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1.
Nutrients ; 14(2)2022 Jan 07.
Article in English | MEDLINE | ID: covidwho-1613925

ABSTRACT

Despite the ongoing vaccination efforts, there is still an urgent need for safe and effective treatments to help curb the debilitating effects of COVID-19 disease. This systematic review aimed to investigate the efficacy of supplemental curcumin treatment on clinical outcomes and inflammation-related biomarker profiles in COVID-19 patients. We searched PubMed, Scopus, Web of Science, EMBASE, ProQuest, and Ovid databases up to 30 June 2021 to find studies that assessed the effects of curcumin-related compounds in mild to severe COVID-19 patients. Six studies were identified which showed that curcumin supplementation led to a significant decrease in common symptoms, duration of hospitalization and deaths. In addition, all of these studies showed that the intervention led to amelioration of cytokine storm effects thought to be a driving force in severe COVID-19 cases. This was seen as a significant (p < 0.05) decrease in proinflammatory cytokines such as IL1ß and IL6, with a concomitant significant (p < 0.05) increase in anti-inflammatory cytokines, including IL-10, IL-35 and TGF-α. Taken together, these findings suggested that curcumin exerts its beneficial effects through at least partial restoration of pro-inflammatory/anti-inflammatory balance. In conclusion, curcumin supplementation may offer an efficacious and safe option for improving COVID-19 disease outcomes. We highlight the point that future clinical studies of COVID-19 disease should employ larger cohorts of patients in different clinical settings with standardized preparations of curcumin-related compounds.


Subject(s)
COVID-19/drug therapy , Curcumin/administration & dosage , Dietary Supplements , Hospitalization , Phytotherapy/methods , Curcumin/pharmacology , Cytokines/metabolism , Female , Humans , Inflammation Mediators/metabolism , Interleukin-10/metabolism , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Interleukins/metabolism , Male , Patient Acuity , Transforming Growth Factor alpha/metabolism , Treatment Outcome
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.
Ann Med ; 53(1): 257-266, 2021 12.
Article in English | MEDLINE | ID: covidwho-1574445

ABSTRACT

OBJECTIVES: To appraise effective predictors for COVID-19 mortality in a retrospective cohort study. METHODS: A total of 1270 COVID-19 patients, including 984 admitted in Sino French New City Branch (training and internal validation sets randomly split at 7:3 ratio) and 286 admitted in Optical Valley Branch (external validation set) of Wuhan Tongji hospital, were included in this study. Forty-eight clinical and laboratory features were screened with LASSO method. Further multi-tree extreme gradient boosting (XGBoost) machine learning-based model was used to rank importance of features selected from LASSO and subsequently constructed death risk prediction model with simple-tree XGBoost model. Performances of models were evaluated by AUC, prediction accuracy, precision, and F1 scores. RESULTS: Six features, including disease severity, age, levels of high-sensitivity C-reactive protein (hs-CRP), lactate dehydrogenase (LDH), ferritin, and interleukin-10 (IL-10), were selected as predictors for COVID-19 mortality. Simple-tree XGBoost model conducted by these features can predict death risk accurately with >90% precision and >85% sensitivity, as well as F1 scores >0.90 in training and validation sets. CONCLUSION: We proposed the disease severity, age, serum levels of hs-CRP, LDH, ferritin, and IL-10 as significant predictors for death risk of COVID-19, which may help to identify the high-risk COVID-19 cases. KEY MESSAGES A machine learning method is used to build death risk model for COVID-19 patients. Disease severity, age, hs-CRP, LDH, ferritin, and IL-10 are death risk factors. These findings may help to identify the high-risk COVID-19 cases.


Subject(s)
COVID-19/mortality , Clinical Decision Rules , Hospitalization , Machine Learning , Adult , Aged , Aged, 80 and over , C-Reactive Protein/metabolism , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/physiopathology , Cardiovascular Diseases/epidemiology , China/epidemiology , Cohort Studies , Comorbidity , Diabetes Mellitus/epidemiology , Female , Ferritins/metabolism , Humans , Hypertension/epidemiology , Interleukin-10/metabolism , L-Lactate Dehydrogenase/metabolism , Male , Middle Aged , Prognosis , Reproducibility of Results , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index
4.
Biomedica ; 41(Sp. 2): 86-102, 2021 10 15.
Article in English, Spanish | MEDLINE | ID: covidwho-1529016

ABSTRACT

INTRODUCTION: Immunological markers have been described during COVID-19 and persist after recovery. These immune markers are associated with clinical features among SARSCoV-2 infected individuals. Nevertheless, studies reporting a comprehensive analysis of the immune changes occurring during SARS-CoV-2 infection are still limited. OBJECTIVE: To evaluate the production of proinflammatory cytokines, the antibody response, and the phenotype and function of NK cells and T cells in a Colombian family cluster with SARS-CoV-2 infection. MATERIALS AND METHODS: Proinflammatory cytokines were evaluated by RT-PCR and ELISA. The frequency, phenotype, and function of NK cells (cocultures with K562 cells) and T-cells (stimulated with spike/RdRp peptides) were assessed by flow cytometry. Anti-SARS-CoV-2 antibodies were determined using indirect immunofluorescence and plaque reduction neutralization assay. RESULTS: During COVID-19, we observed a high proinflammatory-cytokine production and a reduced CD56bright-NK cell and cytotoxic response. Compared with healthy controls, infected individuals had a higher frequency of dysfunctional CD8+ T cells CD38+HLA-DR-. During the acute phase, CD8+ T cells stimulated with viral peptides exhibited a monofunctional response characterized by high IL-10 production. However, during recovery, we observed a bifunctional response characterized by the co-expression of CD107a and granzyme B or perforin. CONCLUSION: Although the proinflammatory response is a hallmark of SARS-CoV-2 infection, other phenotypic and functional alterations in NK cells and CD8+ T cells could be associated with the outcome of COVID-19. However, additional studies are required to understand these alterations and to guide future immunotherapy strategies.


Introducción. Se han descrito diferentes marcadores inmunológicos durante la COVID-19, los cuales persisten incluso después de la convalecencia y se asocian con los estadios clínicos de la infección. Sin embargo, aún son pocos los estudios orientados al análisis exhaustivo de las alteraciones del sistema inmunológico en el curso de la infección. Objetivo. Evaluar la producción de citocinas proinflamatorias, la reacción de anticuerpos, y el fenotipo y la función de las células NK y los linfocitos T en una familia colombiana con infección por SARS-CoV-2. Materiales y métodos. Se evaluaron las citocinas proinflamatorias mediante RT-PCR y ELISA; la frecuencia, el fenotipo y la función de las células NK (en cocultivos con células K562) y linfocitos T CD8+ (estimulados con péptidos spike/RdRp) mediante citometría de flujo, y los anticuerpos anti-SARS-CoV-2, mediante inmunofluorescencia indirecta y prueba de neutralización por reducción de placa. Resultados. Durante la COVID-19 hubo una producción elevada de citocinas proinflamatorias, con disminución de las células NK CD56bright y reacción citotóxica. Comparados con los controles sanos, los individuos infectados presentaron con gran frecuencia linfocitos T CD8+ disfuncionales CD38+HLA-DR-. Además, en los linfocitos T CD8+ estimulados con péptidos virales, predominó una reacción monofuncional con gran producción de IL-10 durante la fase aguda y una reacción bifuncional caracterizada por la coexpresión de CD107a y granzima B o perforina durante la convalecencia. Conclusión. Aunque la reacción inflamatoria caracteriza la infección por SARS-CoV-2, hay otras alteraciones fenotípicas y funcionales en células NK y linfocitos T CD8+ que podrían asociarse con la progresión de la infección. Se requieren estudios adicionales para entender estas alteraciones y guiar futuras estrategias de inmunoterapia.


Subject(s)
COVID-19/immunology , Killer Cells, Natural , SARS-CoV-2/immunology , T-Lymphocytes , Adult , Antibodies, Viral/analysis , CD56 Antigen/immunology , Case-Control Studies , Colombia , Family Health , Granzymes/metabolism , Humans , Interleukin-10/metabolism , Interleukin-1beta/blood , Interleukin-6/blood , Interleukin-8/blood , K562 Cells , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Lymphocyte Activation , Male , Middle Aged , Perforin/metabolism , Phenotype , Receptors, CCR7/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Tumor Necrosis Factor-alpha/blood , Young Adult
5.
Int Immunopharmacol ; 101(Pt A): 108264, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1487769

ABSTRACT

Topoisomerase (TOP) inhibitors were commonly used as chemotherapeutic agents in the treatment of cancers. In our present study, we found that etoposide (ETO), a topoisomerase 2 (TOP2) inhibitor, upregulated the production of Interleukin 10 (IL-10) in lipopolysaccharide (LPS)-stimulated macrophages. Besides, other TOP2 inhibitors including doxorubicin hydrochloride (DOX) and teniposide (TEN) were also able to augment IL-10 production. Meanwhile, the expression levels of pro-inflammatory factors, for example IL-6 and TNF-α, were also decreased accordingly by the treatment of the TOP2 inhibitors. Of note, ETO facilitated IL-10 secretion, which might be regulated by transcription factor Maf via PI3K/AKT pathway, as pharmaceutic blockage of kinase PI3K or AKT attenuated ETO-induced Maf and IL-10 expression. Further, in LPS-induced mice sepsis model, the enhanced generation of IL-10 was observed in ETO-treated mice, whereas pro-inflammatory cytokines were decreased, which significantly reduced the mortality of mice from LPS-induced lethal cytokine storm. Taken together, these results indicated that ETO may exhibit an anti-inflammatory role by upregulating the alteration of transcription factor Maf and promoting subsequential IL-10 secretion via PI3K/Akt pathway in LPS-induced macrophages. Therefore, ETO may serve as a potential anti-inflammatory agent and employed to severe pro-inflammatory diseases including COVID-19.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Etoposide/pharmacology , Interleukin-10/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-maf/genetics , Topoisomerase II Inhibitors/pharmacology , Animals , Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Cell Line , Disease Models, Animal , Down-Regulation/drug effects , Etoposide/therapeutic use , Female , Interleukin-10/genetics , Interleukin-6/genetics , Interleukin-6/metabolism , Lipopolysaccharides/toxicity , Macrophages/drug effects , Mice , Mice, Inbred C57BL , Proto-Oncogene Proteins c-maf/metabolism , Shock, Septic/chemically induced , Shock, Septic/drug therapy , Topoisomerase II Inhibitors/therapeutic use , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Up-Regulation/drug effects
6.
J Immunol ; 207(7): 1848-1856, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1377034

ABSTRACT

Immune cell responses are strikingly altered in patients with severe coronavirus disease 2019 (COVID-19), but the immunoregulatory process in these individuals is not fully understood. In this study, 23 patients with mild and 22 patients with severe COVID-19 and 6 asymptomatic carriers of COVID-19 were enrolled, along with 44 healthy controls (HC). Peripheral immune cells in HC and patients with COVID-19 were comprehensively profiled using mass cytometry. We found that in patients with severe COVID-19, the number of HLA-DRlow/- monocytes was significantly increased, but that of mucosal-associated invariant T (MAIT) cells was greatly reduced. MAIT cells were highly activated but functionally impaired in response to Escherichia coli and IL-12/IL-18 stimulation in patients with severe COVID-19, especially those with microbial coinfection. Single-cell transcriptome analysis revealed that IFN-stimulated genes were significantly upregulated in peripheral MAIT cells and monocytes from patients with severe COVID-19. IFN-α pretreatment suppressed MAIT cells' response to E. coli by triggering high levels of IL-10 production by HLA-DRlow/--suppressive monocytes. Blocking IFN-α or IL-10 receptors rescued MAIT cell function in patients with severe COVID-19. Moreover, plasma from patients with severe COVID-19 inhibited HLA-DR expression by monocytes through IL-10. These data indicate a unique pattern of immune dysregulation in severe COVID-19, which is characterized by enrichment of suppressive HLA-DRlow/- monocytes associated with functional impairment of MAIT cells through the IFN/IL-10 pathway.


Subject(s)
COVID-19/immunology , Escherichia coli Infections/immunology , Escherichia coli/physiology , Interleukin-10/metabolism , Monocytes/immunology , Mucosal-Associated Invariant T Cells/immunology , SARS-CoV-2/physiology , Adolescent , Adult , Asymptomatic Diseases , Cells, Cultured , Child , Coinfection , Disease Progression , Female , Humans , Immune Tolerance , Lymphocyte Activation , Male , Middle Aged , Severity of Illness Index , Young Adult
7.
Biomedica ; 41(Sp. 2): 86-102, 2021 10 15.
Article in English, Spanish | MEDLINE | ID: covidwho-1332335

ABSTRACT

INTRODUCTION: Immunological markers have been described during COVID-19 and persist after recovery. These immune markers are associated with clinical features among SARSCoV-2 infected individuals. Nevertheless, studies reporting a comprehensive analysis of the immune changes occurring during SARS-CoV-2 infection are still limited. OBJECTIVE: To evaluate the production of proinflammatory cytokines, the antibody response, and the phenotype and function of NK cells and T cells in a Colombian family cluster with SARS-CoV-2 infection. MATERIALS AND METHODS: Proinflammatory cytokines were evaluated by RT-PCR and ELISA. The frequency, phenotype, and function of NK cells (cocultures with K562 cells) and T-cells (stimulated with spike/RdRp peptides) were assessed by flow cytometry. Anti-SARS-CoV-2 antibodies were determined using indirect immunofluorescence and plaque reduction neutralization assay. RESULTS: During COVID-19, we observed a high proinflammatory-cytokine production and a reduced CD56bright-NK cell and cytotoxic response. Compared with healthy controls, infected individuals had a higher frequency of dysfunctional CD8+ T cells CD38+HLA-DR-. During the acute phase, CD8+ T cells stimulated with viral peptides exhibited a monofunctional response characterized by high IL-10 production. However, during recovery, we observed a bifunctional response characterized by the co-expression of CD107a and granzyme B or perforin. CONCLUSION: Although the proinflammatory response is a hallmark of SARS-CoV-2 infection, other phenotypic and functional alterations in NK cells and CD8+ T cells could be associated with the outcome of COVID-19. However, additional studies are required to understand these alterations and to guide future immunotherapy strategies.


Introducción. Se han descrito diferentes marcadores inmunológicos durante la COVID-19, los cuales persisten incluso después de la convalecencia y se asocian con los estadios clínicos de la infección. Sin embargo, aún son pocos los estudios orientados al análisis exhaustivo de las alteraciones del sistema inmunológico en el curso de la infección. Objetivo. Evaluar la producción de citocinas proinflamatorias, la reacción de anticuerpos, y el fenotipo y la función de las células NK y los linfocitos T en una familia colombiana con infección por SARS-CoV-2. Materiales y métodos. Se evaluaron las citocinas proinflamatorias mediante RT-PCR y ELISA; la frecuencia, el fenotipo y la función de las células NK (en cocultivos con células K562) y linfocitos T CD8+ (estimulados con péptidos spike/RdRp) mediante citometría de flujo, y los anticuerpos anti-SARS-CoV-2, mediante inmunofluorescencia indirecta y prueba de neutralización por reducción de placa. Resultados. Durante la COVID-19 hubo una producción elevada de citocinas proinflamatorias, con disminución de las células NK CD56bright y reacción citotóxica. Comparados con los controles sanos, los individuos infectados presentaron con gran frecuencia linfocitos T CD8+ disfuncionales CD38+HLA-DR-. Además, en los linfocitos T CD8+ estimulados con péptidos virales, predominó una reacción monofuncional con gran producción de IL-10 durante la fase aguda y una reacción bifuncional caracterizada por la coexpresión de CD107a y granzima B o perforina durante la convalecencia. Conclusión. Aunque la reacción inflamatoria caracteriza la infección por SARS-CoV-2, hay otras alteraciones fenotípicas y funcionales en células NK y linfocitos T CD8+ que podrían asociarse con la progresión de la infección. Se requieren estudios adicionales para entender estas alteraciones y guiar futuras estrategias de inmunoterapia.


Subject(s)
COVID-19/immunology , Killer Cells, Natural , SARS-CoV-2/immunology , T-Lymphocytes , Adult , Antibodies, Viral/analysis , CD56 Antigen/immunology , Case-Control Studies , Colombia , Family Health , Granzymes/metabolism , Humans , Interleukin-10/metabolism , Interleukin-1beta/blood , Interleukin-6/blood , Interleukin-8/blood , K562 Cells , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Lymphocyte Activation , Male , Middle Aged , Perforin/metabolism , Phenotype , Receptors, CCR7/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Tumor Necrosis Factor-alpha/blood , Young Adult
8.
Int J Mol Sci ; 22(13)2021 Jun 26.
Article in English | MEDLINE | ID: covidwho-1304664

ABSTRACT

Hepatitis C virus (HCV) is one of the main triggers of chronic liver disease. Despite tremendous progress in the HCV field, there is still no vaccine against this virus. Potential vaccines can be based on its recombinant proteins. To increase the humoral and, especially, cellular immune response to them, more effective adjuvants are needed. Here, we evaluated a panel of compounds as potential adjuvants using the HCV NS5B protein as an immunogen. These compounds included inhibitors of polyamine biosynthesis and urea cycle, the mTOR pathway, antioxidants, and cellular receptors. A pronounced stimulation of cell proliferation and interferon-γ (IFN-γ) secretion in response to concanavalin A was shown for antioxidant N-acetylcysteine (NAC), polyamine biosynthesis inhibitor 2-difluoromethylornithine (DFMO), and TLR9 agonist CpG ODN 1826 (CpG). Their usage during the immunization of mice with the recombinant NS5B protein significantly increased antibody titers, enhanced lymphocyte proliferation and IFN-γ production. NAC and CpG decreased relative Treg numbers; CpG increased the number of myeloid-derived suppressor cells (MDSCs), whereas neither NAC nor DFMO affected MDSC counts. NAC and DFMO suppressed NO and interleukin 10 (IL-10) production by splenocytes, while DFMO increased the levels of IL-12. This is the first evidence of immunomodulatory activity of NAC and DFMO during prophylactic immunization against infectious diseases.


Subject(s)
Acetylcysteine/pharmacology , Adjuvants, Immunologic/pharmacology , Eflornithine/pharmacology , Hepatitis C/immunology , Immunity, Active/drug effects , Viral Nonstructural Proteins/immunology , Animals , Cell Proliferation , Cells, Cultured , Female , Immunogenicity, Vaccine/drug effects , Interferon-gamma/metabolism , Interleukin-10/metabolism , Interleukin-12/metabolism , Mice , Mice, Inbred DBA , Myeloid-Derived Suppressor Cells/drug effects , Myeloid-Derived Suppressor Cells/immunology , Nitric Oxide/metabolism , Oligodeoxyribonucleotides/pharmacology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , Viral Hepatitis Vaccines/immunology
10.
Viral Immunol ; 34(8): 567-572, 2021 10.
Article in English | MEDLINE | ID: covidwho-1266103

ABSTRACT

Interleukin-10 (IL-10) gene polymorphisms have been associated with severity and outcomes in patients with respiratory and nonrespiratory viral infections. The aim of this study was to assess whether rs1800871 and rs1800872 polymorphisms of IL-10 gene are associated with the clinical outcomes of COVID-19 in a Mexican population. Study subjects were 193 COVID-19 patients. The genotyping was carried out with real-time PCR and serum IL-10 levels were measured with enzyme-linked immunosorbent assay. Logistic regression analysis was used for analysis association with clinical outcomes. There was no evidence of an association between alleles, genotypes, or haplotypes frequencies between patient groups according to severity and outcomes. The rs1800871 and rs1800872 polymorphisms might not be genetic risk factors for severity and mortality for COVID-19 in Mexican mestizos patients from northwest Mexico.


Subject(s)
COVID-19/genetics , Interleukin-10/genetics , Polymorphism, Genetic , Adult , Aged , Alleles , COVID-19/immunology , COVID-19/therapy , Female , Genotype , Haplotypes , Humans , Interleukin-10/metabolism , Male , Mexico , Middle Aged , SARS-CoV-2
11.
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
12.
PLoS Pathog ; 17(4): e1009531, 2021 04.
Article in English | MEDLINE | ID: covidwho-1231265

ABSTRACT

Most individuals who consume foods contaminated with the bacterial pathogen Listeria monocytogenes (Lm) develop mild symptoms, while others are susceptible to life-threatening systemic infections (listeriosis). Although it is known that the risk of severe disease is increased in certain human populations, including the elderly, it remains unclear why others who consume contaminated food develop listeriosis. Here, we used a murine model to discover that pulmonary coinfections can impair the host's ability to adequately control and eradicate systemic Lm that cross from the intestines to the bloodstream. We found that the resistance of mice to oral Lm infection was dramatically reduced by coinfection with Streptococcus pneumoniae (Spn), a bacterium that colonizes the respiratory tract and can also cause severe infections in the elderly. Exposure to Spn or microbial products, including a recombinant Lm protein (L1S) and lipopolysaccharide (LPS), rendered otherwise resistant hosts susceptible to severe systemic Lm infection. In addition, we show that this increase in susceptibility was dependent on an increase in the production of interleukin-10 (IL-10) from Ncr1+ cells, including natural killer (NK) cells. Lastly, the ability of Ncr1+ cell derived IL-10 to increase disease susceptibility correlated with a dampening of both myeloid cell accumulation and myeloid cell phagocytic capacity in infected tissues. These data suggest that efforts to minimize inflammation in response to an insult at the respiratory mucosa render the host more susceptible to infections by Lm and possibly other pathogens that access the oral mucosa.


Subject(s)
Listeria monocytogenes/immunology , Listeriosis/immunology , Pneumonia/immunology , Animals , Disease Progression , Disease Susceptibility , Female , Interleukin-10/metabolism , Killer Cells, Natural/metabolism , Killer Cells, Natural/physiology , Lipopolysaccharides , Listeria monocytogenes/pathogenicity , Listeriosis/complications , Listeriosis/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mouth Diseases/complications , Mouth Diseases/immunology , Mouth Diseases/microbiology , Mouth Diseases/pathology , Pneumonia/complications , Pneumonia/etiology , Pneumonia/pathology
13.
Clin Infect Dis ; 71(15): 769-777, 2020 07 28.
Article in English | MEDLINE | ID: covidwho-1217822

ABSTRACT

BACKGROUND: From December 2019 to February 2020, 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a serious outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China. Related clinical features are needed. METHODS: We reviewed 69 patients who were hospitalized in Union hospital in Wuhan between 16 January and 29 January 2020. All patients were confirmed to be infected with SARS-CoV-2, and the final date of follow-up was 4 February 2020. RESULTS: The median age of 69 enrolled patients was 42.0 years (interquartile range 35.0-62.0), and 32 patients (46%) were men. The most common symptoms were fever (60 [87%]), cough (38 [55%]), and fatigue (29 [42%]). Most patients received antiviral therapy (66 [98.5%] of 67 patients) and antibiotic therapy (66 [98.5%] of 67 patients). As of 4 February 2020, 18 (26.9%) of 67 patients had been discharged, and 5 patients had died, with a mortality rate of 7.5%. According to the lowest SpO2 during admission, cases were divided into the SpO2 ≥ 90% group (n = 55) and the SpO2 < 90% group (n = 14). All 5 deaths occurred in the SpO2 < 90% group. Compared with SpO2 ≥ 90% group, patients of the SpO2 < 90% group were older and showed more comorbidities and higher plasma levels of interleukin (IL) 6, IL10, lactate dehydrogenase, and C reactive protein. Arbidol treatment showed tendency to improve the discharging rate and decrease the mortality rate. CONCLUSIONS: COVID-19 appears to show frequent fever, dry cough, and increase of inflammatory cytokines, and induced a mortality rate of 7.5%. Older patients or those with underlying comorbidities are at higher risk of death.


Subject(s)
Coronavirus Infections/pathology , Coronavirus Infections/virology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Adult , Aged , Betacoronavirus/pathogenicity , C-Reactive Protein/metabolism , COVID-19 , China , Coronavirus Infections/metabolism , Cough/metabolism , Cough/pathology , Cough/virology , Female , Fever/metabolism , Fever/pathology , Fever/virology , Hospitalization , Humans , Interleukin-10/metabolism , Interleukin-6/metabolism , Male , Middle Aged , Pandemics , Patient Discharge , Pneumonia, Viral/metabolism , SARS-CoV-2
14.
Clin Infect Dis ; 71(16): 2052-2060, 2020 11 19.
Article in English | MEDLINE | ID: covidwho-1153150

ABSTRACT

BACKGROUND: The World Health Organization characterizes novel coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as a pandemic. Here, we investigated the clinical, cytokine levels; T-cell proportion; and related gene expression occurring in patients with COVID-19 on admission and after initial treatment. METHODS: Eleven patients diagnosed with COVID-19 with similar initial treatment regimens were enrolled in the hospital. Plasma cytokine, peripheral T cell proportions, and microfluidic quantitative polymerase chain reaction analyses for gene expression were conducted. RESULTS: Five patients with mild and 6 with severe disease were included. Cough and fever were the primary symptoms in the 11 COVID-19 cases. Older age, higher neutrophil count, and higher C-reactive protein levels were found in severe cases. IL-10 level significantly varied with disease progression and treatment. Decreased T-cell proportions were observed in patients with COVID-19, especially in severe cases, and all were returned to normal in patients with mild disease after initial treatment, but only CD4+ T cells returned to normal in severe cases. The number of differentially expressed genes (DEGs) increased with the disease progression, and decreased after initial treatment. All downregulated DEGs in severe cases mainly involved Th17-cell differentiation, cytokine-mediated signaling pathways, and T-cell activation. After initial treatment in severe cases, MAP2K7 and SOS1 were upregulated relative to that on admission. CONCLUSIONS: Our findings show that a decreased T-cell proportion with downregulated gene expression related to T-cell activation and differentiation occurred in patients with severe COVID-19, which may help to provide effective treatment strategies for COVID-19.


Subject(s)
COVID-19/immunology , COVID-19/pathology , Aged , CD4-Positive T-Lymphocytes/metabolism , COVID-19/virology , Cell Differentiation/physiology , Computational Biology , Female , Humans , Interleukin-10/metabolism , MAP Kinase Kinase 7/metabolism , Male , Microfluidics , Middle Aged , SOS1 Protein/metabolism , Signal Transduction/physiology , Th17 Cells/metabolism
15.
Acta Pharmacol Sin ; 43(1): 64-75, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1142428

ABSTRACT

Coronavirus disease 2019 (COVID-19) broke out in December 2019. Due its high morbility and mortality, it is necessary to summarize the clinical characteristics of COVID-19 patients to provide more theoretical basis for future treatment. In the current study, we conducted a retrospective analysis of the clinical characteristics of COVID-19 patients and explored the risk factors for the severity of illness. A total of 101 COVID-19 patients hospitalized in Leishenshan Hospital (Wuhan, China) was classified into three sub-types: moderate (n = 47), severe (n = 36), and critical (n = 18); their clinical data were collected from the Electronic Medical Record. We showed that among the 101 COVID-19 patients, the median age was 62 years (IQR 51-74); 50 (49.5%) patients were accompanied by hypertension, while 25 (24.8%) and 22 (21.8%) patients suffered from diabetes and heart diseases, respectively, with complications. All patients were from Wuhan who had a definite history of exposure to the epidemic area. Multivariate logistic regression analysis revealed that older age, diabetes, chronic liver disease, percentage of neutrophils (N%) > 75%, CRP > 4 mg/L, D-dimer > 0.55 mg/L, IL-2R > 710 U/mL, IL-8 > 62 pg/mL, and IL-10 > 9.1 pg/mL were independent variables associated with severe COVID-19. In conclusion, we have identified the independent risk factors for the severity of COVID-19 pneumonia, including older age, diabetes, chronic liver disease, higher levels of N%, CRP, D-dimer, IL-2R, IL-8, and IL-10, providing evidence for more accurate risk prediction.


Subject(s)
COVID-19/pathology , Aged , COVID-19/metabolism , China , Female , Hospitalization , Humans , Interleukin-10/metabolism , Male , Middle Aged , Neutrophils/metabolism , Neutrophils/pathology , Retrospective Studies , Risk Factors , Severity of Illness Index
16.
Clin Chem Lab Med ; 59(3): 599-607, 2021 02 23.
Article in English | MEDLINE | ID: covidwho-1067439

ABSTRACT

OBJECTIVES: Severe coronavirus disease 2019 (COVID-19) is associated with a dysregulated immune state. While research has focused on the hyperinflammation, little research has been performed on the compensatory anti-inflammatory response. The aim of this study was to evaluate the anti-inflammatory cytokine response to COVID-19, by assessing interleukin-10 (IL-10) and IL-10/lymphocyte count ratio and their association with outcomes. METHODS: Adult patients presenting to the emergency department (ED) with laboratory-confirmed COVID-19 were recruited. The primary endpoint was maximum COVID-19 severity within 30 days of index ED visit. RESULTS: A total of 52 COVID-19 patients were enrolled. IL-10 and IL-10/lymphocyte count were significantly higher in patients with severe disease (p<0.05), as well as in those who developed severe acute kidney injury (AKI) and new positive bacterial cultures (all p≤0.01). In multivariable analysis, a one-unit increase in IL-10 and IL-10/lymphocyte count were associated with 42% (p=0.031) and 32% (p=0.013) increased odds, respectively, of severe COVID-19. When standardized to a one-unit standard deviations scale, an increase in the IL-10 was a stronger predictor of maximum 30-day severity and severe AKI than increases in IL-6 or IL-8. CONCLUSIONS: The hyperinflammatory response to COVID-19 is accompanied by a simultaneous anti-inflammatory response, which is associated with poor outcomes and may increase the risk of new positive bacterial cultures. IL-10 and IL-10/lymphocyte count at ED presentation were independent predictors of COVID-19 severity. Moreover, elevated IL-10 was more strongly associated with outcomes than pro-inflammatory IL-6 or IL-8. The anti-inflammatory response in COVID-19 requires further investigation to enable more precise immunomodulatory therapy against SARS-CoV-2.


Subject(s)
COVID-19/diagnosis , Interleukin-10/metabolism , Acute Kidney Injury/blood , Acute Kidney Injury/complications , Acute Kidney Injury/diagnosis , Adult , Aged , Bacterial Infections/blood , Bacterial Infections/complications , Bacterial Infections/diagnosis , COVID-19/blood , COVID-19/complications , Cohort Studies , Emergency Service, Hospital , Female , Hospitalization , Humans , Interleukin-10/blood , Lymphocyte Count , Male , Middle Aged , Prognosis
17.
Trends Immunol ; 42(1): 3-5, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065236

ABSTRACT

A unique feature of the cytokine storm in coronavirus disease 2019 (COVID-19) is the dramatic elevation of interleukin 10 (IL-10). This was thought to be a negative feedback mechanism to suppress inflammation. However, several lines of clinical evidence suggest that dramatic early proinflammatory IL-10 elevation may play a pathological role in COVID-19 severity.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Interleukin-10/immunology , SARS-CoV-2/immunology , COVID-19/epidemiology , COVID-19/virology , Cytokine Release Syndrome/metabolism , Epidemics , Humans , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-10/metabolism , Lymphocytes/immunology , Lymphocytes/metabolism , Models, Immunological , SARS-CoV-2/physiology , Severity of Illness Index
18.
Mol Cell Biochem ; 476(1): 93-107, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-737128

ABSTRACT

Mesenchymal stem cells (MSCs) can alleviate acute respiratory distress syndrome (ARDS), but the mechanisms involved are unclear, especially about their specific effects on cellular mitochondrial respiratory function. Thirty mice were allocated into the Control, LPS, and LPS + Bone marrow mesenchymal stem cell (BMSC) group (n = 10/group). Mouse alveolar epithelial cells (MLE-12) and macrophage cells (RAW264.7) were divided into the same groups. Pathological variation, inflammation-related factors, reactive oxygen species (ROS), ATP levels, and oxygen consumption rate (OCR) were analyzed. Pathologic features of ARDS were observed in the LPS group and were significantly alleviated by BMSCs. The trend in inflammation-related factors among the three groups was the LPS group > LPS + BMSC group > Control group. In the MLE-12 co-culture system, IL-6 was increased in the LPS group but not significantly reduced in the LPS + BMSC group. In the RAW264.7 co-culture system, IL-1ß, TNF-α, and IL-10 levels were all increased in the LPS group, IL-1ß and TNF-α levels were reduced by BMSCs, while IL-10 level kept increasing. ROS and ATP levels were increased and decreased respectively in both MLE-12 and RAW264.7 cells in the LPS groups but reversed by BMSCs. Basal OCR, ATP-linked OCR, and maximal OCR were lower in the LPS groups. Impaired basal OCR and ATP-linked OCR in MLE-12 cells were partially restored by BMSCs, while impaired basal OCR and maximal OCR in RAW264.7 cells were restored by BMSCs. BMSCs improved the mitochondrial respiration dysfunction of macrophages and alveolar epithelial cells induced by LPS, alleviated lung tissue injury, and inflammatory response in a mouse model of ARDS.


Subject(s)
Epithelium/metabolism , Mesenchymal Stem Cells/cytology , Mitochondria/metabolism , Pulmonary Alveoli/metabolism , Respiratory Distress Syndrome/metabolism , Adenosine Triphosphate/metabolism , Animals , Bone Marrow Cells/cytology , Coculture Techniques , Inflammation , Interleukin-10/metabolism , Interleukin-6/metabolism , Lipopolysaccharides/metabolism , Lung Injury/metabolism , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Oxygen Consumption , RAW 264.7 Cells
19.
Cell Death Dis ; 11(11): 957, 2020 11 06.
Article in English | MEDLINE | ID: covidwho-912894

ABSTRACT

A global effort is currently undertaken to restrain the COVID-19 pandemic. Host immunity has come out as a determinant for COVID-19 clinical outcomes, and several studies investigated the immune profiling of SARS-CoV-2 infected people to properly direct the clinical management of the disease. Thus, lymphopenia, T-cell exhaustion, and the increased levels of inflammatory mediators have been described in COVID-19 patients, in particular in severe cases1. Age represents a key factor in COVID-19 morbidity and mortality2. Understanding age-associated immune signatures of patients are therefore important to identify preventive and therapeutic strategies. In this study, we investigated the immune profile of COVID-19 hospitalized patients identifying a distinctive age-dependent immune signature associated with disease severity. Indeed, defined circulating factors - CXCL8, IL-10, IL-15, IL-27, and TNF-α - positively correlate with older age, longer hospitalization, and a more severe form of the disease and may thus represent the leading signature in critical COVID-19 patients.


Subject(s)
Coronavirus Infections/pathology , Cytokines/metabolism , Pneumonia, Viral/pathology , Age Factors , Aged , Aged, 80 and over , Antibodies, Viral/blood , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , COVID-19 , Cluster Analysis , Coronavirus Infections/immunology , Coronavirus Infections/virology , Female , Humans , Immunoglobulin G/blood , Interleukin-10/metabolism , Interleukin-8/metabolism , Length of Stay , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2 , Severity of Illness Index , Tumor Necrosis Factor-alpha/metabolism
20.
EBioMedicine ; 61: 103026, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-838033

ABSTRACT

BACKGROUND: Prognostic tools are required to guide clinical decision-making in COVID-19. METHODS: We studied the relationship between the ratio of interleukin (IL)-6 to IL-10 and clinical outcome in 80 patients hospitalized for COVID-19, and created a simple 5-point linear score predictor of clinical outcome, the Dublin-Boston score. Clinical outcome was analysed as a three-level ordinal variable ("Improved", "Unchanged", or "Declined"). For both IL-6:IL-10 ratio and IL-6 alone, we associated clinical outcome with a) baseline biomarker levels, b) change in biomarker level from day 0 to day 2, c) change in biomarker from day 0 to day 4, and d) slope of biomarker change throughout the study. The associations between ordinal clinical outcome and each of the different predictors were performed with proportional odds logistic regression. Associations were run both "unadjusted" and adjusted for age and sex. Nested cross-validation was used to identify the model for incorporation into the Dublin-Boston score. FINDINGS: The 4-day change in IL-6:IL-10 ratio was chosen to derive the Dublin-Boston score. Each 1 point increase in the score was associated with a 5.6 times increased odds for a more severe outcome (OR 5.62, 95% CI -3.22-9.81, P = 1.2 × 10-9). Both the Dublin-Boston score and the 4-day change in IL-6:IL-10 significantly outperformed IL-6 alone in predicting clinical outcome at day 7. INTERPRETATION: The Dublin-Boston score is easily calculated and can be applied to a spectrum of hospitalized COVID-19 patients. More informed prognosis could help determine when to escalate care, institute or remove mechanical ventilation, or drive considerations for therapies. FUNDING: Funding was received from the Elaine Galwey Research Fellowship, American Thoracic Society, National Institutes of Health and the Parker B Francis Research Opportunity Award.


Subject(s)
Coronavirus Infections/diagnosis , Interleukin-10/metabolism , Interleukin-6/metabolism , Pneumonia, Viral/diagnosis , Adult , Aged , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/virology , Female , Humans , Logistic Models , Male , Middle Aged , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Prognosis , SARS-CoV-2 , Time Factors
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