells in patients with PS were predominated by the accumulation of CD4-positive (CD4+) T cells secreting interleukin 17A (IL-17A), short-lived effector-like CD8+ T cells (CD27-negative [CD27-] CD62L-), and senescent T cells with excessive secretion of granzyme B/perforin/interferon gamma (IFN-γ). NK cells were characterized by the excessive secretion of granzyme B and perforin and the downregulation of NKP30 and NKP46; highly activated NKT and γδ T cells exhibited NKP30 and TIM-3 upregulation and NKB1 downregulation in patients with PS. However, immunosuppressive cells were comparable between the two groups. The interrelationship of immune cells in COVID-19 was intrinsically identified, whereby T cells secreting IL-2, IL-4, and IL-17A were enriched among CD28+ and CD57- cells and cells secreting perforin/granzyme B/IFN-γ/tumor necrosis factor alpha (TNF-α)-expressed markers of terminal differentiation. CD57+ NK cells, CD4+Perforin+ T cells, and CD8+ CD27+ CD62L+ T cells were identified as the independent predictors for residual lesions. Overall, our findings unveil the profound imbalance of immune landscape that may correlate with organ damage and rehabilitation in COVID-19. IMPORTANCE A considerable proportion of COVID-19 survivors have residual lung lesions such as ground-glass opacity and fiber streak shadow. To determine the relationship between host immunity and residual lung lesions, we performed an extensive analysis of immune responses in convalescent patients with COVID-19 1 year after discharge. We found significant differences in immunological characteristics between patients with pulmonary sequelae and patients without pulmonary sequelae 1 year after discharge. Our study highlights the profound imbalance of immune landscape in the COVID-19 patients with pulmonary sequelae, characterized by the robust activation of cytotoxic T cells, NK cells, and γδ T cells, as well as the deficiencies of immunosuppressive cells. Importantly, CD57+ NK cells, CD4+Perforin+ T cells, and CD8+ CD27+ CD62L+ T cells were identified as the independent predictors for residual lesions.


Subject(s)
COVID-19/immunology , Adult , CD28 Antigens/metabolism , CD4-Positive T-Lymphocytes/metabolism , CD57 Antigens/metabolism , CD8-Positive T-Lymphocytes/metabolism , COVID-19/metabolism , Female , Hepatitis A Virus Cellular Receptor 2/metabolism , Humans , Immunity, Cellular/immunology , Immunity, Cellular/physiology , Interleukin-17/metabolism , Interleukin-2/metabolism , Interleukin-4/metabolism , L-Selectin/metabolism , Male , Middle Aged , Natural Cytotoxicity Triggering Receptor 1/metabolism , Natural Cytotoxicity Triggering Receptor 3/metabolism
5.
Front Immunol ; 12: 672523, 2021.
Article in English | MEDLINE | ID: covidwho-1389182

ABSTRACT

Lower respiratory infections are among the leading causes of morbidity and mortality worldwide. These potentially deadly infections are further exacerbated due to the growing incidence of antimicrobial resistance. To combat these infections there is a need to better understand immune mechanisms that promote microbial clearance. This need in the context of lung infections has been further heightened with the emergence of SARS-CoV-2. Group 3 innate lymphoid cells (ILC3s) are a recently discovered tissue resident innate immune cell found at mucosal sites that respond rapidly in the event of an infection. ILC3s have clear roles in regulating mucosal immunity and tissue homeostasis in the intestine, though the immunological functions in lungs remain unclear. It has been demonstrated in both viral and bacterial pneumonia that stimulated ILC3s secrete the cytokines IL-17 and IL-22 to promote both microbial clearance as well as tissue repair. In this review, we will evaluate regulation of ILC3s during inflammation and discuss recent studies that examine ILC3 function in the context of both bacterial and viral pulmonary infections.


Subject(s)
COVID-19/immunology , Immunity, Mucosal/immunology , Lymphocytes/immunology , Pneumonia, Bacterial/immunology , Respiratory Mucosa/immunology , SARS-CoV-2/immunology , Bacteria/immunology , COVID-19/mortality , COVID-19/pathology , Immunity, Innate/immunology , Inflammation/immunology , Interleukin-17/metabolism , Interleukins/metabolism , Lung/immunology , Lymphocyte Activation/immunology , Respiratory Mucosa/cytology
6.
Bioessays ; 43(2): e2000232, 2021 02.
Article in English | MEDLINE | ID: covidwho-1372696

ABSTRACT

Immunity against SARS-CoV-2 that is acquired by convalescent COVID-19 patients is examined in reference to (A) the Th17 cell generation system in psoriatic epidermis and (B) a recently discovered phenomenon in which Th17 cells are converted into tissue-resident memory T (TRM ) cells with Th1 phenotype. Neutrophils that are attracted to the site of infection secrete IL-17A, which stimulates lung epithelial cells to express CCL20. Natural Th17 (nTh17) cells are recruited to the infection site by CCL20 and expand in the presence of IL-23. These nTh17 cells are converted to TRM cells upon encounter with SARS-CoV-2 and continue to exist as ex-Th17 cells, which exert Th1-like immunity during a memory response. G-CSF can induce nTh17 cell accumulation at the infection site because it promotes neutrophil egress from the bone marrow. Hence, G-CSF may be effective against COVID-19. Administration of G-CSF to patients infected with SARS-CoV-2 is worth a clinical trial.


Subject(s)
Granulocyte Colony-Stimulating Factor/therapeutic use , Neutrophils/immunology , SARS-CoV-2/immunology , Th1 Cells/immunology , Th17 Cells/immunology , COVID-19/drug therapy , COVID-19/immunology , Chemokine CCL20/metabolism , Humans , Immunologic Memory/immunology , Interleukin-17/metabolism , Interleukin-23 Subunit p19/immunology , Neutrophils/drug effects , Th17 Cells/drug effects
7.
Sci Rep ; 11(1): 16814, 2021 08 19.
Article in English | MEDLINE | ID: covidwho-1366830

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has emerged as a pandemic. Paucity of information concerning the virus and therapeutic interventions have made SARS-CoV-2 infection a genuine threat to global public health. Therefore, there is a growing need for understanding the molecular mechanism of SARS-CoV-2 infection at cellular level. To address this, we undertook a systems biology approach by analyzing publicly available RNA-seq datasets of SARS-CoV-2 infection of different cells and compared with other lung pathogenic infections. Our study identified several key genes and pathways uniquely associated with SARS-CoV-2 infection. Genes such as interleukin (IL)-6, CXCL8, CCL20, CXCL1 and CXCL3 were upregulated, which in particular regulate the cytokine storm and IL-17 signaling pathway. Of note, SARS-CoV-2 infection strongly activated IL-17 signaling pathway compared with other respiratory viruses. Additionally, this transcriptomic signature was also analyzed to predict potential drug repurposing and small molecule inhibitors. In conclusion, our comprehensive data analysis identifies key molecular pathways to reveal underlying pathological etiology and potential therapeutic targets in SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , Interleukin-17/genetics , SARS-CoV-2/physiology , Systems Biology/methods , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Chemokine CCL20/genetics , Chemokine CXCL1/genetics , Chemokines, CXC/genetics , Drug Repositioning , Humans , Interleukin-17/metabolism , Interleukin-6/genetics , Interleukin-8/genetics , Organ Specificity , Signal Transduction , Transcriptome
8.
Cytokine ; 146: 155627, 2021 10.
Article in English | MEDLINE | ID: covidwho-1293702

ABSTRACT

BACKGROUND: One of the main pathophysiological mechanisms underlying the severe course of COVID-19 is the hyper-inflammatory syndrome associated with progressive damage of lung tissue and multi-organ dysfunction. IL-17 has been suggested to be involved in hyper-inflammatory syndrome. OBJECTIVE: To evaluate the efficacy and safety of the IL-17 inhibitor netakimab in patients with severe COVID-19. STUDY DESIGN: In our retrospective case-control study we evaluated the efficacy of netakimab in hospitalized patients with severe COVID-19 outside the intensive care unit (ICU). Patients in the experimental group were treated with standard of care therapy and netakimab at a dose of 120 mg subcutaneously. RESULTS: 171 patients with severe COVID-19 were enrolled in our study, and 88 of them received netakimab. On the 3 day of therapy, body temperature, SpO2/FiO2, NEWS2 score, and CRP improved significantly in the netakimab group compared to the control group. Other clinical outcomes such as transfer to ICU (11.4% vs 9.6%), need for mechanical ventilation (10.2% vs 9.6%), 28-day mortality (10.2% vs 8.4%), did not differ between the groups. CONCLUSION: In hospitalized patients with severe COVID-19, anti-IL-17 therapy might mitigate the inflammatory response and improve oxygenation, but do not affect the need for mechanical ventilation and mortality.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/therapy , Hospitalization/statistics & numerical data , Inpatients/statistics & numerical data , Interleukin-17/antagonists & inhibitors , SARS-CoV-2/drug effects , Aged , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/complications , COVID-19/virology , Case-Control Studies , Diarrhea/chemically induced , Dyspnea/chemically induced , Female , Humans , Inflammation/complications , Inflammation/drug therapy , Interleukin-17/immunology , Interleukin-17/metabolism , Length of Stay/statistics & numerical data , Male , Middle Aged , Pilot Projects , Respiration, Artificial , Retrospective Studies , SARS-CoV-2/physiology , Severity of Illness Index , Treatment Outcome
9.
Int Immunopharmacol ; 97: 107828, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1253058

ABSTRACT

In various pathological conditions, cellular immunity plays an important role in immune responses. Amongimmunecells, T lymphocytes pdomotecellular and humoralresponses as well as innate immunity. Therefore, careful investigation of these cells has a significant impact on accurate knowledge in COVID-19diseasepathogenesis. In current research, the frequency and function of various T lymphocytes involved in immune responses examined in SARS-CoV-2 patients with various disease severity compared to normal subjects. In order to make an accurate comparison among patients with various disease severity, this study was performed on asymptomatic recovered cases (n = 20), ICU hospitalized patients (n = 30), non-ICU hospitalized patients (n = 30), and normal subjects (n = 20). To precisely evaluate T cells activity following purification, their cytokine secretion activity was examined. Similarly, immediately after purification of Treg cells, their inhibitory activity on T cells was investigated. The results showed that COVID-19 patients with severe disease (ICU hospitalized patients) not only had a remarkable increase in Th1 and Th17 but also a considerable decrease in Th2 and Treg cells. More importantly, as the IL-17 and IFN-γ secretion was sharply increased in severe disease, the secretion of IL-10 and IL-4 was decreased. Furthermore, the inhibitory activity of Treg cells was reduced in severe disease patients in comparison to other groups. In severe COVID-19 disease, current findings indicate when the inflammatory arm of cellular immunity is significantly increased, a considerable reduction in anti-inflammatory and regulatory arm occurred.


Subject(s)
COVID-19/blood , COVID-19/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/virology , Adult , Aged , Cytokines/immunology , Cytokines/metabolism , Female , Healthy Volunteers , Humans , Immunity, Cellular , Inflammation/metabolism , Interferon-gamma/metabolism , Interleukin-10/metabolism , Interleukin-17/metabolism , Interleukin-4/metabolism , Leukocytes/immunology , Leukocytes/metabolism , Male , Middle Aged , Severity of Illness Index , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism , Th2 Cells/immunology , Th2 Cells/metabolism , Young Adult
10.
Int J Mol Sci ; 22(10)2021 May 15.
Article in English | MEDLINE | ID: covidwho-1236794

ABSTRACT

Acute lung injury (ALI) afflicts approximately 200,000 patients annually and has a 40% mortality rate. The COVID-19 pandemic has massively increased the rate of ALI incidence. The pathogenesis of ALI involves tissue damage from invading microbes and, in severe cases, the overexpression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). This study aimed to develop a therapy to normalize the excess production of inflammatory cytokines and promote tissue repair in the lipopolysaccharide (LPS)-induced ALI. Based on our previous studies, we tested the insulin-like growth factor I (IGF-I) and BTP-2 therapies. IGF-I was selected, because we and others have shown that elevated inflammatory cytokines suppress the expression of growth hormone receptors in the liver, leading to a decrease in the circulating IGF-I. IGF-I is a growth factor that increases vascular protection, enhances tissue repair, and decreases pro-inflammatory cytokines. It is also required to produce anti-inflammatory 1,25-dihydroxyvitamin D. BTP-2, an inhibitor of cytosolic calcium, was used to suppress the LPS-induced increase in cytosolic calcium, which otherwise leads to an increase in proinflammatory cytokines. We showed that LPS increased the expression of the primary inflammatory mediators such as toll like receptor-4 (TLR-4), IL-1ß, interleukin-17 (IL-17), TNF-α, and interferon-γ (IFN-γ), which were normalized by the IGF-I + BTP-2 dual therapy in the lungs, along with improved vascular gene expression markers. The histologic lung injury score was markedly elevated by LPS and reduced to normal by the combination therapy. In conclusion, the LPS-induced increases in inflammatory cytokines, vascular injuries, and lung injuries were all improved by IGF-I + BTP-2 combination therapy.


Subject(s)
Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Anilides/pharmacology , Cytokines/metabolism , Gene Expression Regulation/drug effects , Insulin-Like Growth Factor I/pharmacology , Thiadiazoles/pharmacology , Acute Lung Injury/pathology , Acute Lung Injury/virology , Anilides/therapeutic use , Animals , COVID-19/complications , Calcium/metabolism , Calcium Channels/metabolism , Cytokines/genetics , Disease Models, Animal , Female , Gene Expression Regulation/genetics , Immunohistochemistry , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor I/therapeutic use , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-17/genetics , Interleukin-17/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lipopolysaccharides/toxicity , Mice , Mice, Inbred C57BL , Signal Transduction/drug effects , Signal Transduction/genetics , Thiadiazoles/therapeutic use , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
11.
Viruses ; 13(2)2021 02 03.
Article in English | MEDLINE | ID: covidwho-1060774

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comprises mild courses of disease as well as progression to severe disease, characterised by lung and other organ failure. The immune system is considered to play a crucial role for the pathogenesis of COVID-19, although especially the contribution of innate-like T cells remains poorly understood. Here, we analysed the phenotype and function of mucosal-associated invariant T (MAIT) cells, innate-like T cells with potent antimicrobial effector function, in patients with mild and severe COVID-19 by multicolour flow cytometry. Our data indicate that MAIT cells are highly activated in patients with COVID-19, irrespective of the course of disease, and express high levels of proinflammatory cytokines such as IL-17A and TNFα ex vivo. Of note, expression of the activation marker HLA-DR positively correlated with SAPS II score, a measure of disease severity. Upon MAIT cell-specific in vitro stimulation, MAIT cells however failed to upregulate expression of the cytokines IL-17A and TNFα, as well as cytolytic proteins, that is, granzyme B and perforin. Thus, our data point towards an altered cytokine expression profile alongside an impaired antibacterial and antiviral function of MAIT cells in COVID-19 and thereby contribute to the understanding of COVID-19 immunopathogenesis.


Subject(s)
COVID-19/immunology , Lymphocyte Activation , Mucosal-Associated Invariant T Cells/immunology , Adaptive Immunity , COVID-19/physiopathology , Cytokines/metabolism , Female , Granzymes/metabolism , HLA-DR Antigens , Humans , Interleukin-17/metabolism , Killer Cells, Natural/immunology , Male , Mucosal-Associated Invariant T Cells/metabolism , Severity of Illness Index , T-Lymphocyte Subsets/immunology , Tumor Necrosis Factor-alpha/metabolism
12.
EBioMedicine ; 63: 103197, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1014450

ABSTRACT

BACKGROUND: SARS-CoV-2 has caused a global pandemic, infecting millions of people. A safe, effective vaccine is urgently needed and remains a global health priority. Subunit vaccines are used successfully against other viruses when administered in the presence of an effective adjuvant. METHODS: We evaluated three different clinically tested adjuvant systems in combination with the SARS-CoV-2 pre-fusion stabilized (S-2P) spike protein using a one-dose regimen in mice. FINDINGS: Whilst spike protein alone was only weakly immunogenic, the addition of either Aluminum hydroxide, a squalene based oil-in-water emulsion system (SE) or a cationic liposome-based adjuvant significantly enhanced antibody responses against the spike receptor binding domain (RBD). Kinetics of antibody responses differed, with SE providing the most rapid response. Neutralizing antibodies developed after a single immunization in all adjuvanted groups with ID50 titers ranging from 86-4063. Spike-specific CD4 T helper responses were also elicited, comprising mainly of IFN-γ and IL-17 producing cells in the cationic liposome adjuvanted group, and more IL-5- and IL-10-secreting cells in the AH group. INTERPRETATION: These results demonstrate that adjuvanted spike protein subunit vaccine is a viable strategy for rapidly eliciting SARS-CoV-2 neutralizing antibodies and CD4 T cell responses of various qualities depending on the adjuvant used, which can be explored in further vaccine development against COVID-19. FUNDING: This work was supported by the European Union Horizon 2020 research and innovation program under grant agreement no. 101003653.


Subject(s)
Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , CD4-Positive T-Lymphocytes/immunology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/immunology , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/chemistry , Aluminum Hydroxide/chemistry , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/metabolism , COVID-19/pathology , COVID-19/virology , Female , Immunization , Interferon-gamma/metabolism , Interleukin-17/metabolism , Liposomes/chemistry , Mice , Mice, Inbred C57BL , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Squalene/chemistry , Vaccines, Subunit/immunology
14.
Sci Immunol ; 5(51)2020 09 28.
Article in English | MEDLINE | ID: covidwho-808356

ABSTRACT

Severe COVID-19 is characterized by excessive inflammation of the lower airways. The balance of protective versus pathological immune responses in COVID-19 is incompletely understood. Mucosa-associated invariant T (MAIT) cells are antimicrobial T cells that recognize bacterial metabolites, and can also function as innate-like sensors and mediators of antiviral responses. Here, we investigated the MAIT cell compartment in COVID-19 patients with moderate and severe disease, as well as in convalescence. We show profound and preferential decline in MAIT cells in the circulation of patients with active disease paired with strong activation. Furthermore, transcriptomic analyses indicated significant MAIT cell enrichment and pro-inflammatory IL-17A bias in the airways. Unsupervised analysis identified MAIT cell CD69high and CXCR3low immunotypes associated with poor clinical outcome. MAIT cell levels normalized in the convalescent phase, consistent with dynamic recruitment to the tissues and later release back into the circulation when disease is resolved. These findings indicate that MAIT cells are engaged in the immune response against SARS-CoV-2 and suggest their possible involvement in COVID-19 immunopathogenesis.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/pathology , Mucosal-Associated Invariant T Cells/immunology , Pneumonia, Viral/pathology , Adult , Aged , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , COVID-19 , Coronavirus Infections/immunology , Female , Humans , Immunity, Innate/immunology , Inflammation/immunology , Interleukin-17/metabolism , Lectins, C-Type/metabolism , Lymphocyte Activation/immunology , Male , Middle Aged , Pandemics , Pneumonia, Viral/immunology , Receptors, CXCR3/metabolism , SARS-CoV-2 , Young Adult
15.
Cell ; 183(4): 982-995.e14, 2020 11 12.
Article in English | MEDLINE | ID: covidwho-756809

ABSTRACT

Initially, children were thought to be spared from disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a month into the epidemic, a novel multisystem inflammatory syndrome in children (MIS-C) emerged. Herein, we report on the immune profiles of nine MIS-C cases. All MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with intact neutralization capability. Cytokine profiling identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1), and mucosal immune dysregulation (IL-17A, CCL20, and CCL28). Immunophenotyping of peripheral blood revealed reductions of non-classical monocytes, and subsets of NK and T lymphocytes, suggesting extravasation to affected tissues. Finally, profiling the autoantigen reactivity of MIS-C plasma revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal, and immune-cell antigens. All patients were treated with anti-IL-6R antibody and/or IVIG, which led to rapid disease resolution.


Subject(s)
Inflammation/pathology , Systemic Inflammatory Response Syndrome/pathology , Adolescent , Antibodies, Viral/blood , Autoantibodies/blood , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , COVID-19 , Chemokine CCL3/metabolism , Child , Child, Preschool , Coronavirus Infections/complications , Coronavirus Infections/pathology , Coronavirus Infections/virology , Female , Humans , Immunity, Humoral , Infant , Infant, Newborn , Inflammation/metabolism , Interleukin-17/metabolism , Interleukin-18/metabolism , Killer Cells, Natural/cytology , Killer Cells, Natural/metabolism , Male , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Young Adult
16.
J Immunol ; 205(4): 892-898, 2020 08 15.
Article in English | MEDLINE | ID: covidwho-638521

ABSTRACT

SARS-CoV-2, the virus causing COVID-19, has infected millions and has caused hundreds of thousands of fatalities. Risk factors for critical illness from SARS-CoV-2 infection include male gender, obesity, diabetes, and age >65. The mechanisms underlying the susceptibility to critical illness are poorly understood. Of interest, these comorbidities have previously been associated with increased signaling of Th17 cells. Th17 cells secrete IL-17A and are important for clearing extracellular pathogens, but inappropriate signaling has been linked to acute respiratory distress syndrome. Currently there are few treatment options for SARS-CoV-2 infections. This review describes evidence linking risk factors for critical illness in COVID-19 with increased Th17 cell activation and IL-17 signaling that may lead to increased likelihood for lung injury and respiratory failure. These findings provide a basis for testing the potential use of therapies directed at modulation of Th17 cells and IL-17A signaling in the treatment of COVID-19.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/immunology , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Interleukin-17/antagonists & inhibitors , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Th17 Cells/drug effects , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19 , Comorbidity , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Critical Illness , Female , Humans , Interleukin-17/metabolism , Male , Pandemics , Pneumonia, Viral/virology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/mortality , Respiratory Distress Syndrome/virology , Risk Factors , SARS-CoV-2 , Signal Transduction/drug effects , Signal Transduction/immunology , Th17 Cells/immunology
SELECTION OF CITATIONS
SEARCH DETAIL