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1.
Biochemistry (Mosc) ; 86(4): 389-396, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-2078751

ABSTRACT

The novel coronavirus disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a major public health emergency worldwide with over 118.27-million confirmed COVID-19 cases and 2.62-million deaths recorded, as of March 12, 2021. Although this disease primarily targets lungs, damages in other organs, such as heart, kidney, liver, and testis, may occur. Testis is the cornerstone of male reproduction, while reproductive health is the most valuable resource for continuity of the human race. Given the unique nature of SARS-CoV-2, the mechanisms of its impact on the testes have yet to be fully explored. Notably, coronaviruses have been found to invade target cells through the angiotensin-converting enzyme 2 receptor, which can be found in the respiratory, gastrointestinal, cardiovascular, urinary tract, and reproductive organs, such as testes. Coronavirus studies have suggested that testes might be a potential target for SARS-CoV-2 infection. The first etiopathogenic concept proposed by current hypotheses indicates that the virus can invade testes through the angiotensin-converting enzyme 2 receptor. Next, the activated inflammatory response in the testes, disease-associated fever, and COVID-19 medications might be implicated in testicular alterations. Although evidence regarding the presence of SARS-CoV-2 mRNA in semen remains controversial, this emphasizes the need for researchers to pay closer attention to sexually transmitted diseases and male fertility after recovering from COVID-19. In this review the latest updates regarding COVID-19-associated testicular dysfunction are summarized and possible pathogenic mechanisms are discussed.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Fertility , Pandemics , SARS-CoV-2/metabolism , Testis/metabolism , COVID-19/mortality , COVID-19/pathology , Humans , Male , Testis/pathology , Testis/virology
2.
Nutrients ; 14(19)2022 Sep 28.
Article in English | MEDLINE | ID: covidwho-2066296

ABSTRACT

The link between being pregnant and overweight or obese and the infectivity and virulence of the SARS CoV-2 virus is likely to be caused by SARS-CoV-2 spike protein glycosylation, which may work as a glycan shield. Methylglyoxal (MGO), an important advanced glycation end-product (AGE), and glycated albumin (GA) are the results of poor subclinical glucose metabolism and are indices of oxidative stress. Forty-one consecutive cases of SARS-CoV-2-positive pregnant patients comprising 25% pre-pregnancy overweight women and 25% obese women were recruited. The aim of our study was to compare the blood levels of MGO and GA in pregnant women with asymptomatic and symptomatic SARS-CoV-2 infection with pregnant women without SARS-CoV-2 infection with low risk and uneventful pregnancies and to evaluate the relative perinatal outcomes. The MGO and GA values of the SARS-CoV-2 cases were statistically significantly higher than those of the negative control subjects. In addition, the SARS-CoV-2-positive pregnant patients who suffered of moderate to severe COVID-19 syndrome had higher values of GA than those infected and presenting with mild symptoms or those with asymptomatic infection. Premature delivery and infants of a small size for their gestational age were overrepresented in this cohort, even in mild-asymptomatic patients for whom delivery was not indicated by the COVID-19 syndrome. Moreover, ethnic minorities were overrepresented among the severe cases. The AGE-RAGE oxidative stress axis on the placenta and multiple organs caused by MGO and GA levels, associated with the biological mechanisms of the glycation of the SARS-CoV-2 spike protein, could help to explain the infectivity and virulence of this virus in pregnant patients affected by being overweight or obese or having gestational diabetes, and the increased risk of premature delivery and/or low newborn weight.


Subject(s)
COVID-19 , Pregnancy Complications, Infectious , Premature Birth , COVID-19/pathology , Female , Glucose , Glycosylation , Humans , Infant, Newborn , Inflammation , Obesity , Overweight , Pregnancy , Pregnancy Complications, Infectious/pathology , Pregnancy Complications, Infectious/virology , Pregnancy Outcome , Pregnant Women , Pyruvaldehyde , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
4.
Hum Genomics ; 16(1): 33, 2022 08 26.
Article in English | MEDLINE | ID: covidwho-2021342

ABSTRACT

BACKGROUND: The tripartite motif containing (TRIM)-22 participates in innate immune responses and exhibits antiviral activities. The present study aimed to assess of the relationship between TRIM22 single-nucleotide polymorphisms and clinical parameters with the coronavirus disease 2019 (COVID-19) infection severity. METHODS: TRIM22 polymorphisms (rs7113258, rs7935564, and rs1063303) were genotyped using TaqMan polymerase chain reaction (PCR) assay in 495 dead and 497 improved severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients. RESULTS: In this study, the frequencies of TRIM22 rs1063303 GG, rs7935564 GG, and rs7113258 TT were significantly higher in dead patients than in improved patients, and higher viral load with low PCR Ct value was noticed in dead patients. The multivariate logistic regression analysis revealed that the lower levels of low-density lipoprotein (LDL), cholesterol, PCR Ct value, and lower 25-hydroxyvitamin D, and also higher levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and TRIM22 rs1063303 GG, rs7113258 TT, and rs3824949 GG genotypes were related to the COVID-19 infection severity. CONCLUSION: Our finding proved the probable relationship between the COVID-19 infection severity with the genotypes of TRIM22 SNPs and clinical parameters. More research is required worldwide to show the association between the COVID-19 infection severity and host genetic factors.


Subject(s)
COVID-19 , Minor Histocompatibility Antigens , Polymorphism, Single Nucleotide , Repressor Proteins , Tripartite Motif Proteins , Humans , COVID-19/genetics , COVID-19/pathology , Minor Histocompatibility Antigens/genetics , Repressor Proteins/genetics , SARS-CoV-2 , Tripartite Motif Proteins/genetics
5.
Nature ; 611(7934): 139-147, 2022 11.
Article in English | MEDLINE | ID: covidwho-2016757

ABSTRACT

Severe SARS-CoV-2 infection1 has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic2-5. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential6-10, although their origins and resolution have remained unclear11. Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity12,13, as a dominant feature of severe and critical COVID-19 (refs. 14-18). Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naive-derived, low-mutation IgG1 population of antibody-secreting cells (ASCs) reflecting features of low selective pressure. These features correlate with progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens and carbamylated proteins, emerging 10-15 days after the onset of symptoms. Detailed analysis of the low-selection compartment shows a high frequency of clonotypes specific for both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against the glomerular basement membrane. We further identify the contraction of this pathway on recovery, re-establishment of tolerance standards and concomitant loss of acute-derived ASCs irrespective of antigen specificity. However, serological autoreactivity persists in a subset of patients with postacute sequelae, raising important questions as to the contribution of emerging autoreactivity to continuing symptomology on recovery. In summary, this study demonstrates the origins, breadth and resolution of autoreactivity in severe COVID-19, with implications for early intervention and the treatment of patients with post-COVID sequelae.


Subject(s)
Autoantibodies , B-Lymphocytes , COVID-19 , Humans , Autoantibodies/immunology , B-Lymphocytes/immunology , B-Lymphocytes/pathology , COVID-19/immunology , COVID-19/pathology , COVID-19/physiopathology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Immunoglobulin G/immunology , Single-Cell Analysis , Autoantigens/immunology , Basement Membrane/immunology
7.
Sci Rep ; 12(1): 4058, 2022 03 08.
Article in English | MEDLINE | ID: covidwho-2004786

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is a key host protein by which severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters and multiplies within cells. The level of ACE2 expression in the lung is hypothesised to correlate with an increased risk of severe infection and complications in COrona VIrus Disease 2019 (COVID-19). To test this hypothesis, we compared the protein expression status of ACE2 by immunohistochemistry (IHC) in post-mortem lung samples of patients who died of severe COVID-19 and lung samples obtained from non-COVID-19 patients for other indications. IHC for CD61 and CD163 was performed for the assessment of platelet-rich microthrombi and macrophages, respectively. IHC for SARS-CoV-2 viral antigen was also performed. In a total of 55, 44 COVID-19 post-mortem lung samples were tested for ACE2, 36 for CD163, and 26 for CD61, compared to 15 non-covid 19 control lung sections. Quantification of immunostaining, random sampling, and correlation analysis were used to substantiate the morphologic findings. Our results show that ACE2 protein expression was significantly higher in COVID-19 post-mortem lung tissues than in controls, regardless of sample size. Histomorphology in COVID-19 lungs showed diffuse alveolar damage (DAD), acute bronchopneumonia, and acute lung injury with SARS-CoV-2 viral protein detected in a subset of cases. ACE2 expression levels were positively correlated with increased expression levels of CD61 and CD163. In conclusion, our results show significantly higher ACE2 protein expression in severe COVID-19 disease, correlating with increased macrophage infiltration and microthrombi, suggesting a pathobiological role in disease severity.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , Lung/metabolism , Acute Lung Injury/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/genetics , Antigens, CD/genetics , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/genetics , Antigens, Differentiation, Myelomonocytic/metabolism , Autopsy , COVID-19/virology , Case-Control Studies , Female , Humans , Immunohistochemistry , Integrin beta3/genetics , Integrin beta3/metabolism , Lung/pathology , Male , Middle Aged , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , SARS-CoV-2/isolation & purification , Severity of Illness Index , Young Adult
8.
Emerg Microbes Infect ; 11(1): 2160-2175, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1997031

ABSTRACT

Pandemic outbreaks of viruses such as influenza virus or SARS-CoV-2 are associated with high morbidity and mortality and thus pose a massive threat to global health and economics. Physiologically relevant models are needed to study the viral life cycle, describe the pathophysiological consequences of viral infection, and explore possible drug targets and treatment options. While simple cell culture-based models do not reflect the tissue environment and systemic responses, animal models are linked with huge direct and indirect costs and ethical questions. Ex vivo platforms based on tissue explants have been introduced as suitable platforms to bridge the gap between cell culture and animal models. We established a murine lung tissue explant platform for two respiratory viruses, influenza A virus (IAV) and SARS-CoV-2. We observed efficient viral replication, associated with the release of inflammatory cytokines and the induction of an antiviral interferon response, comparable to ex vivo infection in human lung explants. Endolysosomal entry could be confirmed as a potential host target for pharmacological intervention, and the potential repurposing potentials of fluoxetine and interferons for host-directed therapy previously seen in vitro could be recapitulated in the ex vivo model.


Subject(s)
COVID-19 , Lung , Orthomyxoviridae Infections , Animals , Antiviral Agents/pharmacology , COVID-19/pathology , Fluoxetine/pharmacology , Humans , Influenza A virus/physiology , Influenza, Human/pathology , Interferons , Lung/virology , Mice , Orthomyxoviridae Infections/pathology , SARS-CoV-2/physiology , Tissue Culture Techniques , Virus Replication
9.
Proc Natl Acad Sci U S A ; 119(35): e2200960119, 2022 08 30.
Article in English | MEDLINE | ID: covidwho-1991765

ABSTRACT

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.


Subject(s)
Brain , COVID-19 , Central Nervous System Viral Diseases , SARS-CoV-2 , Astrocytes/pathology , Astrocytes/virology , Brain/pathology , Brain/virology , COVID-19/complications , COVID-19/pathology , Central Nervous System Viral Diseases/etiology , Central Nervous System Viral Diseases/pathology , Humans
10.
J Virol ; 96(17): e0096722, 2022 09 14.
Article in English | MEDLINE | ID: covidwho-1986331

ABSTRACT

Host factors play critical roles in SARS-CoV-2 infection-associated pathology and the severity of COVID-19. In this study, we systematically analyzed the roles of SARS-CoV-2-induced host factors, doublecortin-like kinase 1 (DCLK1), and S100A9 in viral pathogenesis. In autopsied subjects with COVID-19 and pre-existing chronic liver disease, we observed high levels of DCLK1 and S100A9 expression and immunosuppressive (DCLK1+S100A9+CD206+) M2-like macrophages and N2-like neutrophils in lungs and livers. DCLK1 and S100A9 expression were rarely observed in normal controls, COVID-19-negative subjects with chronic lung disease, or COVID-19 subjects without chronic liver disease. In hospitalized patients with COVID-19, we detected 2 to 3-fold increased levels of circulating DCLK1+S100A9+ mononuclear cells that correlated with disease severity. We validated the SARS-CoV-2-dependent generation of these double-positive immune cells in coculture. SARS-CoV-2-induced DCLK1 expression correlated with the activation of ß-catenin, a known regulator of the DCLK1 promoter. Gain and loss of function studies showed that DCLK1 kinase amplified live virus production and promoted cytokine, chemokine, and growth factor secretion by peripheral blood mononuclear cells. Inhibition of DCLK1 kinase blocked pro-inflammatory caspase-1/interleukin-1ß signaling in infected cells. Treatment of SARS-CoV-2-infected cells with inhibitors of DCLK1 kinase and S100A9 normalized cytokine/chemokine profiles and attenuated DCLK1 expression and ß-catenin activation. In conclusion, we report previously unidentified roles of DCLK1 in augmenting SARS-CoV-2 viremia, inflammatory cytokine expression, and dysregulation of immune cells involved in innate immunity. DCLK1 could be a potential therapeutic target for COVID-19, especially in patients with underlying comorbid diseases associated with DCLK1 expression. IMPORTANCE High mortality in COVID-19 is associated with underlying comorbidities such as chronic liver diseases. Successful treatment of severe/critical COVID-19 remains challenging. Herein, we report a targetable host factor, DCLK1, that amplifies SARS-CoV-2 production, cytokine secretion, and inflammatory pathways via activation of ß-catenin(p65)/DCLK1/S100A9/NF-κB signaling. Furthermore, we observed in the lung, liver, and blood an increased prevalence of immune cells coexpressing DCLK1 and S100A9, a myeloid-derived proinflammatory protein. These cells were associated with increased disease severity in COVID-19 patients. Finally, we used a novel small-molecule inhibitor of DCLK1 kinase (DCLK1-IN-1) and S100A9 inhibitor (tasquinimod) to decrease virus production in vitro and normalize hyperinflammatory responses known to contribute to disease severity in COVID-19.


Subject(s)
COVID-19 , Doublecortin-Like Kinases , COVID-19/metabolism , COVID-19/pathology , Calgranulin B/metabolism , Chemokines/metabolism , Cytokines/metabolism , Doublecortin-Like Kinases/antagonists & inhibitors , Doublecortin-Like Kinases/metabolism , Humans , Intracellular Signaling Peptides and Proteins/genetics , Leukocytes, Mononuclear/metabolism , Quinolones/pharmacology , SARS-CoV-2 , beta Catenin/metabolism
11.
J Exp Med ; 219(2)2022 02 07.
Article in English | MEDLINE | ID: covidwho-1984990

ABSTRACT

In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRß repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.


Subject(s)
COVID-19/complications , Hepatitis A Virus Cellular Receptor 2/metabolism , Interferon-gamma/metabolism , Killer Cells, Natural/immunology , Monocytes/metabolism , Receptors, IgG/metabolism , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocytes/immunology , Adolescent , Alveolar Epithelial Cells/pathology , B-Lymphocytes/immunology , Blood Vessels/pathology , COVID-19/immunology , COVID-19/pathology , Cell Proliferation , Child , Cohort Studies , Complement Activation , Cytokines/metabolism , Enterocytes/pathology , Female , Humans , Immunity, Humoral , Inflammation/pathology , Interferon Type I/metabolism , Interleukin-15/metabolism , Lymphocyte Activation/immunology , Male , Receptors, Antigen, T-Cell/metabolism , SARS-CoV-2/immunology , Superantigens/metabolism , Systemic Inflammatory Response Syndrome/pathology
13.
J Immunol Res ; 2022: 9764002, 2022.
Article in English | MEDLINE | ID: covidwho-1973966

ABSTRACT

COVID-19 has several mechanisms that can lead to lymphocyte depletion/exhaustion. The checkpoint inhibitor molecule programmed death protein 1 (PD-1) and its programmed death-ligand 1 (PDL-1) play an important role in inhibiting cellular activity as well as the depletion of these cells. In this study, we evaluated PD-1 expression in TCD4+, TCD8+, and CD19+ lymphocytes from SARS-CoV-2-infected patients. A decreased frequency of total lymphocytes and an increased PD-1 expression in TCD4+ and CD19+ lymphocytes were verified in severe/critical COVID-19 patients. In addition, we found a decreased frequency of total monocytes with an increased PD-1 expression on CD14+ monocytes in severe/critical patients in association with the time of infection. Moreover, we observed an increase in sPD-L1 circulant levels associated with the severity of the disease. Overall, these data indicate an important role of the PD-1/PDL-1 axis in COVID-19 and may provide a severity-associated biomarker and therapeutic target during SARS-CoV-2 infection.


Subject(s)
B7-H1 Antigen , COVID-19 , Programmed Cell Death 1 Receptor , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , COVID-19/diagnosis , COVID-19/pathology , Humans , Monocytes/metabolism , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/metabolism , SARS-CoV-2 , Up-Regulation
14.
Viruses ; 14(8)2022 07 30.
Article in English | MEDLINE | ID: covidwho-1969507

ABSTRACT

The coronavirus 2019 (COVID-19) disease has long-term effects, known as post-COVID conditions (PCC) or long-COVID. Post-COVID-19 syndrome is defined by signs and symptoms that occur during or after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection which persist for more than 12 weeks and cannot be supported by an alternative diagnosis. The cardiovascular damage caused by COVID-19 in the severe forms of the disease is induced by severe systemic inflammation, considered to be one of the causes of myocardial lesions, with increased levels of circulating cytokines and toxic response mediators. We have focused on conditions that can induce long-COVID-19, or multisystem inflammatory syndrome in adults or children (MIS-C/MIS-A), with an emphasis on endocrinological and metabolic disorders. Although described less frequently in children than in adults, long-COVID syndrome should not be confused with MIS-C, which is an acute condition characterized by multisystem involvement and paraclinical evidence of inflammation in a pediatric patient who tested positive for SARS-CoV-2. At the same time, we mention that the MIS-A symptoms remit within a few weeks, while the duration of long-COVID is measured in months. Long-COVID syndrome, along with its complications, MIS-A and MIS-C, represents an important challenge in the medical community. Underlying comorbidities can expose both COVID-19 adult and pediatric patients to a higher risk of negative outcomes not only during, but in the aftermath of the SARS-CoV-2 infection as well.


Subject(s)
COVID-19 , Adult , COVID-19/complications , COVID-19/pathology , Child , Humans , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/epidemiology
15.
BMJ Case Rep ; 15(7)2022 Jul 28.
Article in English | MEDLINE | ID: covidwho-1962124

ABSTRACT

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that may be triggered by inflammation, including infection or vaccination. Since the start of the COVID-19 pandemic, several case reports were published on de novo or relapsed immune TTP (iTTP) in COVID-19-infected patients. Case reports of iTTP episodes following vaccination against COVID-19 are also emerging. We report a case of relapsed iTTP in a patient who received Moderna mRNA-1273 SARS-CoV-2 vaccine and developed concurrent severe COVID-19 infection. The patient's iTTP was successfully managed with caplacizumab, therapeutic plasma exchange and high-dose steroids. We summarise published cases of iTTP associated with COVID-19 infection or vaccination.


Subject(s)
COVID-19 Vaccines , COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Purpura, Thrombotic Thrombocytopenic , 2019-nCoV Vaccine mRNA-1273 , COVID-19/pathology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Pandemics , Plasma Exchange , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Purpura, Thrombocytopenic, Idiopathic/therapy , Purpura, Thrombotic Thrombocytopenic/chemically induced , Purpura, Thrombotic Thrombocytopenic/therapy , Recurrence , SARS-CoV-2 , Vaccination/adverse effects
16.
Proc Natl Acad Sci U S A ; 119(33): e2203437119, 2022 08 16.
Article in English | MEDLINE | ID: covidwho-1960624

ABSTRACT

The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1-expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)-containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.


Subject(s)
COVID-19 , Lung , Myosin Light Chains , SARS-CoV-2 , Severity of Illness Index , Thromboinflammation , Vasculitis , COVID-19/blood , COVID-19/complications , COVID-19/pathology , Humans , Leukocytes, Mononuclear , Lung/blood supply , Lung/metabolism , Lung/pathology , Lung/virology , Myosin Light Chains/blood , RNA-Seq , SARS-CoV-2/isolation & purification , Single-Cell Analysis , Spectrometry, X-Ray Emission , Thromboinflammation/pathology , Thromboinflammation/virology , Vasculitis/pathology , Vasculitis/virology
17.
Nature ; 609(7928): 801-807, 2022 09.
Article in English | MEDLINE | ID: covidwho-1960390

ABSTRACT

Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including ß-hydroxybutyrate (BHB)1-6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with  influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4+ T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4+ T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19.


Subject(s)
COVID-19 , Energy Metabolism , Ketones , Respiratory Distress Syndrome , SARS-CoV-2 , T-Lymphocytes , 3-Hydroxybutyric Acid/biosynthesis , 3-Hydroxybutyric Acid/metabolism , Amino Acids/biosynthesis , Amino Acids/metabolism , Animals , COVID-19/complications , COVID-19/immunology , COVID-19/pathology , Diet, Ketogenic , Esters/metabolism , Glutathione/biosynthesis , Glutathione/metabolism , Glycolysis , Interferon-gamma/biosynthesis , Ketone Bodies/metabolism , Ketones/metabolism , Mice , Orthomyxoviridae/pathogenicity , Oxidation-Reduction , Oxidative Phosphorylation , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/virology , SARS-CoV-2/pathogenicity , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/pathology
18.
Pflugers Arch ; 474(10): 1069-1076, 2022 10.
Article in English | MEDLINE | ID: covidwho-1955965

ABSTRACT

Proinflammatory cytokines target vascular endothelial cells during COVID-19 infections. In particular, the endothelial glycocalyx (eGC), a proteoglycan-rich layer on top of endothelial cells, was identified as a vulnerable, vasoprotective structure during infections. Thus, eGC damage can be seen as a hallmark in the development of endothelial dysfunction and inflammatory processes. Using sera derived from patients suffering from COVID-19, we could demonstrate that the eGC became progressively worse in relation to disease severity (mild vs severe course) and in correlation to IL-6 levels. This could be prevented by administering low doses of spironolactone, a well-known and highly specific aldosterone receptor antagonist. Our results confirm that SARS-CoV-2 infections cause eGC damage and endothelial dysfunction and we outline the underlying mechanisms and suggest potential therapeutic options.


Subject(s)
COVID-19 , Glycocalyx , Mineralocorticoid Receptor Antagonists , SARS-CoV-2 , Spironolactone , COVID-19/blood , COVID-19/drug therapy , COVID-19/pathology , Cytokines/pharmacology , Endothelial Cells/drug effects , Endothelial Cells/pathology , Glycocalyx/drug effects , Glycocalyx/pathology , Humans , Interleukin-6/blood , Mineralocorticoid Receptor Antagonists/pharmacology , Mineralocorticoid Receptor Antagonists/therapeutic use , Proteoglycans/analysis , Proteoglycans/blood , Spironolactone/pharmacology , Spironolactone/therapeutic use
19.
Int J Mol Sci ; 23(9)2022 May 09.
Article in English | MEDLINE | ID: covidwho-1953474

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 19 (COVID-19), a disease that has affected more than 500 million people worldwide since the end of 2019. Due to its high complications and death rates, there is still a need to find the best therapy for SARS-CoV-2 infection. The dysregulation of the inflammatory response in COVID-19 plays a very important role in disease progression. It has been observed that abnormal activity of Nuclear Factor kappa B (NF-κB) is directly associated with, inter alia, increased synthesis of proinflammatory factors. Therefore, this review paper focuses on the functions of NF-κB in the development of SARS-CoV-2 infection and potential application of NF-κB inhibitors in COVID-19 immunotherapy. A comprehensive literature search was performed using the MEDLINE/PubMed database. In the current review, it is highlighted that NF-κB plays important functions in the modulation of an adaptive inflammatory response, including inducing the expression of proinflammatory genes. Increased activation of NF-κB in SARS-CoV-2 infection was observed. The association between NF-κB activation and the expression of SARS-CoV-2 structural and non-structural proteins were also reported. It was observed that modulation of NF-κB using, e.g., traditional Chinese medicine or glucocorticosteroids resulted in decreased synthesis of proinflammatory factors caused by SARS-CoV-2 infection. This review summarizes the role of NF-κB in COVID-19 and describes its potential immunotherapeutic target in treatment of SARS-CoV-2 infection. However, indisputably more studies involving patients with a severe course of COVID-19 are sorely needed.


Subject(s)
COVID-19/pathology , NF-kappa B/metabolism , COVID-19/drug therapy , COVID-19/immunology , Humans , Inflammation/pathology , SARS-CoV-2
20.
Front Immunol ; 13: 934264, 2022.
Article in English | MEDLINE | ID: covidwho-1952335

ABSTRACT

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), responsible for COVID-19, has caused a global pandemic. Observational studies revealed a condition, herein called as Long-COVID syndrome (PC), that affects both moderately and severely infected patients, reducing quality-of-life. The mechanism/s underlying the onset of fibrotic-like changes in PC are still not well defined. The goal of this study was to understand the involvement of the Absent in melanoma-2 (AIM2) inflammasome in PC-associated lung fibrosis-like changes revealed by chest CT scans. Peripheral blood mononuclear cells (PBMCs) obtained from PC patients who did not develop signs of lung fibrosis were not responsive to AIM2 activation by Poly dA:dT. In sharp contrast, PBMCs from PC patients with signs of lung fibrosis were highly responsive to AIM2 activation, which induced the release of IL-1α, IFN-α and TGF-ß. The recognition of Poly dA:dT was not due to the activation of cyclic GMP-AMP (cGAMP) synthase, a stimulator of interferon response (cGAS-STING) pathways, implying a role for AIM2 in PC conditions. The release of IFN-α was caspase-1- and caspase-4-dependent when AIM2 was triggered. Instead, the release of pro-inflammatory IL-1α and pro-fibrogenic TGF-ß were inflammasome independent because the inhibition of caspase-1 and caspase-4 did not alter the levels of the two cytokines. Moreover, the responsiveness of AIM2 correlated with higher expression of the receptor in circulating CD14+ cells in PBMCs from patients with signs of lung fibrosis.


Subject(s)
COVID-19 , DNA-Binding Proteins , Pulmonary Fibrosis , COVID-19/blood , COVID-19/immunology , COVID-19/pathology , Carrier Proteins , Caspase 1/immunology , DNA-Binding Proteins/blood , DNA-Binding Proteins/immunology , Humans , Inflammasomes/blood , Inflammasomes/immunology , Interferon-alpha/metabolism , Leukocytes, Mononuclear/immunology , Pulmonary Fibrosis/blood , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/virology , SARS-CoV-2 , Transforming Growth Factor beta/metabolism
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