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1.
Nature ; 603(7899): 145-151, 2022 03.
Article in English | MEDLINE | ID: covidwho-1631700

ABSTRACT

COVID-19, which is caused by infection with SARS-CoV-2, is characterized by lung pathology and extrapulmonary complications1,2. Type I interferons (IFNs) have an essential role in the pathogenesis of COVID-19 (refs 3-5). Although rapid induction of type I IFNs limits virus propagation, a sustained increase in the levels of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome5-17. Here we show that the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which controls immunity to cytosolic DNA, is a critical driver of aberrant type I IFN responses in COVID-19 (ref. 18). Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature that is primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS-STING activity was detected in lung samples from patients with COVID-19 with prominent tissue destruction, and was associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, infection with SARS-CoV-2 activates cGAS-STING signalling in endothelial cells through mitochondrial DNA release, which leads to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a principle for the development of host-directed therapeutics.


Subject(s)
COVID-19/immunology , COVID-19/pathology , Interferon Type I/immunology , Membrane Proteins/metabolism , Nucleotidyltransferases/metabolism , SARS-CoV-2/immunology , Animals , COVID-19/metabolism , COVID-19/virology , Cells, Cultured , DNA, Mitochondrial/metabolism , Disease Models, Animal , Disease Progression , Endothelial Cells/pathology , Female , Gene Expression Regulation/immunology , Humans , Immunity, Innate , Lung/immunology , Lung/metabolism , Lung/pathology , Lung/virology , Macrophages/immunology , Membrane Proteins/antagonists & inhibitors , Mice , Mice, Inbred C57BL , Pneumonia/immunology , Pneumonia/metabolism , Pneumonia/pathology , Pneumonia/virology , SARS-CoV-2/pathogenicity , Signal Transduction , Skin/immunology , Skin/metabolism , Skin/pathology
2.
Front Immunol ; 12: 798276, 2021.
Article in English | MEDLINE | ID: covidwho-1606542

ABSTRACT

Effects of initiation of programmed-death-protein 1 (PD1) blockade during active SARS-CoV-2 infection on antiviral immunity, COVID-19 course, and underlying malignancy are unclear. We report on the management of a male in his early 40s presenting with highly symptomatic metastatic lung cancer and active COVID-19 pneumonia. After treatment initiation with pembrolizumab, carboplatin, and pemetrexed, the respiratory situation initially worsened and high-dose corticosteroids were initiated due to suspected pneumonitis. After improvement and SARS-CoV-2 clearance, anti-cancer treatment was resumed without pembrolizumab. Immunological analyses with comparison to otherwise healthy SARS-CoV-2-infected ambulatory patients revealed a strong humoral immune response with higher levels of SARS-CoV-2-reactive IgG and neutralizing serum activity. Additionally, sustained increase of Tfh as well as activated CD4+ and CD8+ T cells was observed. Sequential CT scans showed regression of tumor lesions and marked improvement of the pulmonary situation, with no signs of pneumonitis after pembrolizumab re-challenge as maintenance. At the latest follow-up, the patient is ambulatory and in ongoing partial remission on pembrolizumab. In conclusion, anti-PD1 initiation during active COVID-19 pneumonia was feasible and cellular and humoral immune responses to SARS-CoV-2 appeared enhanced in our hospitalized patient. However, distinguishing COVID-19-associated changes from anti-PD1-associated immune-related pneumonitis posed a considerable clinical, radiographic, and immunologic challenge.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , COVID-19/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , SARS-CoV-2/drug effects , Adult , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , COVID-19/complications , COVID-19/immunology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/immunology , Humans , Immunity, Humoral/drug effects , Immunity, Humoral/immunology , Lung Neoplasms/complications , Lung Neoplasms/immunology , Male , Neoplasm Metastasis , Pneumonia/immunology , Pneumonia/prevention & control , Pneumonia/virology , SARS-CoV-2/immunology
3.
Front Immunol ; 12: 784028, 2021.
Article in English | MEDLINE | ID: covidwho-1581324

ABSTRACT

Background: Extracellular vesicles (EVs) are mediators of cell-to-cell communication in inflammatory lung diseases. They function as carriers for miRNAs which regulate mRNA transcripts and signaling pathways after uptake into recipient cells. We investigated whether miRNAs associated with circulating EVs regulate immunologic processes in COVID-19. Methods: We prospectively studied 20 symptomatic patients with COVID-19 pneumonia, 20 mechanically ventilated patients with severe COVID-19 (severe acute respiratory corona virus-2 syndrome, ARDS) and 20 healthy controls. EVs were isolated by precipitation, total RNA was extracted, profiled by small RNA sequencing and evaluated by differential gene expression analysis (DGE). Differentially regulated miRNAs between groups were bioinformatically analyzed, mRNA target transcripts identified and signaling networks constructed, thereby comparing COVID-19 pneumonia to the healthy state and pneumonia to severe COVID-19 ARDS. Results: DGE revealed 43 significantly and differentially expressed miRNAs (25 downregulated) in COVID-19 pneumonia when compared to controls, and 20 miRNAs (15 downregulated) in COVID-19 ARDS patients in comparison to those with COVID-19 pneumonia. Network analysis for comparison of COVID-19 pneumonia to healthy controls showed upregulated miR-3168 (log2FC=2.28, padjusted<0.001), among others, targeting interleukin-6 (IL6) (25.1, 15.2 - 88.2 pg/ml in COVID-19 pneumonia) and OR52N2, an olfactory smell receptor in the nasal epithelium. In contrast, miR-3168 was significantly downregulated in COVID-19 ARDS (log2FC=-2.13, padjusted=0.003) and targeted interleukin-8 (CXCL8) in a completely activated network. Toll-like receptor 4 (TLR4) was inhibited in COVID-19 pneumonia by miR-146a-5p and upregulated in ARDS by let-7e-5p. Conclusion: EV-derived miRNAs might have important regulative functions in the pathophysiology of COVID-19: CXCL8 regulates neutrophil recruitment into the lung causing epithelial damage whereas activated TLR4, to which SARS-CoV-2 spike protein binds strongly, increases cell surface ACE2 expression and destroys type II alveolar cells that secrete pulmonary surfactants; both resulting in pulmonary-capillary leakage and ARDS. These miRNAs may serve as biomarkers or as possible therapeutic targets.


Subject(s)
Biomarkers/blood , COVID-19/immunology , Extracellular Vesicles/immunology , MicroRNAs/immunology , Aged , Aged, 80 and over , COVID-19/pathology , Disease Progression , Female , Humans , Male , Middle Aged , Pneumonia/immunology , Pneumonia/pathology , SARS-CoV-2 , Signal Transduction/immunology
4.
Int J Mol Sci ; 22(23)2021 Nov 27.
Article in English | MEDLINE | ID: covidwho-1560687

ABSTRACT

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe respiratory disorders that are caused by aspiration, sepsis, trauma, and pneumonia. A clinical feature of ALI/ARDS is the acute onset of severe hypoxemia, and the mortality rate, which is estimated at 38-50%, remains high. Although prostaglandins (PGs) are detected in the bronchoalveolar lavage fluid of patients with ALI/ARDS, the role of PGF2α in ALI remains unclear. We aimed to clarify the role of PGF2α/PGF2α receptor (FP) signaling in acid-induced ALI using an FP receptor antagonist, AL8810. Intratracheal injection of hydrochloric acid (HCl) increased neutrophil migration into the lungs, leading to respiratory dysfunction. Pre-administration of AL8810 further increased these features. Moreover, pre-treatment with AL8810 enhanced the HCl-induced expression of pro-inflammatory cytokines and neutrophil migratory factors in the lungs. Administration of HCl decreased the gene expression of lung surfactant proteins, which was further reduced by co-administration of AL8810. Administration of AL8810 also increased lung edema and reduced mRNA expression of epithelial sodium channel in the lungs, indicating that AL8810 reduced fluid clearance. Furthermore, AL8810 also increased lipopolysaccharide-induced expression of adhesion molecules such as intracellular adhesion molecule-1 and E-selectin in human umbilical vein endothelial cells. These results indicate that inhibition of FP receptors by AL8810 exacerbated HCl-induced ALI.


Subject(s)
Acute Lung Injury/metabolism , Lung/drug effects , Pneumonia/metabolism , Receptors, Prostaglandin/antagonists & inhibitors , Respiratory Distress Syndrome/metabolism , Acute Lung Injury/chemically induced , Acute Lung Injury/pathology , Animals , Disease Models, Animal , Female , Hydrochloric Acid/toxicity , Lung/metabolism , Lung/pathology , Mice , Mice, Inbred C57BL , Pneumonia/chemically induced , Pneumonia/immunology , Pneumonia/pathology , Prostaglandins F/metabolism , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/pathology
5.
Sci Rep ; 11(1): 23216, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1545650

ABSTRACT

This study monitored the long-term immune response to severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection in patients who had recovered from coronavirus disease (COVID)-19. Anti-nucleocapsid immunoglobulin G (anti-N IgG) titer in serum samples collected at a single (N = 302) or multiple time points (N = 229) 3-12 months after COVID-19 symptom onset or SARS-CoV-2 detection in respiratory specimens was measured by semiquantitative chemiluminescent microparticle immunoassay. The 531 patients (966 specimens) were classified according to the presence or absence of pneumonia symptoms. Anti N IgG was detected in 87.5% of patients (328/375) at 3 months, 38.6% (93/241) at 6 months, 23.7% (49/207) at 9 months, and 26.6% (38/143) at 12 months. The anti-N IgG seropositivity rate was significantly lower at 6, 9, and 12 months than at 3 months (P < 0.01) and was higher in the pneumonia group than in the non-pneumonia/asymptomatic group at 6 months (P < 0.01), 9 months (P = 0.04), and 12 months (P = 0.04). The rate started to decline 6-12 months after symptom onset. Anti-N IgG sample/cutoff index was positively correlated with age (r = 0.192, P < 0.01) but negatively correlated with interval between symptom onset and blood sampling (r = - 0.567, P < 0.01). These findings can guide vaccine strategies in recovered COVID-19 patients.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Coronavirus Nucleocapsid Proteins/immunology , Immunoglobulin G/immunology , Pneumonia/immunology , SARS-CoV-2/immunology , Adult , Antibodies, Viral/blood , COVID-19/complications , COVID-19/therapy , COVID-19/virology , Female , Humans , Male , Middle Aged , Phosphoproteins/immunology , Pneumonia/epidemiology , Pneumonia/virology , Retrospective Studies , Thailand/epidemiology , Young Adult
6.
Sci Rep ; 11(1): 22892, 2021 11 24.
Article in English | MEDLINE | ID: covidwho-1532105

ABSTRACT

Clinical and prognostic differences between symptomatic and asymptomatic older patients with COVID-19 are of great interest since frail patients often show atypical presentation of illness. Lung Ultrasound (LUS) has been proven to be a reliable tool for detecting early-phase COVID-19 pneumonic alterations. The current prospective bicentric study aimed to compare LUS score and 3-month overall mortality between asymptomatic and symptomatic older patients with COVID-19, according to frailty status. Patients were stratified according to LUS score tertiles and Clinical Frailty Scale categories. Survival rate was assessed by telephone interviews 3 months after discharge. 64 symptomatic (24 women, aged 80.0 ± 10.8 years) and 46 asymptomatic (31 women, aged 84.3 ± 8.8 years) were consecutively enrolled. LUS score resulted an independent predictor of 3-month mortality [OR 2.27 (CI95% 1.09-4.8), p = 0.03], and the highest mortality rate was observed in symptomatic and asymptomatic pre-frail and frail patients (70.6% and 66.7%, respectively) with greater LUS abnormalities (3rd tertile). In conclusion, LUS identified an acute interstitial lung involvement in most of the older asymptomatic patients. Mortality rate progressively increased according to clinical frailty and LUS score degree, resulting a reliable prognostic tool in both symptomatic and asymptomatic patients.


Subject(s)
COVID-19/diagnostic imaging , COVID-19/mortality , Pneumonia/diagnostic imaging , Aged , Aged, 80 and over , Asymptomatic Diseases/epidemiology , COVID-19/complications , Female , Hospitalization , Humans , Lung/diagnostic imaging , Lung/pathology , Male , Pneumonia/immunology , Prognosis , Prospective Studies , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Tomography, X-Ray Computed/methods , Ultrasonography/methods
7.
Front Immunol ; 12: 689866, 2021.
Article in English | MEDLINE | ID: covidwho-1503883

ABSTRACT

Rapid recruitment of neutrophils to an inflamed site is one of the hallmarks of an effective host defense mechanism. The main pathway through which this happens is by the innate immune response. Neutrophils, which play an important part in innate immune defense, migrate into lungs through the modulation actions of chemokines to execute a variety of pro-inflammatory functions. Despite the importance of chemokines in host immunity, little has been discussed on their roles in host immunity. A holistic understanding of neutrophil recruitment, pattern recognition pathways, the roles of chemokines and the pathophysiological roles of neutrophils in host immunity may allow for new approaches in the treatment of infectious and inflammatory disease of the lung. Herein, this review aims at highlighting some of the developments in lung neutrophil-immunity by focusing on the functions and roles of CXC/CC chemokines and pattern recognition receptors in neutrophil immunity during pulmonary inflammations. The pathophysiological roles of neutrophils in COVID-19 and thromboembolism have also been summarized. We finally summarized various neutrophil biomarkers that can be utilized as prognostic molecules in pulmonary inflammations and discussed various neutrophil-targeted therapies for neutrophil-driven pulmonary inflammatory diseases.


Subject(s)
Immunity, Innate/immunology , Neutrophils/immunology , Pneumonia/immunology , Biomarkers/blood , COVID-19/immunology , Cell Degranulation/immunology , Chemokines/immunology , Clinical Trials as Topic , Extracellular Traps/immunology , Humans , Integrins/immunology , Lung/immunology , Lung/pathology , Neutrophils/drug effects , Pneumonia/diagnosis , Pneumonia/drug therapy , Receptors, Pattern Recognition/immunology , Respiratory Burst/immunology , SARS-CoV-2 , Thromboembolism/immunology
8.
J Immunol ; 207(7): 1776-1784, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1497460

ABSTRACT

Acquired neutrophil dysfunction frequently develops during critical illness, independently increasing the risk for intensive care unit-acquired infection. PI3Kδ is implicated in driving neutrophil dysfunction and can potentially be targeted pharmacologically. The aims of this study were to determine whether PI3Kδ inhibition reverses dysfunction in neutrophils from critically ill patients and to describe potential mechanisms. Neutrophils were isolated from blood taken from critically ill patients requiring intubation and mechanical ventilation, renal support, or blood pressure support. In separate validation experiments, neutrophil dysfunction was induced pharmacologically in neutrophils from healthy volunteers. Phagocytosis and bacterial killing assays were performed, and activity of RhoA and protein kinase A (PKA) was assessed. Inhibitors of PI3Kδ, 3-phosphoinositide-dependent protein kinase-1 (PDK1), and PKA were used to determine mechanisms of neutrophil dysfunction. Sixty-six patients were recruited. In the 27 patients (40.9%) with impaired neutrophil function, PI3Kδ inhibition consistently improved function and significantly increased bacterial killing. These findings were validated in neutrophils from healthy volunteers with salbutamol-induced dysfunction and extended to demonstrate that PI3Kδ inhibition restored killing of clinical isolates of nine pathogens commonly associated with intensive care unit-acquired infection. PI3Kδ activation was associated with PDK1 activation, which in turn phosphorylated PKA, which drove phosphorylation and inhibition of the key regulator of neutrophil phagocytosis, RhoA. These data indicate that, in a significant proportion of critically ill patients, PI3Kδ inhibition can improve neutrophil function through PDK1- and PKA-dependent processes, suggesting that therapeutic use of PI3Kδ inhibitors warrants investigation in this setting.


Subject(s)
COVID-19/immunology , Class I Phosphatidylinositol 3-Kinases/metabolism , Critical Illness , Neutrophils/immunology , Pneumonia/immunology , SARS-CoV-2/physiology , Sepsis/immunology , 3-Phosphoinositide-Dependent Protein Kinases/pharmacology , Adult , Aged , Aged, 80 and over , Bacterial Load , Bacteriolysis , Cells, Cultured , Cyclic AMP-Dependent Protein Kinases/metabolism , Female , Humans , Male , Middle Aged , Phagocytosis , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Respiratory Insufficiency , Risk
9.
Cells ; 10(10)2021 09 29.
Article in English | MEDLINE | ID: covidwho-1444117

ABSTRACT

Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have a potent self-renewal capacity and can differentiate into multiple cell types. They also affect the ambient tissue by the paracrine secretion of numerous factors in vivo, including the induction of other stem cells' differentiation. In vitro, the culture media supernatant is named secretome and contains soluble molecules and extracellular vesicles that retain potent biological function in tissue regeneration. MSCs are considered safe for human treatment; their use does not involve ethical issues, as embryonic stem cells do not require genetic manipulation as induced pluripotent stem cells, and after intravenous injection, they are mainly found in the lugs. Therefore, these cells are currently being tested in various preclinical and clinical trials for several diseases, including COVID-19. Several affected COVID-19 patients develop induced acute respiratory distress syndrome (ARDS) associated with an uncontrolled inflammatory response. This condition causes extensive damage to the lungs and may leave serious post-COVID-19 sequelae. As the disease may cause systemic alterations, such as thromboembolism and compromised renal and cardiac function, the intravenous injection of MSCs may be a therapeutic alternative against multiple pathological manifestations. In this work, we reviewed the literature about MSCs biology, focusing on their function in pulmonary regeneration and their use in COVID-19 treatment.


Subject(s)
COVID-19/blood , COVID-19/therapy , Lung/physiology , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/cytology , Regeneration/physiology , Animals , COVID-19/drug therapy , Cell Differentiation , Cell- and Tissue-Based Therapy , Culture Media , Extracellular Vesicles , Humans , Inflammation , Mice , Mice, SCID , Phenotype , Pneumonia/blood , Pneumonia/immunology , Pneumonia/therapy , Respiratory Distress Syndrome , SARS-CoV-2 , Thromboembolism/blood , Thromboembolism/immunology , Thromboembolism/therapy
10.
Dis Markers ; 2021: 6803510, 2021.
Article in English | MEDLINE | ID: covidwho-1443673

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the most significant public health threat worldwide. Patients with severe COVID-19 usually have pneumonia concomitant with local inflammation and sometimes a cytokine storm. Specific components of the SARS-CoV-2 virus trigger lung inflammation, and recruitment of immune cells to the lungs exacerbates this process, although much remains unknown about the pathogenesis of COVID-19. Our study of lung type II pneumocyte cells (A549) demonstrated that ORF7, an open reading frame (ORF) in the genome of SARS-CoV-2, induced the production of CCL2, a chemokine that promotes the chemotaxis of monocytes, and decreased the expression of IL-8, a chemokine that recruits neutrophils. A549 cells also had an increased level of IL-6. The results of our chemotaxis Transwell assay suggested that ORF7 augmented monocyte infiltration and reduced the number of neutrophils. We conclude that the ORF7 of SARS-CoV-2 may have specific effects on the immunological changes in tissues after infection. These results suggest that the functions of other ORFs of SARS-CoV-2 should also be comprehensively examined.


Subject(s)
COVID-19/metabolism , Chemotaxis , Monocytes/pathology , Neutrophils/pathology , Open Reading Frames/physiology , Pneumonia/pathology , Viral Proteins/metabolism , A549 Cells , Chemokine CCL2/metabolism , Humans , In Vitro Techniques , Monocytes/immunology , Monocytes/metabolism , Neutrophils/immunology , Neutrophils/metabolism , Pneumonia/immunology , Pneumonia/metabolism , SARS-CoV-2/metabolism , Viral Proteins/genetics
11.
Cells ; 10(8)2021 07 29.
Article in English | MEDLINE | ID: covidwho-1339532

ABSTRACT

Neutrophils act as the first line of defense during infection and inflammation. Once activated, they are able to fulfil numerous tasks to fight inflammatory insults while keeping a balanced immune response. Besides well-known functions, such as phagocytosis and degranulation, neutrophils are also able to release "neutrophil extracellular traps" (NETs). In response to most stimuli, the neutrophils release decondensed chromatin in a NADPH oxidase-dependent manner decorated with histones and granule proteins, such as neutrophil elastase, myeloperoxidase, and cathelicidins. Although primarily supposed to prevent microbial dissemination and fight infections, there is increasing evidence that an overwhelming NET response correlates with poor outcome in many diseases. Lung-related diseases especially, such as bacterial pneumonia, cystic fibrosis, chronic obstructive pulmonary disease, aspergillosis, influenza, and COVID-19, are often affected by massive NET formation. Highly vascularized areas as in the lung are susceptible to immunothrombotic events promoted by chromatin fibers. Keeping this fragile equilibrium seems to be the key for an appropriate immune response. Therapies targeting dysregulated NET formation might positively influence many disease progressions. This review highlights recent findings on the pathophysiological influence of NET formation in different bacterial, viral, and non-infectious lung diseases and summarizes medical treatment strategies.


Subject(s)
Extracellular Traps/immunology , Neutrophils/immunology , Pneumonia/immunology , COVID-19/immunology , Disease Progression , Humans , Neutrophils/microbiology , Neutrophils/virology , Pneumonia/microbiology , Pneumonia/pathology , Pneumonia/virology
12.
PLoS One ; 16(7): e0254374, 2021.
Article in English | MEDLINE | ID: covidwho-1320545

ABSTRACT

While establishing worldwide collective immunity with anti SARS-CoV-2 vaccines, COVID-19 remains a major health issue with dramatic ensuing economic consequences. In the transition, repurposing existing drugs remains the fastest cost-effective approach to alleviate the burden on health services, most particularly by reducing the incidence of the acute respiratory distress syndrome associated with severe COVID-19. We undertook a computational repurposing approach to identify candidate therapeutic drugs to control progression towards severe airways inflammation during COVID-19. Molecular profiling data were obtained from public sources regarding SARS-CoV-2 infected epithelial or endothelial cells, immune dysregulations associated with severe COVID-19 and lung inflammation induced by other respiratory viruses. From these data, we generated a protein-protein interactome modeling the evolution of lung inflammation during COVID-19 from inception to an established cytokine release syndrome. This predictive model assembling severe COVID-19-related proteins supports a role for known contributors to the cytokine storm such as IL1ß, IL6, TNFα, JAK2, but also less prominent actors such as IL17, IL23 and C5a. Importantly our analysis points out to alarmins such as TSLP, IL33, members of the S100 family and their receptors (ST2, RAGE) as targets of major therapeutic interest. By evaluating the network-based distances between severe COVID-19-related proteins and known drug targets, network computing identified drugs which could be repurposed to prevent or slow down progression towards severe airways inflammation. This analysis confirmed the interest of dexamethasone, JAK2 inhibitors, estrogens and further identified various drugs either available or in development interacting with the aforementioned targets. We most particularly recommend considering various inhibitors of alarmins or their receptors, currently receiving little attention in this indication, as candidate treatments for severe COVID-19.


Subject(s)
Alarmins/immunology , Antiviral Agents/pharmacology , COVID-19/complications , Drug Repositioning , Pneumonia/complications , Pneumonia/drug therapy , Antiviral Agents/immunology , Antiviral Agents/therapeutic use , Humans , Pneumonia/immunology
13.
J Immunol Res ; 2021: 6657894, 2021.
Article in English | MEDLINE | ID: covidwho-1314178

ABSTRACT

BACKGROUND: The 2019 novel coronavirus SARS-CoV-2 caused large outbreaks of COVID-19 worldwide. COVID-19 resembles community-acquired pneumonia (CAP). Our aim was to identify lymphocyte subpopulations to distinguish between COVID-19 and CAP. METHODS: We compared the peripheral blood lymphocytes and their subsets in 296 patients with COVID-19 and 130 patients with CAP. Parameters for independent prediction of COVID-19 were calculated by logistic regression. RESULTS: The main lymphocyte subpopulations (CD3+CD4+, CD16+CD56+, and CD4+/CD8+ ratio) and cytokines (TNF-α and IFN-γ) of COVID-19 patients were significantly different from that of CAP patients. CD16+CD56+%, CD4+/CD8+ratio, CD19+, and CD3+CD4+ were identified as predictors of COVID-19 diagnosis by logistic regression. In addition, the CD3+CD4+counts, CD3+CD8+ counts, andTNF-α are independent predictors of disease severity in patients. CONCLUSIONS: Lymphopenia is an important part of SARS-CoV-2 infection, and lymphocyte subsets and cytokines may be useful to predict the severity and clinical outcomes of the disease.


Subject(s)
CD4-CD8 Ratio , COVID-19/blood , Interferon-gamma/blood , Lymphocyte Subsets/cytology , Pneumonia/blood , Tumor Necrosis Factor-alpha/blood , Adult , Aged , COVID-19/immunology , COVID-19/pathology , COVID-19 Testing , Community-Acquired Infections/microbiology , Female , Humans , Lymphocyte Subsets/immunology , Lymphopenia/blood , Lymphopenia/pathology , Male , Middle Aged , Pneumonia/immunology , Pneumonia/pathology , Prognosis , SARS-CoV-2/immunology , Severity of Illness Index
14.
Clin Lymphoma Myeloma Leuk ; 21(10): e810-e816, 2021 10.
Article in English | MEDLINE | ID: covidwho-1313014

ABSTRACT

BACKGROUND: We previously reported elsewhere of a follicular lymphoma patient suffering from persistent COVID-19 pneumonia that was still ongoing at 2 months after onset. MATERIALS AND METHODS: We provide a follow-up report of the case along with a literature review of immunocompromised lymphoma patients experiencing prolonged COVID-19 infections. RESULTS: Although requiring a full 1 year, the presented case eventually achieved spontaneous resolution of COVID-19 pneumonia. Anti-SARS-CoV-2 antibodies could not be detected throughout the disease course, but COVID-19-directed T-cell response was found to be intact. The patient also developed secondary immune thrombocytopenia subsequent to COVID-19 pneumonia. We found 19 case reports of immunocompromised lymphoma patients with prolonged COVID-19 infections in the literature. All 5 patients who died did not receive convalescent plasma therapy, whereas resolution of COVID-19 infection was achieved in 8 out of 9 patients who received convalescent plasma therapy. CONCLUSIONS: We demonstrate through the presented case that while time-consuming, resolution of COVID-19 infections may be achieved without aid from humoral immunity if cellular immunity is intact. Immunocompromised lymphoma patients are at risk of a prolonged disease course of COVID-19, and convalescent plasma therapy may be a promising approach in such patients.


Subject(s)
COVID-19/immunology , Lymphoma, Follicular/drug therapy , Pneumonia/immunology , Rituximab/therapeutic use , SARS-CoV-2/immunology , Thrombocytopenia/immunology , Antineoplastic Agents, Immunological/therapeutic use , COVID-19/virology , Female , Follow-Up Studies , Humans , Immunocompromised Host/immunology , Lymphoma, Follicular/complications , Lymphoma, Follicular/immunology , Maintenance Chemotherapy/methods , Middle Aged , Pneumonia/complications , Pneumonia/virology , Remission, Spontaneous , SARS-CoV-2/physiology , T-Lymphocytes/immunology , T-Lymphocytes/virology , Thrombocytopenia/complications
15.
Immunity ; 54(7): 1578-1593.e5, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1246000

ABSTRACT

Immune profiling of COVID-19 patients has identified numerous alterations in both innate and adaptive immunity. However, whether those changes are specific to SARS-CoV-2 or driven by a general inflammatory response shared across severely ill pneumonia patients remains unknown. Here, we compared the immune profile of severe COVID-19 with non-SARS-CoV-2 pneumonia ICU patients using longitudinal, high-dimensional single-cell spectral cytometry and algorithm-guided analysis. COVID-19 and non-SARS-CoV-2 pneumonia both showed increased emergency myelopoiesis and displayed features of adaptive immune paralysis. However, pathological immune signatures suggestive of T cell exhaustion were exclusive to COVID-19. The integration of single-cell profiling with a predicted binding capacity of SARS-CoV-2 peptides to the patients' HLA profile further linked the COVID-19 immunopathology to impaired virus recognition. Toward clinical translation, circulating NKT cell frequency was identified as a predictive biomarker for patient outcome. Our comparative immune map serves to delineate treatment strategies to interfere with the immunopathologic cascade exclusive to severe COVID-19.


Subject(s)
COVID-19/immunology , SARS-CoV-2/pathogenicity , Adult , Angiotensin-Converting Enzyme 2/metabolism , Antigen Presentation , Biomarkers/blood , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , COVID-19/pathology , Female , HLA Antigens/genetics , HLA Antigens/immunology , Humans , Immunity, Innate , Immunophenotyping , Male , Middle Aged , Natural Killer T-Cells/immunology , Pneumonia/immunology , Pneumonia/pathology , SARS-CoV-2/immunology , Severity of Illness Index , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
16.
Nat Commun ; 12(1): 3006, 2021 05 21.
Article in English | MEDLINE | ID: covidwho-1238000

ABSTRACT

Coronavirus disease 2019 (COVID-19) can lead to pneumonia and hyperinflammation. Here we show a sensitive method to measure polyclonal T cell activation by downstream effects on responder cells like basophils, plasmacytoid dendritic cells, monocytes and neutrophils in whole blood. We report a clear T cell hyporeactivity in hospitalized COVID-19 patients that is pronounced in ventilated patients, associated with prolonged virus persistence and reversible with clinical recovery. COVID-19-induced T cell hyporeactivity is T cell extrinsic and caused by plasma components, independent of occasional immunosuppressive medication of the patients. Monocytes respond stronger in males than females and IL-2 partially restores T cell activation. Downstream markers of T cell hyporeactivity are also visible in fresh blood samples of ventilated patients. Based on our data we developed a score to predict fatal outcomes and identify patients that may benefit from strategies to overcome T cell hyporeactivity.


Subject(s)
COVID-19/immunology , Inflammation/immunology , Lymphocyte Activation/immunology , Pneumonia/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adult , Aged , Basophils/immunology , COVID-19/virology , Cells, Cultured , Dendritic Cells/immunology , Female , Humans , Male , Middle Aged , Monocytes/immunology , Neutrophils/immunology , SARS-CoV-2/physiology , Young Adult
17.
Int Arch Allergy Immunol ; 182(8): 765-774, 2021.
Article in English | MEDLINE | ID: covidwho-1234321

ABSTRACT

PURPOSE: The aim of this study is to evaluate the frequency of cardiac involvement in patients with coronavirus disease 2019 (COVID-19), possible immune mechanisms of myocardial injury, and the place of cardiovascular pathology among other prognostic factors. METHODS: The study included 86 patients (48 male, 60.2 ± 16.6 years) with COVID-19. In addition to common investigation, examination of troponin T (n = 18) and anti-heart antibodies (AHA, n = 34) were used. The average hospital period was 14 [12; 18] days. RESULTS: The incidence of cardiovascular disease and symptoms was 45.3%. Arrhythmias, heart failure, low-QRS voltage, repolarization disorders, and pericardial effusion were the typical for coronavirus cardiac injury. The level of AHA was increased in 73.5%. Significant (p < 0.05) correlations of AHA level with inflammatory activity, pneumonia, respiratory failure, cardiac symptoms, and death were found. D-dimer >0.5 µg/mL had a sensitivity of 79.2% and specificity of 60% in the prediction of cardiovascular manifestations. Cardiac failure was one of the causes of death in 3/8 patients (37.5%). Lethality in the presence of cardiovascular pathology was 17.9 versus 2.2% without it, p < 0.05. The most powerful prognostic model includes age, diabetes, oxygen therapy volume, maximum leukocyte level, C-reactive protein, and D-dimer (correlation coefficient 0.871, p < 0.001). The model with only age, diabetes, and cardiovascular disease included also had predictive power (correlation coefficient 0.568, p < 0.001). CONCLUSIONS: The cardiovascular pathology is frequent in patients with COVID-19 and strong correlates with the D-dimer. It indicates the high significance of prothrombotic and ischemic mechanisms. High AHA levels may reflect an inflammatory heart injury. The cardiovascular pathology is associated with higher lethality.


Subject(s)
COVID-19/immunology , Cardiovascular Diseases/immunology , Myocardium/immunology , Pneumonia/immunology , SARS-CoV-2/physiology , Aged , Autoantibodies/blood , COVID-19/diagnosis , COVID-19/epidemiology , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Female , Humans , Incidence , Inflammation , Male , Middle Aged , Models, Statistical , Myocardium/metabolism , Myocardium/pathology , Pneumonia/epidemiology , Prognosis , Russia/epidemiology , Troponin T/metabolism
18.
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
19.
J Clin Immunol ; 41(6): 1131-1145, 2021 08.
Article in English | MEDLINE | ID: covidwho-1216234

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a public health emergency. The most common symptoms of COVID-19 are fever, cough, and fatigue. While most patients with COVID-19 present with mild illness, some patients develop pneumonia, an important risk factor for mortality, at early stage of viral infection, putting these patients at increased risk of death. So far, little has been known about differences in the T cell repertoires between COVID-19 patients with and without pneumonia during SARS-CoV-2 infection. Herein, we aimed to investigate T cell receptor (TCR) repertoire profiles and patient-specific SARS-CoV-2-associated TCR clusters between COVID-19 patients with mild disease (no sign of pneumonia) and pneumonia. The TCR sequencing was conducted to characterize the peripheral TCR repertoire profile and diversity. The TCR clustering and CDR3 annotation were exploited to further discover groups of patient-specific TCR clonotypes with potential SARS-CoV-2 antigen specificities. Our study indicated a slight decrease in the TCR repertoire diversity and a skewed CDR3 length usage in patients with pneumonia compared to those with mild disease. The SARS-CoV-2-associated TCR clusters enriched in patients with mild disease exhibited significantly higher TCR generation probabilities and most of which were highly shared among patients, compared with those from pneumonia patients. Importantly, using similarity network-based clustering followed by the sequence conservation analysis, we found different patterns of CDR3 sequence motifs between mild disease- and pneumonia-specific SARS-CoV-2-associated public TCR clusters. Our results showed that characteristics of overall TCR repertoire and SARS-CoV-2-associated TCR clusters/clonotypes were divergent between COVID-19 patients with mild disease and patients with pneumonia. These findings provide important insights into the correlation between the TCR repertoire and disease severity in COVID-19 patients.


Subject(s)
COVID-19/immunology , Pneumonia/immunology , Receptors, Antigen, T-Cell/genetics , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Adult , Aged , Disease Progression , Female , Humans , Male , Middle Aged , Pandemics , Receptors, Antigen, T-Cell/metabolism , Sequence Analysis, DNA , Severity of Illness Index
20.
J Immunother Cancer ; 9(4)2021 04.
Article in English | MEDLINE | ID: covidwho-1209683

ABSTRACT

The clinically indistinguishable overlap between pneumonitis caused due to immune checkpoint inhibition (ICI) and pneumonia associated with COVID-19 has posed considerable challenges for patients with cancer and oncologists alike. The cancer community continues to face the challenges that lay at the complex immunological intersection of immune-based cancer therapy and immune dysregulation that results from COVID-19. Is there compounded immune dysregulation that could lead to poor outcomes? Could ICIs, in fact, ameliorate SARS-CoV-2-driven T-cell exhaustion?A little more is known about the kinetics of the viral replication in immunocompromised patients now as compared with earlier during the pandemic. Working knowledge of the diagnostic and therapeutic nuances of SARS-CoV-2 infection in patients with active cancers, issues related to viability and replication potential of the virus, unclear role of corticosteroids among those with diminished or dysfunctional effector T-cell repertoire, and the type of immunotherapy with differential risk of pneumonitis will inform decision making related to immunotherapy choices and decision for ICI continuation in the era of COVID-19.


Subject(s)
COVID-19/immunology , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy/methods , Neoplasms/therapy , Pneumonia/immunology , SARS-CoV-2/immunology , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Diagnosis, Differential , Humans , Immune Checkpoint Inhibitors/adverse effects , Immunocompromised Host/immunology , Immunotherapy/adverse effects , Neoplasms/immunology , Pneumonia/chemically induced , Pneumonia/diagnosis , SARS-CoV-2/physiology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
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