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1.
Elife ; 112022 Jun 06.
Article in English | MEDLINE | ID: covidwho-1934562

ABSTRACT

COVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of SARS-CoV-2-infected apoptotic cells exacerbates inflammatory cytokine production, inhibits the expression of efferocytic receptors, and impairs continual efferocytosis by macrophages. We also provide evidence supporting that lung monocytes and macrophages from severe COVID-19 patients have compromised efferocytic capacity. Our findings reveal that dysfunctional efferocytosis of SARS-CoV-2-infected cell corpses suppresses macrophage anti-inflammation and efficient tissue repair programs and provides mechanistic insights for the excessive production of pro-inflammatory cytokines and accumulation of tissue damage associated with COVID-19 immunopathogenesis.


Subject(s)
COVID-19 , SARS-CoV-2 , Anti-Inflammatory Agents/pharmacology , Apoptosis , Humans , Macrophages/metabolism , Phagocytosis
2.
Cells ; 11(5)2022 03 01.
Article in English | MEDLINE | ID: covidwho-1715131

ABSTRACT

Severe COVID-19 patients present a clinical and laboratory overlap with other hyperinflammatory conditions such as hemophagocytic lymphohistiocytosis (HLH). However, the underlying mechanisms of these conditions remain to be explored. Here, we investigated the transcriptome of 1596 individuals, including patients with COVID-19 in comparison to healthy controls, other acute inflammatory states (HLH, multisystem inflammatory syndrome in children [MIS-C], Kawasaki disease [KD]), and different respiratory infections (seasonal coronavirus, influenza, bacterial pneumonia). We observed that COVID-19 and HLH share immunological pathways (cytokine/chemokine signaling and neutrophil-mediated immune responses), including gene signatures that stratify COVID-19 patients admitted to the intensive care unit (ICU) and COVID-19_nonICU patients. Of note, among the common differentially expressed genes (DEG), there is a cluster of neutrophil-associated genes that reflects a generalized hyperinflammatory state since it is also dysregulated in patients with KD and bacterial pneumonia. These genes are dysregulated at the protein level across several COVID-19 studies and form an interconnected network with differentially expressed plasma proteins that point to neutrophil hyperactivation in COVID-19 patients admitted to the intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils. Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention.


Subject(s)
COVID-19 , Lymphohistiocytosis, Hemophagocytic , Artificial Intelligence , COVID-19/complications , COVID-19/genetics , Child , Humans , Lymphohistiocytosis, Hemophagocytic/complications , Neutrophil Activation , SARS-CoV-2 , Systemic Inflammatory Response Syndrome
3.
Lancet Reg Health Am ; 7: 100167, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1587081

ABSTRACT

BACKGROUND: The dominant effect of age on COVID-19 mortality obscures the impact of other risk factors. Although the elderly is at a greater risk of severe disease and death due to COVID-19, the interaction of obesity and age was not carefully assessed. This analysis is especially critical for prioritizing groups to receive COVID-19 vaccination. METHODS: Starting with 1,120,767 unvaccinated individuals registered in a Brazilian surveillance system, we selected 313,898 hospitalized COVID-19 patients aged 20 to 89 who had a BMI ≥ 25 kg/m2 and cardiovascular diseases (CVD) or diabetes, as well as individuals with no risk factors associated with severe COVID-19. Patient data were stratified by age, obesity, BMI, and comorbidities, and subsequently, subjected to crude and adjusted odds ratio, hazard ratio, and Kaplan-Meier curves. Disease outcomes were invasive and non-invasive ventilatory support, intensive care unit (ICU) admission, and death. FINDINGS: Obesity alone is a risk factor for in-hospital mortality and is more significant than cardiovascular disease and diabetes. Furthermore, obesity, cardiovascular disease, and diabetes increase the risk of severity and death by COVID-19 more significantly in young adults than in the elderly. When categorizing patients by obesity classes, the severity of obesity was found to be associated with a higher risk of admission to the ICU and death from COVID-19 than the non-obese young adults or elderly population. INTERPRETATION: Our findings highlight the increased risk of severe COVID-19 on the Brazilian obese youth. As SARS-CoV-2 may become a recurrent seasonal infection, future vaccination campaigns against COVID-19 should prioritize obese young individuals. FUNDINGS: This work was supported by the Brazilian National Council for Scientific and Technological Development (grant number 313662/2017-7 and 307356/2017-5; the São Paulo Research Foundation (grant numbers 2018/14933-2); and CAPES.

4.
Nat Commun ; 12(1): 6844, 2021 11 25.
Article in English | MEDLINE | ID: covidwho-1537310

ABSTRACT

COVID-19 manifests as a milder disease in children than adults, but the underlying mechanisms are not fully characterized. Here we assess the difference in cellular or humoral immune responses of pediatric and adult COVID-19 patients to see if these factors contribute to the severity dichotomy. Children's non-specific immune profile is dominated by naive lymphocytes and HLA-DRhighCX3CR1low dendritic cells; meanwhile, children show strong specific antibody and T cell responses for viral structural proteins, with their T cell responses differing from adults by having weaker CD8+TNF+ T cells responses to S peptide pool but stronger responses to N and M peptide pools. Finally, viral mRNA is more abundant in pediatric patients. Our data thus support a scenario in which SARS-CoV-2 infected children contribute to transmission yet are less susceptible to COVID-19 symptoms due to strong and differential responses to the virus.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Immunity, Humoral , RNA, Viral , SARS-CoV-2/genetics , Vaccines, Synthetic/immunology , Adolescent , Adult , Aged , Antibodies, Viral/blood , Brazil , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes , COVID-19/prevention & control , COVID-19 Vaccines , Child , Child, Preschool , Cytokines/blood , Female , Humans , Immunity, Innate , Male , Middle Aged , RNA, Messenger , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes , Viral Structural Proteins/immunology , Young Adult
5.
Front Med (Lausanne) ; 8: 637885, 2021.
Article in English | MEDLINE | ID: covidwho-1399143

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect a broad range of human tissues by using the host receptor angiotensin-converting enzyme 2 (ACE2). Individuals with comorbidities associated with severe COVID-19 display higher levels of ACE2 in the lungs compared to those without comorbidities, and conditions such as cell stress, elevated glucose levels and hypoxia may also increase the expression of ACE2. Here, we showed that patients with Barrett's esophagus (BE) have a higher expression of ACE2 in BE tissues compared to normal squamous esophagus, and that the lower pH associated with BE may drive this increase in expression. Human primary monocytes cultured in reduced pH displayed increased ACE2 expression and higher viral load upon SARS-CoV-2 infection. We also showed in two independent cohorts of 1,357 COVID-19 patients that previous use of proton pump inhibitors is associated with 2- to 3-fold higher risk of death compared to those not using the drugs. Our work suggests that pH has a great influence on SARS-CoV-2 Infection and COVID-19 severity.

7.
Blood ; 138(25): 2702-2713, 2021 12 23.
Article in English | MEDLINE | ID: covidwho-1365304

ABSTRACT

Multiple organ dysfunction is the most severe outcome of sepsis progression and is highly correlated with a worse prognosis. Excessive neutrophil extracellular traps (NETs) are critical players in the development of organ failure during sepsis. Therefore, interventions targeting NET release would likely effectively prevent NET-based organ injury associated with this disease. Herein, we demonstrate that the pore-forming protein gasdermin D (GSDMD) is active in neutrophils from septic humans and mice and plays a crucial role in NET release. Inhibition of GSDMD with disulfiram or genic deletion abrogated NET formation, reducing multiple organ dysfunction and sepsis lethality. Mechanistically, we demonstrate that during sepsis, activation of the caspase-11/GSDMD pathway controls NET release by neutrophils during sepsis. In summary, our findings uncover a novel therapeutic use for disulfiram and suggest that GSDMD is a therapeutic target to improve sepsis treatment.


Subject(s)
Extracellular Traps/genetics , Gene Deletion , Intracellular Signaling Peptides and Proteins/genetics , Multiple Organ Failure/genetics , Phosphate-Binding Proteins/genetics , Sepsis/genetics , Acetaldehyde Dehydrogenase Inhibitors/therapeutic use , Adoptive Transfer , Aged , Animals , Cells, Cultured , Disulfiram/therapeutic use , Female , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Male , Mice, Inbred C57BL , Middle Aged , Multiple Organ Failure/pathology , Multiple Organ Failure/therapy , Phosphate-Binding Proteins/antagonists & inhibitors , Sepsis/pathology , Sepsis/therapy
8.
Biol Res ; 54(1): 20, 2021 Jul 08.
Article in English | MEDLINE | ID: covidwho-1301896

ABSTRACT

The current COVID-19 pandemic has already claimed more than 3.7 million victims and it will cause more deaths in the coming months. Tools that track the number and locations of cases are critical for surveillance and help in making policy decisions for controlling the outbreak. However, the current surveillance web-based dashboards run on proprietary platforms, which are often expensive and require specific computational knowledge. We developed a user-friendly web tool, named OUTBREAK, that facilitates epidemic surveillance by showing in an animated graph the timeline and geolocations of cases of an outbreak. It permits even non-specialist users to input data most conveniently and track outbreaks in real-time. We applied our tool to visualize the SARS 2003, MERS, and COVID19 epidemics, and provided them as examples on the website. Through the zoom feature, it is also possible to visualize cases at city and even neighborhood levels. We made the tool freely available at https://outbreak.sysbio.tools/ . OUTBREAK has the potential to guide and help health authorities to intervene and minimize the effects of outbreaks.


Subject(s)
COVID-19 , Pandemics , Disease Outbreaks , Geographic Mapping , Humans , SARS-CoV-2
9.
Clin Nutr ESPEN ; 44: 475-478, 2021 08.
Article in English | MEDLINE | ID: covidwho-1242904

ABSTRACT

BACKGROUND & AIMS: Obesity is associated with low grade systemic inflammation and insulin resistance. Although metabolic and immunological changes may contribute to the increased risk for COVID-19 mortality in obese, little is known about the impact of obesity in the lungs of patients with COVID-19. METHODS: We analyzed gene expression profiles of autopsy lungs of a cohort of 14 COVID-19 patients and 4 control individuals. Patients were divided into 3 groups according to their comorbidities: hypertension, type 2 diabetes (T2D) and obesity. We then identified the molecular alterations associated with these comorbidities in COVID-19 patients. RESULTS: Patients with only hypertension showed higher levels of inflammatory genes and B-cell related genes when compared to those with T2D and obesity. However, the levels of IFN-gamma, IL22, and CD274 (a ligand that binds to receptor PD1) were higher in COVID-19 patients with T2D and obesity. Several metabolic- and immune-associated genes such as G6PD, LCK and IL10 were significantly induced in the lungs of the obese group. CONCLUSION: Our findings suggest that SARS-CoV-2 infection in the lungs may exacerbate the immune response and chronic condition in obese COVID-19 patients.


Subject(s)
COVID-19/complications , COVID-19/genetics , Gene Expression/genetics , Lung/immunology , Obesity/complications , Obesity/genetics , Autopsy , COVID-19/immunology , Cohort Studies , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/immunology , Humans , Hypertension/complications , Hypertension/genetics , Hypertension/immunology , Obesity/immunology , SARS-CoV-2
10.
JCI Insight ; 6(10)2021 05 24.
Article in English | MEDLINE | ID: covidwho-1241077

ABSTRACT

The fact that the COVID-19 fatality rate varies by sex and age is poorly understood. Notably, the outcome of SARS-CoV-2 infections mostly depends on the control of cytokine storm and the increasingly recognized pathological role of uncontrolled neutrophil activation. Here, we used an integrative approach with publicly available RNA-Seq data sets of nasopharyngeal swabs and peripheral blood leukocytes from patients with SARS-CoV-2, according to sex and age. Female and young patients infected by SARS-CoV-2 exhibited a larger number of differentially expressed genes (DEGs) compared with male and elderly patients, indicating a stronger immune modulation. Among them, we found an association between upregulated cytokine/chemokine- and downregulated neutrophil-related DEGs. This was correlated with a closer relationship between female and young subjects, while the relationship between male and elderly patients was closer still. The association between these cytokine/chemokines and neutrophil DEGs is marked by a strongly correlated interferome network. Here, female patients exhibited reduced transcriptional levels of key proinflammatory/neutrophil-related genes, such as CXCL8 receptors (CXCR1 and CXCR2), IL-1ß, S100A9, ITGAM, and DBNL, compared with male patients. These genes are well known to be protective against inflammatory damage. Therefore, our work suggests specific immune-regulatory pathways associated with sex and age of patients infected with SARS-CoV-2 and provides a possible association between inverse modulation of cytokine/chemokine and neutrophil transcriptional signatures.


Subject(s)
COVID-19/genetics , Cytokines/genetics , Gene Regulatory Networks , Adult , Age Factors , Aged , COVID-19/epidemiology , COVID-19/immunology , Cytokines/immunology , Female , Humans , Male , Middle Aged , Neutrophils/immunology , Neutrophils/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Sex Factors , Transcriptome
11.
Sci Rep ; 11(1): 9026, 2021 04 27.
Article in English | MEDLINE | ID: covidwho-1205454

ABSTRACT

The use of RT-LAMP (reverse transcriptase-loop mediated isothermal amplification) has been considered as a promising point-of-care method to diagnose COVID-19. In this manuscript we show that the RT-LAMP reaction has a sensitivity of only 200 RNA virus copies, with a color change from pink to yellow occurring in 100% of the 62 clinical samples tested positive by RT-qPCR. We also demonstrated that this reaction is 100% specific for SARS-CoV-2 after testing 57 clinical samples infected with dozens of different respiratory viruses and 74 individuals without any viral infection. Although the majority of manuscripts recently published using this technique describe only the presence of two-color states (pink = negative and yellow = positive), we verified by naked-eye and absorbance measurements that there is an evident third color cluster (orange), in general related to positive samples with low viral loads, but which cannot be defined as positive or negative by the naked eye. Orange colors should be repeated or tested by RT-qPCR to avoid a false diagnostic. RT-LAMP is therefore very reliable for samples with a RT-qPCR Ct < 30 being as sensitive and specific as a RT-qPCR test. All reactions were performed in 30 min at 65 °C. The use of reaction time longer than 30 min is also not recommended since nonspecific amplifications may cause false positives.


Subject(s)
COVID-19/diagnosis , Molecular Diagnostic Techniques/methods , Nucleic Acid Amplification Techniques/methods , RNA, Viral/metabolism , SARS-CoV-2/genetics , COVID-19/virology , COVID-19 Nucleic Acid Testing , Colorimetry , Humans , Real-Time Polymerase Chain Reaction , SARS-CoV-2/isolation & purification , Viral Load
12.
Int J Infect Dis ; 105: 579-587, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1126872

ABSTRACT

BACKGROUND: The progression and severity of COVID-19 vary significantly in the population. While the hallmarks of SARS-CoV-2 and severe COVID-19 within routine laboratory parameters are emerging, the impact of sex and age on these profiles is still unknown. METHODS: A multidimensional analysis was performed involving millions of records of laboratory parameters and diagnostic tests for 178 887 individuals from Brazil, of whom 33 266 tested positive for SARS-CoV-2. Analyzed data included those relating to complete blood cell count, electrolytes, metabolites, arterial blood gases, enzymes, hormones, cancer biomarkers, and others. FINDINGS: COVID-19 induced similar alterations in laboratory parameters in males and females. CRP and ferritin were increased, especially in older men with COVID-19, whereas abnormal liver function tests were common across several age groups, except for young women. Low peripheral blood basophils and eosinophils were more common in the elderly with COVID-19. Both male and female COVID-19 patients admitted to intensive care units displayed alterations in the coagulation system, and higher values for neutrophils, CRP, and lactate dehydrogenase. CONCLUSIONS: Our study uncovered the laboratory profiles of a large cohort of COVID-19 patients, which formed the basis of discrepancies influenced by aging and biological sex. These profiles directly linked COVID-19 disease presentation to an intricate interplay between sex, age, and immune activation.


Subject(s)
COVID-19/blood , Inflammation/etiology , SARS-CoV-2 , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , C-Reactive Protein/analysis , Female , Humans , Intensive Care Units , Male , Middle Aged , Sex Characteristics , Young Adult
13.
Science ; 369(6508): 1255-1260, 2020 09 04.
Article in English | MEDLINE | ID: covidwho-675945

ABSTRACT

Brazil currently has one of the fastest-growing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemics in the world. Because of limited available data, assessments of the impact of nonpharmaceutical interventions (NPIs) on this virus spread remain challenging. Using a mobility-driven transmission model, we show that NPIs reduced the reproduction number from >3 to 1 to 1.6 in São Paulo and Rio de Janeiro. Sequencing of 427 new genomes and analysis of a geographically representative genomic dataset identified >100 international virus introductions in Brazil. We estimate that most (76%) of the Brazilian strains fell in three clades that were introduced from Europe between 22 February and 11 March 2020. During the early epidemic phase, we found that SARS-CoV-2 spread mostly locally and within state borders. After this period, despite sharp decreases in air travel, we estimated multiple exportations from large urban centers that coincided with a 25% increase in average traveled distances in national flights. This study sheds new light on the epidemic transmission and evolutionary trajectories of SARS-CoV-2 lineages in Brazil and provides evidence that current interventions remain insufficient to keep virus transmission under control in this country.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Basic Reproduction Number , Bayes Theorem , Betacoronavirus/classification , Brazil/epidemiology , COVID-19 , COVID-19 Testing , Cities/epidemiology , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Coronavirus Infections/prevention & control , Coronavirus Infections/virology , Europe , Evolution, Molecular , Genome, Viral , Humans , Models, Genetic , Models, Statistical , Pandemics/prevention & control , Phylogeny , Phylogeography , Pneumonia, Viral/prevention & control , Pneumonia, Viral/virology , SARS-CoV-2 , Spatio-Temporal Analysis , Travel , Urban Population
14.
Cell Metab ; 32(3): 437-446.e5, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-670096

ABSTRACT

COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes and macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently promotes glycolysis. HIF-1α-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19.


Subject(s)
Betacoronavirus/physiology , Blood Glucose/metabolism , Coronavirus Infections/complications , Diabetes Complications/complications , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Monocytes/metabolism , Pneumonia, Viral/complications , Adult , COVID-19 , Cell Line , Coronavirus Infections/metabolism , Diabetes Complications/metabolism , Diabetes Mellitus/metabolism , Female , Glycolysis , Humans , Inflammation/complications , Inflammation/metabolism , Male , Middle Aged , Monocytes/virology , Pandemics , Pneumonia, Viral/metabolism , Reactive Oxygen Species/metabolism , SARS-CoV-2 , Signal Transduction
15.
J Infect Dis ; 222(4): 556-563, 2020 07 23.
Article in English | MEDLINE | ID: covidwho-593365

ABSTRACT

Patients who died from COVID-19 often had comorbidities, such as hypertension, diabetes, and chronic obstructive lung disease. Although angiotensin-converting enzyme 2 (ACE2) is crucial for SARS-CoV-2 to bind and enter host cells, no study has systematically assessed the ACE2 expression in the lungs of patients with these diseases. Here, we analyzed over 700 lung transcriptome samples from patients with comorbidities associated with severe COVID-19 and found that ACE2 was highly expressed in these patients compared to control individuals. This finding suggests that patients with such comorbidities may have higher chances of developing severe COVID-19. Correlation and network analyses revealed many potential regulators of ACE2 in the human lung, including genes related to histone modifications, such as HAT1, HDAC2, and KDM5B. Our systems biology approach offers a possible explanation for increased COVID-19 severity in patients with certain comorbidities.


Subject(s)
Coronavirus Infections/epidemiology , Lung/enzymology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Angiotensin-Converting Enzyme 2 , COVID-19 , Case-Control Studies , Cerebrovascular Disorders/epidemiology , Cerebrovascular Disorders/genetics , Comorbidity , Coronary Disease/epidemiology , Coronary Disease/genetics , Coronavirus Infections/enzymology , Coronavirus Infections/genetics , Diabetes Complications/epidemiology , Diabetes Complications/genetics , Epigenomics , Female , Humans , Hypertension/epidemiology , Hypertension/genetics , Male , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/enzymology , Pneumonia, Viral/genetics , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/genetics , Severity of Illness Index , Systems Biology , Transcriptome
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