Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 14 de 14
Filter
1.
Am J Hum Genet ; 109(3): 471-485, 2022 Mar 03.
Article in English | MEDLINE | ID: covidwho-1679508

ABSTRACT

Humans exhibit remarkable interindividual and interpopulation immune response variability upon microbial challenges. Cytokines play a vital role in regulating inflammation and immune responses, but dysregulation of cytokine responses has been implicated in different disease states. Host genetic factors were previously shown to significantly impact cytokine response heterogeneity mainly in European-based studies, but it is unclear whether these findings are transferable to non-European individuals. Here, we aimed to identify genetic variants modulating cytokine responses in healthy adults of East African ancestry from Tanzania. We leveraged both cytokine and genetic data and performed genome-wide cytokine quantitative trait loci (cQTLs) mapping. The results were compared with another cohort of healthy adults of Western European ancestry via direct overlap and functional enrichment analyses. We also performed meta-analyses to identify cQTLs with congruent effect direction in both populations. In the Tanzanians, cQTL mapping identified 80 independent suggestive loci and one genome-wide significant locus (TBC1D22A) at chromosome 22; SNP rs12169244 was associated with IL-1b release after Salmonella enteritidis stimulation. Remarkably, the identified cQTLs varied significantly when compared to the European cohort, and there was a very limited percentage of overlap (1.6% to 1.9%). We further observed ancestry-specific pathways regulating induced cytokine responses, and there was significant enrichment of the interferon pathway specifically in the Tanzanians. Furthermore, contrary to the Europeans, genetic variants in the TLR10-TLR1-TLR6 locus showed no effect on cytokine response. Our data reveal both ancestry-specific effects of genetic variants and pathways on cytokine response heterogeneity, hence arguing for the importance of initiatives to include diverse populations into genomics research.

2.
Annu Rev Immunol ; 39: 667-693, 2021 04 26.
Article in English | MEDLINE | ID: covidwho-1457607

ABSTRACT

Traditionally, the innate and adaptive immune systems are differentiated by their specificity and memory capacity. In recent years, however, this paradigm has shifted: Cells of the innate immune system appear to be able to gain memory characteristics after transient stimulation, resulting in an enhanced response upon secondary challenge. This phenomenon has been called trained immunity. Trained immunity is characterized by nonspecific increased responsiveness, mediated via extensive metabolic and epigenetic reprogramming. Trained immunity explains the heterologous effects of vaccines, which result in increased protection against secondary infections. However, in chronic inflammatory conditions, trained immunity can induce maladaptive effects and contribute to hyperinflammation and progression of cardiovascular disease, autoinflammatory syndromes, and neuroinflammation. In this review we summarize the current state of the field of trained immunity, its mechanisms, and its roles in both health and disease.


Subject(s)
Immunologic Memory , Vaccines , Animals , Cell Differentiation , Humans , Immune System , Immunity, Innate
3.
Front Immunol ; 12: 720090, 2021.
Article in English | MEDLINE | ID: covidwho-1374235

ABSTRACT

Male sex and old age are risk factors for COVID-19 severity, but the underlying causes are unknown. A possible explanation for this might be the differences in immunological profiles in males and the elderly before the infection. With this in mind, we analyzed the abundance of circulating proteins and immune populations associated with severe COVID-19 in 2 healthy cohorts. Besides, given the seasonal profile of COVID-19, the seasonal response against SARS-CoV-2 could also be different in the elderly and males. Therefore, PBMCs of female, male, young, and old subjects in different seasons of the year were stimulated with heat-inactivated SARS-CoV-2 to investigate the season-dependent anti-SARS-CoV-2 immune response. We found that several T cell subsets, which are known to be depleted in severe COVID-19 patients, were intrinsically less abundant in men and older individuals. Plasma proteins increasing with disease severity, including HGF, IL-8, and MCP-1, were more abundant in the elderly and males. Upon in vitro SARS-CoV-2 stimulation, the elderly produced significantly more IL-1RA and had a dysregulated IFNγ response with lower production in the fall compared with young individuals. Our results suggest that the immune characteristics of severe COVID-19, described by a differential abundance of immune cells and circulating inflammatory proteins, are intrinsically present in healthy men and the elderly. This might explain the susceptibility of men and the elderly to SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , Adolescent , Adult , Age Factors , Aged , Aging/immunology , Blood Proteins/immunology , COVID-19/physiopathology , Cohort Studies , Disease Susceptibility , Female , Humans , Immunity, Cellular , Immunologic Factors , Male , Middle Aged , Patient Acuity , Risk Assessment , Seasons , Sex Factors , T-Lymphocyte Subsets/immunology , Young Adult
4.
Biosci Rep ; 41(7)2021 07 30.
Article in English | MEDLINE | ID: covidwho-1290282

ABSTRACT

Patients with sepsis display increased concentrations of sTREM-1 (soluble Triggering Receptor Expressed on Myeloid cells 1), and a phase II clinical trial focusing on TREM-1 modulation is ongoing. We investigated whether sTREM-1 circulating concentrations are associated with the outcome of patients with coronavirus disease 2019 (COVID-19) to assess the role of this pathway in COVID-19. This observational study was performed in two independent cohorts of patients with COVID-19. Plasma concentrations of sTREM-1 were assessed after ICU admission (pilot cohort) or after COVID-19 diagnosis (validation cohort). Routine laboratory and clinical parameters were collected from electronic patient files. Results showed sTREM-1 plasma concentrations were significantly elevated in patients with COVID-19 (161 [129-196] pg/ml) compared to healthy controls (104 [75-124] pg/ml; P<0.001). Patients with severe COVID-19 needing ICU admission displayed even higher sTREM-1 concentrations compared to less severely ill COVID-19 patients receiving clinical ward-based care (235 [176-319] pg/ml and 195 [139-283] pg/ml, respectively, P = 0.017). In addition, higher sTREM-1 plasma concentrations were observed in patients who did not survive the infection (326 [207-445] pg/ml) compared to survivors (199 [142-278] pg/ml, P<0.001). Survival analyses indicated that patients with higher sTREM-1 concentrations are at higher risk for death (hazard ratio = 3.3, 95%CI: 1.4-7.8). In conclusion, plasma sTREM-1 concentrations are elevated in patients with COVID-19, relate to disease severity, and discriminate between survivors and non-survivors. This suggests that the TREM-1 pathway is involved in the inflammatory reaction and the disease course of COVID-19, and therefore may be considered as a therapeutic target in severely ill patients with COVID-19.


Subject(s)
COVID-19/diagnosis , Triggering Receptor Expressed on Myeloid Cells-1/blood , Aged , Biomarkers/blood , COVID-19/blood , COVID-19/mortality , COVID-19/virology , Case-Control Studies , Female , Healthy Volunteers , Hospital Mortality , Humans , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Retrospective Studies , Risk Assessment/methods , SARS-CoV-2/isolation & purification , Severity of Illness Index , Survival Analysis
5.
J Clin Endocrinol Metab ; 106(7): 1994-2009, 2021 06 16.
Article in English | MEDLINE | ID: covidwho-1133638

ABSTRACT

CONTEXT: Lymphopenia is a key feature of immune dysfunction in patients with bacterial sepsis and coronavirus disease 2019 (COVID-19) and is associated with poor clinical outcomes, but the cause is largely unknown. Severely ill patients may present with thyroid function abnormalities, so-called nonthyroidal illness syndrome, and several studies have linked thyrotropin (thyroid stimulating hormone, TSH) and the thyroid hormones thyroxine (T4) and 3,5,3'-triiodothyronine (T3) to homeostatic regulation and function of lymphocyte populations. OBJECTIVE: This work aimed to test the hypothesis that abnormal thyroid function correlates with lymphopenia in patients with severe infections. METHODS: A retrospective analysis of absolute lymphocyte counts, circulating TSH, T4, free T4 (FT4), T3, albumin, and inflammatory biomarkers was performed in 2 independent hospitalized study populations: bacterial sepsis (n = 224) and COVID-19 patients (n = 161). A subgroup analysis was performed in patients with severe lymphopenia and normal lymphocyte counts. RESULTS: Only T3 significantly correlated (ρ = 0.252) with lymphocyte counts in patients with bacterial sepsis, and lower concentrations were found in severe lymphopenic compared to nonlymphopenic patients (n = 56 per group). Severe lymphopenic COVID-19 patients (n = 17) showed significantly lower plasma concentrations of TSH, T4, FT4, and T3 compared to patients without lymphopenia (n = 18), and demonstrated significantly increased values of the inflammatory markers interleukin-6, C-reactive protein, and ferritin. Remarkably, after 1 week of follow-up, the majority (12 of 15) of COVID-19 patients showed quantitative recovery of their lymphocyte numbers, whereas TSH and thyroid hormones remained mainly disturbed. CONCLUSION: Abnormal thyroid function correlates with lymphopenia in patients with severe infections, like bacterial sepsis and COVID-19, but future studies need to establish whether a causal relationship is involved.


Subject(s)
COVID-19/complications , Euthyroid Sick Syndromes/diagnosis , Lymphopenia/immunology , Sepsis/complications , Aged , Aged, 80 and over , COVID-19/blood , COVID-19/immunology , Euthyroid Sick Syndromes/blood , Euthyroid Sick Syndromes/immunology , Female , Greece , Humans , Lymphocyte Count , Lymphopenia/blood , Lymphopenia/diagnosis , Male , Netherlands , Retrospective Studies , SARS-CoV-2/immunology , Sepsis/blood , Sepsis/immunology , Thyroid Hormones/blood , Thyroid Hormones/immunology , Thyrotropin/blood , Thyrotropin/immunology
6.
Med (N Y) ; 2(4): 378-383, 2021 04 09.
Article in English | MEDLINE | ID: covidwho-1111773

ABSTRACT

Age is a key risk factor associated with the severity of symptoms caused by SARS-CoV-2, and there is an urgent need to reduce COVID-19 morbidity and mortality in elderly individuals. We discuss evidence suggesting that trained immunity elicited by BCG vaccination may improve immune responses and can serve as a strategy to combat COVID-19 in this population.


Subject(s)
COVID-19 , Aged , Humans , Immunity, Innate , Immunologic Memory , SARS-CoV-2 , Vaccination
7.
J Infect Dis ; 223(2): 214-224, 2021 02 03.
Article in English | MEDLINE | ID: covidwho-1081282

ABSTRACT

BACKGROUND: Excessive activation of immune responses in coronavirus disease 2019 (COVID-19) is considered to be related to disease severity, complications, and mortality rate. The complement system is an important component of innate immunity and can stimulate inflammation, but its role in COVID-19 is unknown. METHODS: A prospective, longitudinal, single center study was performed in hospitalized patients with COVID-19. Plasma concentrations of complement factors C3a, C3c, and terminal complement complex (TCC) were assessed at baseline and during hospital admission. In parallel, routine laboratory and clinical parameters were collected from medical files and analyzed. RESULTS: Complement factors C3a, C3c, and TCC were significantly increased in plasma of patients with COVID-19 compared with healthy controls (P < .05). These complement factors were especially elevated in intensive care unit patients during the entire disease course (P < .005 for C3a and TCC). More intense complement activation was observed in patients who died and in those with thromboembolic events. CONCLUSIONS: Patients with COVID-19 demonstrate activation of the complement system, which is related to disease severity. This pathway may be involved in the dysregulated proinflammatory response associated with increased mortality rate and thromboembolic complications. Components of the complement system might have potential as prognostic markers for disease severity and as therapeutic targets in COVID-19.


Subject(s)
COVID-19/immunology , Complement Activation/immunology , SARS-CoV-2/immunology , Aged , Aged, 80 and over , COVID-19/mortality , Complement C3c/immunology , Cytokines/blood , Disease Progression , Female , Humans , Immunity, Innate , Inflammation/immunology , Longitudinal Studies , Male , Middle Aged , Mortality , Netherlands/epidemiology , Prospective Studies , Respiratory Distress Syndrome/immunology , Severity of Illness Index
8.
J Infect Dis ; 223(8): 1322-1333, 2021 04 23.
Article in English | MEDLINE | ID: covidwho-1057852

ABSTRACT

The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive proinflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis revealed no specific inflammatory endotypes in COVID-19 patients. Functional assays revealed abrogated adaptive cytokine production (interferon-γ, interleukin-17, and interleukin-22) and prominent T-cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlights potential biomarkers of disease severity.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , Immunity, Innate/immunology , Aged , Biomarkers/blood , COVID-19/blood , COVID-19/virology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Cytokines/immunology , Female , Humans , Inflammation/blood , Inflammation/immunology , Inflammation/virology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/virology , Lymphopenia/blood , Lymphopenia/immunology , Lymphopenia/virology , Male , Middle Aged , SARS-CoV-2/immunology , Severity of Illness Index
9.
Cell Rep Med ; 1(9): 100146, 2020 12 22.
Article in English | MEDLINE | ID: covidwho-917453

ABSTRACT

Hydroxychloroquine is being investigated for a potential prophylactic effect in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but its mechanism of action is poorly understood. Circulating leukocytes from the blood of coronavirus disease 2019 (COVID-19) patients show increased responses to Toll-like receptor ligands, suggestive of trained immunity. By analyzing interferon responses of peripheral blood mononuclear cells from healthy donors conditioned with heat-killed Candida, trained innate immunity can be modeled in vitro. In this model, hydroxychloroquine inhibits the responsiveness of these innate immune cells to virus-like stimuli and interferons. This is associated with a suppression of histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation of inflammation-related genes, changes in the cellular lipidome, and decreased expression of interferon-stimulated genes. Our findings indicate that hydroxychloroquine inhibits trained immunity in vitro, which may not be beneficial for the antiviral innate immune response to SARS-CoV-2 infection in patients.


Subject(s)
Hydroxychloroquine/pharmacology , Immunity, Innate/drug effects , Immunologic Memory/drug effects , Interferons/immunology , COVID-19/drug therapy , COVID-19/immunology , Epigenesis, Genetic/drug effects , Humans , Hydroxychloroquine/therapeutic use , Immunomodulation , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lipid Metabolism/drug effects , SARS-CoV-2 , Severity of Illness Index
11.
Front Immunol ; 11: 575047, 2020.
Article in English | MEDLINE | ID: covidwho-895305

ABSTRACT

Reports suggest a role of endothelial dysfunction and loss of endothelial barrier function in COVID-19. It is well established that the endothelial glycocalyx-degrading enzyme heparanase contributes to vascular leakage and inflammation. Low molecular weight heparins (LMWH) serve as an inhibitor of heparanase. We hypothesize that heparanase contributes to the pathogenesis of COVID-19, and that heparanase may be inhibited by LMWH. To test this hypothesis, heparanase activity and heparan sulfate levels were measured in plasma of healthy controls (n = 10) and COVID-19 patients (n = 48). Plasma heparanase activity and heparan sulfate levels were significantly elevated in COVID-19 patients. Heparanase activity was associated with disease severity including the need for intensive care, lactate dehydrogenase levels, and creatinine levels. Use of prophylactic LMWH in non-ICU patients was associated with a reduced heparanase activity. Since there is no other clinically applied heparanase inhibitor currently available, therapeutic treatment of COVID-19 patients with low molecular weight heparins should be explored.


Subject(s)
Endothelium/pathology , Glucuronidase/antagonists & inhibitors , Glucuronidase/blood , Heparin Antagonists/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Tight Junctions/pathology , Aged , Betacoronavirus , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Creatinine/blood , Critical Care , Cross-Sectional Studies , Female , Glucuronidase/metabolism , Heparitin Sulfate/blood , Humans , Interleukin-6/blood , L-Lactate Dehydrogenase/blood , Male , Middle Aged , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , SARS-CoV-2
12.
Curr Biol ; 30(18): R1014-R1018, 2020 09 21.
Article in English | MEDLINE | ID: covidwho-703973

ABSTRACT

Recently, a petition was offered to the European Commission calling for an immediate ban on animal testing. Although a Europe-wide moratorium on the use of animals in science is not yet possible, there has been a push by the non-scientific community and politicians for a rapid transition to animal-free innovations. Although there are benefits for both animal welfare and researchers, advances on alternative methods have not progressed enough to be able to replace animal research in the foreseeable future. This trend has led first and foremost to a substantial increase in the administrative burden and hurdles required to make timely advances in research and treatments for human and animal diseases. The current COVID-19 pandemic clearly highlights how much we actually rely on animal research. COVID-19 affects several organs and systems, and the various animal-free alternatives currently available do not come close to this complexity. In this Essay, we therefore argue that the use of animals is essential for the advancement of human and veterinary health.


Subject(s)
Animal Experimentation , Biomedical Research , Coronavirus Infections , Disease Models, Animal , Pandemics , Pneumonia, Viral , Animals , Betacoronavirus , COVID-19 , Humans , SARS-CoV-2
13.
Cell Rep Med ; 1(5): 100073, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-694416

ABSTRACT

Bacille Calmette-Guérin (BCG) induces long-term boosting of innate immunity, termed trained immunity, and decreases susceptibility to respiratory tract infections. BCG vaccination trials for reducing SARS-CoV-2 infection are underway, but concerns have been raised regarding the potential harm of strong innate immune responses. To investigate the safety of BCG vaccination, we retrospectively assessed coronavirus disease 2019 (COVID-19) and related symptoms in three cohorts of healthy volunteers who either received BCG in the last 5 years or did not. BCG vaccination is not associated with increased incidence of symptoms during the COVID-19 outbreak in the Netherlands. Our data suggest that BCG vaccination might be associated with a decrease in the incidence of sickness during the COVID-19 pandemic (adjusted odds ratio [AOR] 0.58, p < 0.05), and lower incidence of extreme fatigue. In conclusion, recent BCG vaccination is safe, and large randomized trials are needed to reveal if BCG reduces the incidence and/or severity of SARS-CoV-2 infection.


Subject(s)
BCG Vaccine/administration & dosage , COVID-19/epidemiology , Vaccination/statistics & numerical data , Adult , Aged , BCG Vaccine/immunology , COVID-19/immunology , Female , Humans , Immunologic Memory , Incidence , Male , Middle Aged , Netherlands/epidemiology , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Young Adult
14.
JAMA ; 324(7): 663-673, 2020 08 18.
Article in English | MEDLINE | ID: covidwho-676817

ABSTRACT

Importance: Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objective: To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19. Design, Setting, and Participants: Case series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments. Exposure: Severe COVID-19. Main Outcome and Measures: Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects. Results: The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod. Conclusions and Relevance: In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.


Subject(s)
COVID-19/virology , Loss of Function Mutation , SARS-CoV-2/genetics , Adult , Enzyme-Linked Immunosorbent Assay , Fatal Outcome , Hospitalization , Humans , Intensive Care Units , Leukocytes, Mononuclear , Male , Netherlands , Pedigree , RNA, Viral/analysis , Real-Time Polymerase Chain Reaction , SARS-CoV-2/isolation & purification , Young Adult
SELECTION OF CITATIONS
SEARCH DETAIL