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1.
Small Methods ; 5(5): e2001108, 2021 05.
Article in English | MEDLINE | ID: covidwho-1599126

ABSTRACT

During the global outbreak of COVID-19 pandemic, "cytokine storm" conditions are regarded as the fatal step resulting in most mortality. Hemoperfusion is widely used to remove cytokines from the blood of severely ill patients to prevent uncontrolled inflammation induced by a cytokine storm. This article discoveres, for the first time, that 2D Ti3 C2 Tx MXene sheet demonstrates an ultrahigh removal capability for typical cytokine interleukin-6. In particular, MXene shows a 13.4 times higher removal efficiency over traditional activated carbon absorbents. Molecular-level investigations reveal that MXene exhibits a strong chemisorption mechanism for immobilizing cytokine interleukin-6 molecules, which is different from activated carbon absorbents. MXene sheet also demonstrates excellent blood compatibility without any deleterious side influence on the composition of human blood. This work can open a new avenue to use MXene sheets as an ultraefficient hemoperfusion absorbent to eliminate the cytokine storm syndrome in treatment of severe COVID-19 patients.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/drug therapy , Hemoperfusion/methods , Nanostructures/administration & dosage , SARS-CoV-2/immunology , Titanium/administration & dosage , Adsorption , COVID-19/transmission , COVID-19/virology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/virology , Humans , Interleukin-6/immunology , Nanostructures/chemistry , SARS-CoV-2/isolation & purification , Titanium/chemistry
2.
Iran J Immunol ; 18(4): 331-337, 2021 12.
Article in English | MEDLINE | ID: covidwho-1594484

ABSTRACT

BACKGROUND: According to the World Health Organization, Mexico presents one of the highest mortality rates due to coronavirus disease 2019 (COVID-19). The "cytokine storm" phenomenon has been proposed as a pathological hallmark of severe COVID-19. OBJECTIVE: To determine the association of serum cytokine levels with COVID-19 severity. METHODS: We studied the cytokines IL-2, IL-4, IL-6, IL-10, TNF-α, and the IFN-γ serum levels through flow cytometry in 56 COVID-19 patients (24 critical and 32 non-critical) from Northwest Mexico. RESULTS: We observed a significant increase in the IL-6 and the IL-10 levels in the sera of critical patients. These cytokines were also associated with mechanical ventilation necessity and death, IL-6 showing AUC values above 0.7 for both variables; and correlated with Na+, creatinine, and platelet levels. On the other hand, no association was found between IL-2, IL-4, TNF-α, and IFN-γ with tested variables. CONCLUSION: Our results corroborate previous observations regarding IL-6 and IL-10 involvement in the severity of COVID-19.


Subject(s)
COVID-19/blood , COVID-19/physiopathology , Interleukin-10/metabolism , Interleukin-6/metabolism , COVID-19/pathology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/pathology , Female , Humans , Interleukin-10/blood , Interleukin-6/blood , Male , Mexico , Patient Acuity
3.
J Med Virol ; 93(12): 6519-6524, 2021 12.
Article in English | MEDLINE | ID: covidwho-1544297

ABSTRACT

The COVID-19 pandemic, which has ravaged our world for more than a year, still shapes our agenda with a scale of intensity that fluctuates over time. In our study, we aimed to determine the correlation between serum migration inhibitory factor (MIF) level and disease severity in COVID-19 with different prognoses. Between 15 October 2020 and 20 January 2021, 110 patients over the age of 18 who were diagnosed with COVID-19 and 40 volunteer healthcare personnel were included in our study. MIF levels were measured by enzyme-linked immunosorbent assay. In the comparison of serum MIF values in the patient and control group, it was observed that the MIF level was significantly higher in patients with both moderate and severe COVID-19 levels compared to the control group (p = 0.001, 0.001). In the comparison of serum MIF values of moderate to severe COVID-19 patients, it was observed that MIF level was higher in severe patients (p = 0.001). In the receiver operating characteristic curve analysis performed to differentiate between severe and moderate COVID-19 patients with MIF levels, the area under the curve was observed as 0.78. When the cutoff value of the MIF level was taken as 4.455 ng/ml, the sensitivity was 83% and the specificity was 62%. Failure to adequately balance the pro-inflammatory cytokines synthesized in COVID-19 with anti-inflammatory effect is the most important reason for the aggravation of the disease course. Playing a role in pro-inflammatory cytokine synthesis, MIF can provide important information about the disease prognosis in the early period.


Subject(s)
COVID-19/pathology , Cytokine Release Syndrome/blood , Intramolecular Oxidoreductases/blood , Macrophage Migration-Inhibitory Factors/blood , Macrophages/immunology , SARS-CoV-2/immunology , Case-Control Studies , Cytokine Release Syndrome/pathology , Disease Progression , Enzyme-Linked Immunosorbent Assay , Female , Humans , Macrophage Activation/immunology , Male , Middle Aged , Prognosis , Severity of Illness Index
4.
Clin Microbiol Rev ; 34(3)2021 06 16.
Article in English | MEDLINE | ID: covidwho-1501524

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a rapidly evolving pandemic worldwide with at least 68 million COVID-19-positive cases and a mortality rate of about 2.2%, as of 10 December 2020. About 20% of COVID-19 patients exhibit moderate to severe symptoms. Severe COVID-19 manifests as acute respiratory distress syndrome (ARDS) with elevated plasma proinflammatory cytokines, including interleukin 1ß (IL-1ß), IL-6, tumor necrosis factor α (TNF-α), C-X-C motif chemokine ligand 10 (CXCL10/IP10), macrophage inflammatory protein 1 alpha (MIP-1α), and chemokine (C-C motif) ligand 2 (CCL2), with low levels of interferon type I (IFN-I) in the early stage and elevated levels of IFN-I during the advanced stage of COVID-19. Most of the severe and critically ill COVID-19 patients have had preexisting comorbidities, including hypertension, diabetes, cardiovascular diseases, and respiratory diseases. These conditions are known to perturb the levels of cytokines, chemokines, and angiotensin-converting enzyme 2 (ACE2), an essential receptor involved in SARS-CoV-2 entry into the host cells. ACE2 downregulation during SARS-CoV-2 infection activates the angiotensin II/angiotensin receptor (AT1R)-mediated hypercytokinemia and hyperinflammatory syndrome. However, several SARS-CoV-2 proteins, including open reading frame 3b (ORF3b), ORF6, ORF7, ORF8, and the nucleocapsid (N) protein, can inhibit IFN type I and II (IFN-I and -II) production. Thus, hyperinflammation, in combination with the lack of IFN responses against SARS-CoV-2 early on during infection, makes the patients succumb rapidly to COVID-19. Therefore, therapeutic approaches involving anti-cytokine/anti-cytokine-signaling and IFN therapy would favor the disease prognosis in COVID-19. This review describes critical host and viral factors underpinning the inflammatory "cytokine storm" induction and IFN antagonism during COVID-19 pathogenesis. Therapeutic approaches to reduce hyperinflammation and their limitations are also discussed.


Subject(s)
COVID-19/pathology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/pathology , Interferon Type I/blood , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/blood , COVID-19/therapy , Comorbidity , Humans , Immunity, Innate/immunology , Immunization, Passive/methods , Interleukin-6/antagonists & inhibitors , Interleukin-6/blood , Spike Glycoprotein, Coronavirus/metabolism
5.
Hamostaseologie ; 41(5): 379-385, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1483188

ABSTRACT

In 2019 first reports about a new human coronavirus emerged, which causes common cold symptoms as well as acute respiratory distress syndrome. The virus was identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and severe thrombotic events including deep vein thrombosis, pulmonary embolism, and microthrombi emerged as additional symptoms. Heart failure, myocardial infarction, myocarditis, and stroke have also been observed. As main mediator of thrombus formation, platelets became one of the key aspects in SARS-CoV-2 research. Platelets may also directly interact with SARS-CoV-2 and have been shown to carry the SARS-CoV-2 virus. Platelets can also facilitate the virus uptake by secretion of the subtilisin-like proprotein convertase furin. Cleavage of the SARS-CoV-2 spike protein by furin enhances binding capabilities and virus entry into various cell types. In COVID-19 patients, platelet count differs between mild and serious infections. Patients with mild symptoms have a slightly increased platelet count, whereas thrombocytopenia is a hallmark of severe COVID-19 infections. Low platelet count can be attributed to platelet apoptosis and the incorporation of platelets into microthrombi (peripheral consumption) and severe thrombotic events. The observed excessive formation of thrombi is due to hyperactivation of platelets caused by the infection. Various factors have been suggested in the activation of platelets in COVID-19, such as hypoxia, vessel damage, inflammatory factors, NETosis, SARS-CoV-2 interaction, autoimmune reactions, and autocrine activation. COVID-19 does alter chemokine and cytokine plasma concentrations. Platelet chemokine profiles are altered in COVID-19 and contribute to the described chemokine storms observed in severely ill COVID-19 patients.


Subject(s)
Blood Platelets/physiology , Blood Platelets/virology , COVID-19/blood , Blood Platelets/immunology , COVID-19/complications , COVID-19/immunology , Chemokines/blood , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/etiology , Host Microbial Interactions/immunology , Host Microbial Interactions/physiology , Humans , Models, Biological , Pandemics , Platelet Activation/immunology , Platelet Activation/physiology , SARS-CoV-2/pathogenicity , Thrombosis/blood , Thrombosis/etiology
7.
Immunopharmacol Immunotoxicol ; 43(6): 633-643, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1467231

ABSTRACT

The coronavirus disease-19 (COVID-19), at first, was reported in Wuhan, China, and then rapidly became pandemic throughout the world. Cytokine storm syndrome (CSS) in COVID-19 patients is associated with high levels of cytokines and chemokines that cause multiple organ failure, systemic inflammation, and hemodynamic instabilities. Acute respiratory distress syndrome (ARDS), a common complication of COVID-19, is a consequence of cytokine storm. In this regard, several drugs have been being investigated to suppress this inflammatory condition. Purinergic signaling receptors comprising of P1 adenosine and P2 purinoceptors play a critical role in inflammation. Therefore, activation or inhibition of some subtypes of these kinds of receptors is most likely to be beneficial to attenuate cytokine storm. This article summarizes suggested therapeutic drugs with potential anti-inflammatory effects through purinergic receptors.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/prevention & control , Cytokines/blood , Purinergic Antagonists/therapeutic use , Receptors, Purinergic/drug effects , SARS-CoV-2/drug effects , Animals , Anti-Inflammatory Agents/adverse effects , Biomarkers/blood , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Host-Pathogen Interactions , Humans , Ligands , Molecular Targeted Therapy , Multiple Organ Failure/immunology , Multiple Organ Failure/prevention & control , Multiple Organ Failure/virology , Purinergic Antagonists/adverse effects , Receptors, Purinergic/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Signal Transduction
8.
J Steroid Biochem Mol Biol ; 213: 105964, 2021 10.
Article in English | MEDLINE | ID: covidwho-1433601

ABSTRACT

OBJECTIVE: We aimed to evaluate the vitamin D status of pregnant women with COVID-19, and the association between vitamin D level and severity of COVID-19. METHODS: In this case control study, 159 women with a single pregnancy and tested positive for SARS-CoV-2, and randomly selected 332 healthy pregnant women with similar gestational ages were included. COVID-19 patients were classified as mild, moderate, and severe. Vitamin D deficiency was defined as 25-hydroxycholecalciferol <20 ng/mL (50 nmol/L), and 25-OH D vitamin <10 ng/mL was defined as severe vitamin D deficiency, also 25-OH D vitamin level between 20-29 ng/mL (525-725 nmol/L) was defined as vitamin D insufficiency. RESULTS: Vitamin D levels of the pregnant women in the COVID-19 group (12.46) were lower than the control group (18.76). 25-OH D vitamin levels of those in the mild COVID-19 category (13.69) were significantly higher than those in the moderate/severe category (9.06). In terms of taking vitamin D supplementation, there was no statistically significant difference between the groups. However, it was observed that all of those who had severe COVID-19 were the patients who did not take vitamin D supplementation. CONCLUSION: The vitamin D levels are low in pregnant women with COVID-19. Also, there is a significant difference regarding to vitamin D level and COVID-19 severity in pregnant women. Maintenance of adequate vitamin D level can be useful as an approach for the prevention of an aggressive course of the inflammation induced by this novel coronavirus in pregnant women.


Subject(s)
COVID-19/diet therapy , Cytokine Release Syndrome/diet therapy , Dietary Supplements , Pregnancy Complications, Infectious/diet therapy , Vitamin D Deficiency/diet therapy , Vitamin D/administration & dosage , Adult , COVID-19/blood , COVID-19/pathology , COVID-19/virology , Calcifediol/blood , Case-Control Studies , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Female , Gestational Age , Humans , Pregnancy , Pregnancy Complications, Infectious/blood , Pregnancy Complications, Infectious/pathology , Pregnancy Complications, Infectious/virology , SARS-CoV-2/pathogenicity , Severity of Illness Index , Treatment Outcome , Vitamin D/analogs & derivatives , Vitamin D/blood , Vitamin D Deficiency/blood , Vitamin D Deficiency/pathology , Vitamin D Deficiency/virology
9.
Int Immunopharmacol ; 100: 108163, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1415472

ABSTRACT

Zinc deficiency is associated with impaired antiviral response, cytokine releasing syndrome (CRS), and acute respiratory distress syndrome. Notably, similar complications are being observed during severe SARS-CoV-2 infection. We conducted a prospective, single-center, observational study in a tertiary university hospital (CUB-Hôpital Erasme, Brussels) to address the zinc status, the association between the plasma zinc concentration, development of CRS, and the clinical outcomes in PCR-confirmed and hospitalized COVID-19 patients. One hundred and thirty-nine eligible patients were included between May 2020 and November 2020 (median age of 65 years [IQR = 54, 77]). Our cohort's median plasma zinc concentration was 57 µg/dL (interquartile range [IQR] = 45, 67) compared to 74 µg/dL (IQR = 64, 84) in the retrospective non-COVID-19 control group (N = 1513; p < 0.001). Markedly, the absolute majority of COVID-19 patients (96%) were zinc deficient (<80 µg/dL). The median zinc concentration was lower in patients with CRS compared to those without CRS (-5 µg/dL; 95% CI = -10.5, 0.051; p = 0.048). Among the tested outcomes, zinc concentration is significantly correlated with only the length of hospital stay (rho = -0.19; p = 0.022), but not with mortality or morbidity. As such, our findings do not support the role of zinc as a robust prognostic marker among hospitalized COVID-19 patients who in our cohort presented a high prevalence of zinc deficiency. It might be more beneficial to explore the role of zinc as a biomarker for assessing the risk of developing a tissue-damaging CRS and predicting outcomes in patients diagnosed with COVID-19 at the early stage of the disease.


Subject(s)
COVID-19/complications , Cytokine Release Syndrome/etiology , SARS-CoV-2 , Zinc/blood , Aged , COVID-19/blood , Cytokine Release Syndrome/blood , Female , Hospitalization , Humans , Male , Middle Aged , Prospective Studies , Zinc/physiology
10.
Cell Rep ; 37(1): 109793, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1415261

ABSTRACT

The mortality risk of coronavirus disease 2019 (COVID-19) patients has been linked to the cytokine storm caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Understanding the inflammatory responses shared between COVID-19 and other infectious diseases that feature cytokine storms may therefore help in developing improved therapeutic strategies. Here, we use integrative analysis of single-cell transcriptomes to characterize the inflammatory signatures of peripheral blood mononuclear cells from patients with COVID-19, sepsis, and HIV infection. We identify ten hyperinflammatory cell subtypes in which monocytes are the main contributors to the transcriptional differences in these infections. Monocytes from COVID-19 patients share hyperinflammatory signatures with HIV infection and immunosuppressive signatures with sepsis. Finally, we construct a "three-stage" model of heterogeneity among COVID-19 patients, related to the hyperinflammatory and immunosuppressive signatures in monocytes. Our study thus reveals cellular and molecular insights about inflammatory responses to SARS-CoV-2 infection and provides therapeutic guidance to improve treatments for subsets of COVID-19 patients.


Subject(s)
COVID-19/blood , COVID-19/immunology , HIV Infections/blood , Leukocytes, Mononuclear/metabolism , SARS-CoV-2/immunology , Sepsis/blood , Transcriptome , COVID-19/virology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/immunology , Cytokines/blood , Data Analysis , Datasets as Topic , HIV Infections/immunology , HIV-1/immunology , Humans , Inflammation/blood , Leukocytes, Mononuclear/immunology , Sepsis/immunology , Single-Cell Analysis
11.
Arthritis Rheumatol ; 73(10): 1791-1799, 2021 10.
Article in English | MEDLINE | ID: covidwho-1391545

ABSTRACT

OBJECTIVE: Infection with the novel coronavirus SARS-CoV-2 triggers severe illness with high mortality in a subgroup of patients. Such a critical course of COVID-19 is thought to be associated with the development of cytokine storm, a condition seen in macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (HLH). However, specific data demonstrating a clear association of cytokine storm with severe COVID-19 are still lacking. The aim of this study was to directly address whether immune activation in COVID-19 does indeed mimic the conditions found in these classic cytokine storm syndromes. METHODS: Levels of 22 biomarkers were quantified in serum samples from patients with COVID-19 (n = 30 patients, n = 83 longitudinal samples in total), patients with secondary HLH/MAS (n = 50), and healthy controls (n = 9). Measurements were performed using bead array assays and single-marker enzyme-linked immunosorbent assay. Serum biomarker levels were assessed for correlations with disease outcome. RESULTS: In patients with secondary HLH/MAS, we observed pronounced activation of the interleukin-18 (IL-18)-interferon-γ axis, increased serum levels of IL-1 receptor antagonist, intercellular adhesion molecule 1, and IL-8, and strongly reduced levels of soluble Fas ligand in the course of SARS-CoV-2 infection. These observations appeared to discriminate immune dysregulation in critical COVID-19 from the well-recognized characteristics of other cytokine storm syndromes. CONCLUSION: Serum biomarker profiles clearly separate COVID-19 from MAS or secondary HLH in terms of distinguishing the severe systemic hyperinflammation that occurs following SARS-CoV-2 infection. These findings could be useful in determining the efficacy of drugs targeting key molecules and pathways specifically associated with systemic cytokine storm conditions in the treatment of COVID-19.


Subject(s)
COVID-19/diagnosis , Cytokine Release Syndrome/etiology , Interleukin-18/blood , Interleukin-8/blood , Lymphohistiocytosis, Hemophagocytic/diagnosis , Macrophage Activation Syndrome/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/blood , COVID-19/complications , Cytokine Release Syndrome/blood , Diagnosis, Differential , Female , Humans , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/complications , Macrophage Activation Syndrome/blood , Macrophage Activation Syndrome/complications , Male , Middle Aged , Young Adult
12.
Front Immunol ; 12: 659419, 2021.
Article in English | MEDLINE | ID: covidwho-1389180

ABSTRACT

Highly pathogenic virus infections usually trigger cytokine storms, which may have adverse effects on vital organs and result in high mortalities. The two cytokines interleukin (IL)-4 and interferon (IFN)-γ play key roles in the generation and regulation of cytokine storms. However, it is still unclear whether the cytokine with the largest induction amplitude is the same under different virus infections. It is unknown which is the most critical and whether there are any mathematical formulas that can fit the changing rules of cytokines. Three coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2), three influenza viruses (2009H1N1, H5N1 and H7N9), Ebola virus, human immunodeficiency virus, dengue virus, Zika virus, West Nile virus, hepatitis B virus, hepatitis C virus, and enterovirus 71 were included in this analysis. We retrieved the cytokine fold change (FC), viral load, and clearance rate data from these highly pathogenic virus infections in humans and analyzed the correlations among them. Our analysis showed that interferon-inducible protein (IP)-10, IL-6, IL-8 and IL-17 are the most common cytokines with the largest induction amplitudes. Equations were obtained: the maximum induced cytokine (max) FC = IFN-γ FC × (IFN-γ FC/IL-4 FC) (if IFN-γ FC/IL-4 FC > 1); max FC = IL-4 FC (if IFN-γ FC/IL-4 FC < 1). For IFN-γ-inducible infections, 1.30 × log2 (IFN-γ FC) = log10 (viral load) - 2.48 - 2.83 × (clearance rate). The clinical relevance of cytokines and their antagonists is also discussed.


Subject(s)
Cytokine Release Syndrome/immunology , Cytokines/blood , Models, Immunological , Virus Diseases/complications , Biomarkers/blood , Biomarkers/metabolism , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/virology , Cytokines/immunology , Cytokines/metabolism , Humans , Viral Load/immunology , Virus Diseases/blood , Virus Diseases/immunology , Virus Diseases/virology
13.
J Med Virol ; 93(12): 6519-6524, 2021 12.
Article in English | MEDLINE | ID: covidwho-1303276

ABSTRACT

The COVID-19 pandemic, which has ravaged our world for more than a year, still shapes our agenda with a scale of intensity that fluctuates over time. In our study, we aimed to determine the correlation between serum migration inhibitory factor (MIF) level and disease severity in COVID-19 with different prognoses. Between 15 October 2020 and 20 January 2021, 110 patients over the age of 18 who were diagnosed with COVID-19 and 40 volunteer healthcare personnel were included in our study. MIF levels were measured by enzyme-linked immunosorbent assay. In the comparison of serum MIF values in the patient and control group, it was observed that the MIF level was significantly higher in patients with both moderate and severe COVID-19 levels compared to the control group (p = 0.001, 0.001). In the comparison of serum MIF values of moderate to severe COVID-19 patients, it was observed that MIF level was higher in severe patients (p = 0.001). In the receiver operating characteristic curve analysis performed to differentiate between severe and moderate COVID-19 patients with MIF levels, the area under the curve was observed as 0.78. When the cutoff value of the MIF level was taken as 4.455 ng/ml, the sensitivity was 83% and the specificity was 62%. Failure to adequately balance the pro-inflammatory cytokines synthesized in COVID-19 with anti-inflammatory effect is the most important reason for the aggravation of the disease course. Playing a role in pro-inflammatory cytokine synthesis, MIF can provide important information about the disease prognosis in the early period.


Subject(s)
COVID-19/pathology , Cytokine Release Syndrome/blood , Intramolecular Oxidoreductases/blood , Macrophage Migration-Inhibitory Factors/blood , Macrophages/immunology , SARS-CoV-2/immunology , Case-Control Studies , Cytokine Release Syndrome/pathology , Disease Progression , Enzyme-Linked Immunosorbent Assay , Female , Humans , Macrophage Activation/immunology , Male , Middle Aged , Prognosis , Severity of Illness Index
14.
Sci Signal ; 14(690)2021 07 06.
Article in English | MEDLINE | ID: covidwho-1299216

ABSTRACT

Coronavirus disease 2019 (COVID-19) has poorer clinical outcomes in males than in females, and immune responses underlie these sex-related differences. Because immune responses are, in part, regulated by metabolites, we examined the serum metabolomes of COVID-19 patients. In male patients, kynurenic acid (KA) and a high KA-to-kynurenine (K) ratio (KA:K) positively correlated with age and with inflammatory cytokines and chemokines and negatively correlated with T cell responses. Males that clinically deteriorated had a higher KA:K than those that stabilized. KA inhibits glutamate release, and glutamate abundance was lower in patients that clinically deteriorated and correlated with immune responses. Analysis of data from the Genotype-Tissue Expression (GTEx) project revealed that the expression of the gene encoding the enzyme that produces KA, kynurenine aminotransferase, correlated with cytokine abundance and activation of immune responses in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes in COVID-19, suggesting a positive feedback between metabolites and immune responses in males.


Subject(s)
COVID-19/immunology , Kynurenic Acid/immunology , SARS-CoV-2 , Adult , Aged , COVID-19/blood , Case-Control Studies , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Cytokines/blood , Cytokines/immunology , Female , Humans , Kynurenic Acid/blood , Logistic Models , Male , Metabolic Networks and Pathways/immunology , Metabolomics , Middle Aged , Multivariate Analysis , Severity of Illness Index , Sex Factors , Signal Transduction/immunology , Tryptophan/metabolism
15.
Nat Commun ; 12(1): 4117, 2021 07 05.
Article in English | MEDLINE | ID: covidwho-1297301

ABSTRACT

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.


Subject(s)
COVID-19/complications , COVID-19/immunology , Cytokine Release Syndrome/complications , Monocytes/pathology , Neutrophil Activation , Aged , Antigen-Presenting Cells/immunology , COVID-19/blood , COVID-19/virology , Case-Control Studies , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Cytokines/blood , Extracellular Traps/metabolism , Female , Histocompatibility Antigens Class II/metabolism , Humans , Immunophenotyping , Male , Middle Aged , SARS-CoV-2/physiology , Severity of Illness Index
16.
Virol J ; 18(1): 117, 2021 06 04.
Article in English | MEDLINE | ID: covidwho-1259206

ABSTRACT

BACKGROUND: To date, specific cytokines associated with development of acute respiratory distress syndrome (ARDS) and extrapulmonary multiple organ dysfunction (MOD) in COVID-19 patients have not been systematically described. We determined the levels of inflammatory cytokines in patients with COVID-19 and their relationships with ARDS and extrapulmonary MOD. METHODS: The clinical and laboratory data of 94 COVID-19 patients with and without ARDS were analyzed. The levels of inflammatory cytokines (interleukin 6 [IL-6], IL-8, IL-10, and tumor necrosis factor α [TNF-α]) were measured on days 1, 3, and 5 following admission. Seventeen healthy volunteers were recruited as controls. Correlations in the levels of inflammatory cytokines with clinical and laboratory variables were analyzed, furthermore, we also explored the relationships of different cytokines with ARDS and extrapulmonary MOD. RESULTS: The ARDS group had higher serum levels of all 4 inflammatory cytokines than the controls, and these levels steadily increased after admission. The ARDS group also had higher levels of IL-6, IL-8, and IL-10 than the non-ARDS group, and the levels of these cytokines correlated significantly with coagulation parameters and disseminated intravascular coagulation (DIC). The levels of IL-6 and TNF-α correlated with the levels of creatinine and urea nitrogen, and were also higher in ARDS patients with acute kidney injury (AKI). All 4 inflammatory cytokines had negative correlations with PaO2/FiO2. IL-6, IL-8, and TNF-α had positive correlations with the APACHE-II score. Relative to survivors, non-survivors had higher levels of IL-6 and IL-10 at admission, and increasing levels over time. CONCLUSIONS: The cytokine storm apparently contributed to the development of ARDS and extrapulmonary MOD in COVID-19 patients. The levels of IL-6, IL-8, and IL-10 correlated with DIC, and the levels of IL-6 and TNF-α were associated with AKI. Relative to survivors, patients who died within 28 days had increased levels of IL-6 and IL-10.


Subject(s)
COVID-19/blood , Cytokine Release Syndrome/blood , Cytokines/blood , Respiratory Distress Syndrome/blood , Acute Kidney Injury/diagnosis , Aged , Blood Urea Nitrogen , COVID-19/pathology , Creatinine/blood , Cytokine Release Syndrome/diagnosis , Disseminated Intravascular Coagulation/blood , Disseminated Intravascular Coagulation/pathology , Female , Humans , Interleukin-10/blood , Interleukin-6/blood , Interleukin-8/blood , Male , Respiratory Distress Syndrome/pathology , Retrospective Studies , SARS-CoV-2 , Tumor Necrosis Factor-alpha/blood
19.
Int Rev Immunol ; 40(1-2): 54-71, 2021.
Article in English | MEDLINE | ID: covidwho-1236149

ABSTRACT

Lack of standardized therapeutic approaches is arguably the significant contributor to the high burden of mortality observed in the ongoing pandemic of the Coronavirus disease, 2019 (COVID-19). Evidence is accumulating on SARS-CoV-2 specific immune cell dysregulation and consequent tissue injury in COVID-19. Currently, no definite drugs or vaccines are available against the disease; however initial results of the ongoing clinical trials have raised some hope. In this article, taking insights from the emerging empirical evidence about host-virus interactions, we deliberate upon plausible pathogenic mechanisms and suitable therapeutic approaches for COVID-19.


Subject(s)
COVID-19/immunology , COVID-19/pathology , Cytokine Release Syndrome/pathology , Immunity, Innate/immunology , SARS-CoV-2/immunology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Complement Activation/immunology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/immunology , Host-Pathogen Interactions/immunology , Humans , SARS-CoV-2/drug effects
20.
Clin Microbiol Rev ; 34(3)2021 06 16.
Article in English | MEDLINE | ID: covidwho-1226710

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a rapidly evolving pandemic worldwide with at least 68 million COVID-19-positive cases and a mortality rate of about 2.2%, as of 10 December 2020. About 20% of COVID-19 patients exhibit moderate to severe symptoms. Severe COVID-19 manifests as acute respiratory distress syndrome (ARDS) with elevated plasma proinflammatory cytokines, including interleukin 1ß (IL-1ß), IL-6, tumor necrosis factor α (TNF-α), C-X-C motif chemokine ligand 10 (CXCL10/IP10), macrophage inflammatory protein 1 alpha (MIP-1α), and chemokine (C-C motif) ligand 2 (CCL2), with low levels of interferon type I (IFN-I) in the early stage and elevated levels of IFN-I during the advanced stage of COVID-19. Most of the severe and critically ill COVID-19 patients have had preexisting comorbidities, including hypertension, diabetes, cardiovascular diseases, and respiratory diseases. These conditions are known to perturb the levels of cytokines, chemokines, and angiotensin-converting enzyme 2 (ACE2), an essential receptor involved in SARS-CoV-2 entry into the host cells. ACE2 downregulation during SARS-CoV-2 infection activates the angiotensin II/angiotensin receptor (AT1R)-mediated hypercytokinemia and hyperinflammatory syndrome. However, several SARS-CoV-2 proteins, including open reading frame 3b (ORF3b), ORF6, ORF7, ORF8, and the nucleocapsid (N) protein, can inhibit IFN type I and II (IFN-I and -II) production. Thus, hyperinflammation, in combination with the lack of IFN responses against SARS-CoV-2 early on during infection, makes the patients succumb rapidly to COVID-19. Therefore, therapeutic approaches involving anti-cytokine/anti-cytokine-signaling and IFN therapy would favor the disease prognosis in COVID-19. This review describes critical host and viral factors underpinning the inflammatory "cytokine storm" induction and IFN antagonism during COVID-19 pathogenesis. Therapeutic approaches to reduce hyperinflammation and their limitations are also discussed.


Subject(s)
COVID-19/pathology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/pathology , Interferon Type I/blood , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/blood , COVID-19/therapy , Comorbidity , Humans , Immunity, Innate/immunology , Immunization, Passive/methods , Interleukin-6/antagonists & inhibitors , Interleukin-6/blood , Spike Glycoprotein, Coronavirus/metabolism
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