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1.
Allergy ; 77(1): 118-129, 2022 01.
Article in English | MEDLINE | ID: covidwho-1597019

ABSTRACT

BACKGROUND: COVID-19 can present with lymphopenia and extraordinary complex multiorgan pathologies that can trigger long-term sequela. AIMS: Given that inflammasome products, like caspase-1, play a role in the pathophysiology of a number of co-morbid conditions, we investigated caspases across the spectrum of COVID-19 disease. MATERIALS & METHODS: We assessed transcriptional states of multiple caspases and using flow cytometry, the expression of active caspase-1 in blood cells from COVID-19 patients in acute and convalescent stages of disease. Non-COVID-19 subject presenting with various comorbid conditions served as controls. RESULTS: Single-cell RNA-seq data of immune cells from COVID-19 patients showed a distinct caspase expression pattern in T cells, neutrophils, dendritic cells, and eosinophils compared with controls. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared with unexposed controls. Post-COVID-19 patients with lingering symptoms (long-haulers) also showed upregulated caspase-1activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. We observed elevated caspase-3/7levels in red blood cells from COVID-19 patients compared with controls that was reduced following caspase inhibition. DISCUSSION: Our preliminary results suggest an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Further clinical correlations of caspase expression in different stages of COVID-19 will be needed. CONCLUSION: Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19.


Subject(s)
COVID-19 , Caspase Inhibitors , CD4-Positive T-Lymphocytes , COVID-19/complications , COVID-19/drug therapy , Caspase 1 , Caspase 3 , Caspase 7 , Caspase Inhibitors/therapeutic use , Caspases/genetics , Humans
2.
Front Med (Lausanne) ; 7: 585003, 2020.
Article in English | MEDLINE | ID: covidwho-1556373

ABSTRACT

Background: Identifying clinical-features or a scoring-system to predict a benefit from hospital admission for patients with COVID-19 can be of great value for the decision-makers in the health sector. We aimed to identify differences in patients' demographic, clinical, laboratory, and radiological findings of COVID-19 positive cases to develop and validate a diagnostic-model predicting who will develop severe-form and who will need critical-care in the future. Methods: In this observational retrospective study, COVID-19 positive cases (total 417) diagnosed in Al Kuwait Hospital, Dubai, UAE were recruited, and their prognosis in terms of admission to the hospital and the need for intensive care was reviewed until their tests turned negative. Patients were classified according to their clinical state into mild, moderate, severe, and critical. We retrieved all the baseline clinical data, laboratory, and radiological results and used them to identify parameters that can predict admission to the intensive care unit (ICU). Results: Patients with ICU admission showed a distinct clinical, demographic as well as laboratory features when compared to patients who did not need ICU admission. This includes the elder age group, male gender, and presence of comorbidities like diabetes and history of hypertension. ROC and Precision-Recall curves showed that among all variables, D dimers (>1.5 mg/dl), Urea (>6.5 mmol/L), and Troponin (>13.5 ng/ml) could positively predict the admission to ICU in patients with COVID-19. On the other hand, decreased Lymphocyte count and albumin can predict admission to ICU in patients with COVID-19 with acceptable sensitivity (59.32, 95% CI [49.89-68.27]) and specificity (79.31, 95% CI [72.53-85.07]). Conclusion: Using these three predictors with their cut of values can identify patients who are at risk of developing critical COVID-19 and might need aggressive intervention earlier in the course of the disease.

3.
Mucosal Immunol ; 14(5): 1144-1159, 2021 09.
Article in English | MEDLINE | ID: covidwho-1550272

ABSTRACT

Increased IgE is a typical feature of allergic rhinitis. Local class-switch recombination has been intimated but B cell precursors and mechanisms remain elusive. Here we describe the dynamics underlying the generation of IgE-antibody secreting cells (ASC) in human nasal polyps (NP), mucosal tissues rich in ASC without germinal centers (GC). Using VH next generation sequencing, we identified an extrafollicular (EF) mucosal IgD+ naïve-like intermediate B cell population with high connectivity to the mucosal IgE ASC. Mucosal IgD+ B cells, express germline epsilon transcripts and predominantly co-express IgM. However, a small but significant fraction co-express IgG or IgA instead which also show connectivity to ASC IgE. Phenotypically, NP IgD+ B cells display an activated profile and molecular evidence of BCR engagement. Transcriptionally, mucosal IgD+ B cells reveal an intermediate profile between naïve B cells and ASC. Single cell IgE ASC analysis demonstrates lower mutational frequencies relative to IgG, IgA, and IgD ASC consistent with IgE ASC derivation from mucosal IgD+ B cell with low mutational load. In conclusion, we describe a novel mechanism of GC-independent, extrafollicular IgE ASC formation at the nasal mucosa whereby activated IgD+ naïve B cells locally undergo direct and indirect (through IgG and IgA), IgE class switch.


Subject(s)
Antibody Formation/immunology , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , Immunoglobulin D/immunology , Immunoglobulin E/immunology , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Adult , Antibody Formation/genetics , Antibody-Producing Cells/immunology , Antibody-Producing Cells/metabolism , Computational Biology , Gene Expression Profiling , Germinal Center/immunology , High-Throughput Nucleotide Sequencing , Humans , Hypersensitivity/etiology , Hypersensitivity/metabolism , Immunoglobulin Class Switching/genetics , Immunoglobulin Class Switching/immunology , Immunoglobulin Isotypes/genetics , Immunoglobulin Isotypes/immunology , Immunophenotyping , Nasal Polyps/etiology , Nasal Polyps/metabolism , Nasal Polyps/pathology , Pollen/immunology , Seasons , Somatic Hypermutation, Immunoglobulin
4.
J Virol ; 95(15): e0053021, 2021 07 12.
Article in English | MEDLINE | ID: covidwho-1486507

ABSTRACT

Elicitation of lung tissue-resident memory CD8 T cells (TRMs) is a goal of T cell-based vaccines against respiratory viral pathogens, such as influenza A virus (IAV). C-C chemokine receptor type 2 (CCR2)-dependent monocyte trafficking plays an essential role in the establishment of CD8 TRMs in lungs of IAV-infected mice. Here, we used a combination adjuvant-based subunit vaccine strategy that evokes multifaceted (TC1/TC17/TH1/TH17) IAV nucleoprotein-specific lung TRMs to determine whether CCR2 and monocyte infiltration are essential for vaccine-induced TRM development and protective immunity to IAV in lungs. Following intranasal vaccination, neutrophils, monocytes, conventional dendritic cells (DCs), and monocyte-derived dendritic cells internalized and processed vaccine antigen in lungs. We found that basic leucine zipper ATF-like transcription factor 3 (BATF3)-dependent DCs were essential for eliciting T cell responses, but CCR2 deficiency enhanced the differentiation of CD127hi, KLRG-1lo, OX40+ve CD62L+ve, and mucosally imprinted CD69+ve CD103+ve effector and memory CD8 T cells in lungs and airways of vaccinated mice. Mechanistically, increased development of lung TRMs induced by CCR2 deficiency was linked to dampened expression of T-bet but not altered TCF-1 levels or T cell receptor signaling in CD8 T cells. T1/T17 functional programming, parenchymal localization of CD8/CD4 effector and memory T cells, recall T cell responses, and protective immunity to a lethal IAV infection were unaffected in CCR2-deficient mice. Taken together, we identified a negative regulatory role for CCR2 and monocyte trafficking in mucosal imprinting and differentiation of vaccine-induced TRMs. Mechanistic insights from this study may aid the development of T-cell-based vaccines against respiratory viral pathogens, including IAV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). IMPORTANCE While antibody-based immunity to influenza A virus (IAV) is type and subtype specific, lung- and airway-resident memory T cells that recognize conserved epitopes in the internal viral proteins are known to provide heterosubtypic immunity. Hence, broadly protective IAV vaccines need to elicit robust T cell memory in the respiratory tract. We have developed a combination adjuvant-based IAV nucleoprotein vaccine that elicits strong CD4 and CD8 T cell memory in lungs and protects against H1N1 and H5N1 strains of IAV. In this study, we examined the mechanisms that control vaccine-induced protective memory T cells in the respiratory tract. We found that trafficking of monocytes into lungs might limit the development of antiviral lung-resident memory T cells following intranasal vaccination. These findings suggest that strategies that limit monocyte infiltration can potentiate vaccine-induced frontline T-cell immunity to respiratory viruses, such as IAV and SARS-CoV-2.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunity, Mucosal , Immunologic Memory , Influenza A virus/immunology , Influenza Vaccines/immunology , Orthomyxoviridae Infections/immunology , Receptors, CCR2/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , Influenza A virus/genetics , Influenza Vaccines/genetics , Influenza Vaccines/pharmacology , Lung/immunology , Mice , Mice, Knockout , Orthomyxoviridae Infections/genetics , Orthomyxoviridae Infections/prevention & control , Receptors, CCR2/genetics
5.
Viral Immunol ; 34(6): 416-420, 2021.
Article in English | MEDLINE | ID: covidwho-1475758

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has infected millions of individuals in the world. However, the long-term effect of SARS-CoV-2 on the organs of recovered patients remains unclear. This study is to evaluate the impact of SARS-CoV-2 on the spleen and T lymphocytes. Seventy-six patients recovered from COVID-19, including 66 cases of moderate pneumonia and 10 cases of severe pneumonia were enrolled in the observation group. The control group consisted of 55 age-matched healthy subjects. The thickness and length of spleen were measured by using B-ultrasound and the levels of T lymphocytes were detected by flow cytometry. Results showed that the mean length of spleen in the observation group was 89.57 ± 11.49 mm, which was significantly reduced compared with that in the control group (103.82 ± 11.29 mm, p < 0.001). The mean thicknesses of spleen between observation group and control group were 29.97 ± 4.04 mm and 32.45 ± 4.49 mm, respectively, and the difference was significant (p < 0.001). However, no significant difference was observed in the size of spleen between common pneumonia and severe pneumonia (p > 0.05). In addition, the decreased count of T lymphocyte was observed in part of recovered patients. The counts of T suppressor lymphocytes in patients with severe pneumonia were significantly decreased compared with those with moderate pneumonia (p = 0.005). Therefore, these data indicate that SARS-CoV-2 infection affects the size of spleen and T lymphocytes.


Subject(s)
COVID-19/immunology , SARS-CoV-2 , Spleen/pathology , T-Lymphocytes/immunology , Adult , Aged , Female , Humans , Lymphocyte Count , Male , Middle Aged , Young Adult
6.
AJR Am J Roentgenol ; 214(6): 1287-1294, 2020 06.
Article in English | MEDLINE | ID: covidwho-1408325

ABSTRACT

OBJECTIVE. The purpose of this study was to investigate 62 subjects in Wuhan, China, with laboratory-confirmed coronavirus disease (COVID-19) pneumonia and describe the CT features of this epidemic disease. MATERIALS AND METHODS. A retrospective study of 62 consecutive patients with laboratory-confirmed COVID-19 pneumonia was performed. CT images and clinical data were reviewed. Two thoracic radiologists evaluated the distribution and CT signs of the lesions and also scored the extent of involvement of the CT signs. The Mann-Whitney U test was used to compare lesion distribution and CT scores. The chi-square test was used to compare the CT signs of early-phase versus advanced-phase COVID-19 pneumonia. RESULTS. A total of 62 patients (39 men and 23 women; mean [± SD] age, 52.8 ± 12.2 years; range, 30-77 years) with COVID-19 pneumonia were evaluated. Twenty-four of 30 patients who underwent routine blood tests (80.0%) had a decreased lymphocyte count. Of 27 patients who had their erythrocyte sedimentation rate and high-sensitivity C-reactive protein level assessed, 18 (66.7%) had an increased erythrocyte sedimentation rate, and all 27 (100.0%) had an elevated high-sensitivity C-reactive protein level. Multiple lesions were seen on the initial CT scan of 52 of 62 patients (83.9%). Forty-eight of 62 patients (77.4%) had predominantly peripheral distribution of lesions. The mean CT score for the upper zone (3.0 ± 3.4) was significantly lower than that for the middle (4.5 ± 3.8) and lower (4.5 ± 3.7) zones (p = 0.022 and p = 0.020, respectively), and there was no significant difference in the mean CT score of the middle and lower zones (p = 1.00). The mean CT score for the anterior area (4.4 ± 4.1) was significantly lower than that for the posterior area (7.7 ± 6.3) (p = 0.003). CT findings for the patients were as follows: 25 patients (40.3%) had ground-glass opacities (GGO), 21 (33.9%), consolidation; 39 (62.9%), GGO plus a reticular pattern; 34 (54.8%), vacuolar sign; 28 (45.2%), microvascular dilation sign; 35 (56.5%), fibrotic streaks; 21 (33.9%), a subpleural line; and 33 (53.2%), a subpleural transparent line. With regard to bronchial changes seen on CT, 45 patients (72.6%) had air bronchogram, and 11 (17.7%) had bronchus distortion. In terms of pleural changes, CT showed that 30 patients (48.4%) had pleural thickening, 35 (56.5%) had pleural retraction sign, and six (9.7%) had pleural effusion. Compared with early-phase disease (≤ 7 days after the onset of symptoms), advanced-phase disease (8-14 days after the onset of symptoms) was characterized by significantly increased frequencies of GGO plus a reticular pattern, vacuolar sign, fibrotic streaks, a subpleural line, a subpleural transparent line, air bronchogram, bronchus distortion, and pleural effusion; however, GGO significantly decreased in advanced-phase disease. CONCLUSION. CT examination of patients with COVID-19 pneumonia showed a mixed and diverse pattern with both lung parenchyma and the interstitium involved. Identification of GGO and a single lesion on the initial CT scan suggested early-phase disease. CT signs of aggravation and repair coexisted in advanced-phase disease. Lesions presented with a characteristic multifocal distribution in the middle and lower lung regions and in the posterior lung area. A decreased lymphocyte count and an increased high-sensitivity C-reactive protein level were the most common laboratory findings.


Subject(s)
Coronavirus Infections/diagnostic imaging , Pneumonia, Viral/diagnostic imaging , Tomography, X-Ray Computed , Adult , Aged , COVID-19 , China , Female , Humans , Male , Middle Aged , Pandemics , Retrospective Studies
7.
Front Immunol ; 12: 631821, 2021.
Article in English | MEDLINE | ID: covidwho-1344260

ABSTRACT

Neutrophils or polymorphonuclear leukocytes (PMN) are key participants in the innate immune response for their ability to execute different effector functions. These cells express a vast array of membrane receptors that allow them to recognize and eliminate infectious agents effectively and respond appropriately to microenvironmental stimuli that regulate neutrophil functions, such as activation, migration, generation of reactive oxygen species, formation of neutrophil extracellular traps, and mediator secretion, among others. Currently, it has been realized that activated neutrophils can accomplish their effector functions and simultaneously activate mechanisms of cell death in response to different intracellular or extracellular factors. Although several studies have revealed similarities between the mechanisms of cell death of neutrophils and other cell types, neutrophils have distinctive properties, such as a high production of reactive oxygen species (ROS) and nitrogen species (RNS), that are important for their effector function in infections and pathologies such as cancer, autoimmune diseases, and immunodeficiencies, influencing their cell death mechanisms. The present work offers a synthesis of the conditions and molecules implicated in the regulation and activation of the processes of neutrophil death: apoptosis, autophagy, pyroptosis, necroptosis, NETosis, and necrosis. This information allows to understand the duality encountered by PMNs upon activation. The effector functions are carried out to eliminate invading pathogens, but in several instances, these functions involve activation of signaling cascades that culminate in the death of the neutrophil. This process guarantees the correct elimination of pathogenic agents, damaged or senescent cells, and the timely resolution of the inflammation that is essential for the maintenance of homeostasis in the organism. In addition, they alert the organism when the immunological system is being deregulated, promoting the activation of other cells of the immune system, such as B and T lymphocytes, which produce cytokines that potentiate the microbicide functions.


Subject(s)
Cell Death/immunology , Neutrophils/pathology , Apoptosis/immunology , Apoptosis Regulatory Proteins/metabolism , Autophagy/immunology , Extracellular Traps/immunology , Extracellular Traps/metabolism , Free Radicals/metabolism , Humans , Necroptosis/immunology , Necrosis/immunology , Necrosis/metabolism , Neutrophil Activation , Neutrophils/immunology , Neutrophils/metabolism , Phagocytosis/immunology , Pyroptosis/immunology , Receptors, Death Domain/metabolism
8.
Commun Biol ; 4(1): 631, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1283664

ABSTRACT

IL22 is an important cytokine involved in the intestinal defense mechanisms against microbiome. By using ileum-derived organoids, we show that the expression of anti-microbial peptides (AMPs) and anti-viral peptides (AVPs) can be induced by IL22. In addition, we identified a bacterial and a viral route, both leading to IL22 production by T cells, but via different pathways. Bacterial products, such as LPS, induce enterocyte-secreted SAA1, which triggers the secretion of IL6 in fibroblasts, and subsequently IL22 in T cells. This IL22 induction can then be enhanced by macrophage-derived TNFα in two ways: by enhancing the responsiveness of T cells to IL6 and by increasing the expression of IL6 by fibroblasts. Viral infections of intestinal cells induce IFNß1 and subsequently IL7. IFNß1 can induce the expression of IL6 in fibroblasts and the combined activity of IL6 and IL7 can then induce IL22 expression in T cells. We also show that IL22 reduces the expression of viral entry receptors (e.g. ACE2, TMPRSS2, DPP4, CD46 and TNFRSF14), increases the expression of anti-viral proteins (e.g. RSAD2, AOS, ISG20 and Mx1) and, consequently, reduces the viral infection of neighboring cells. Overall, our data indicates that IL22 contributes to the innate responses against both bacteria and viruses.


Subject(s)
Interleukins/biosynthesis , Interleukins/metabolism , Animals , Anti-Bacterial Agents/metabolism , Antiviral Agents/metabolism , Cell Culture Techniques , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Enterocytes/immunology , Enterocytes/metabolism , Female , Fibroblasts/immunology , Fibroblasts/metabolism , Interleukins/immunology , Intestinal Mucosa/metabolism , Intestines/physiology , Mice , Mice, Inbred C57BL , Myeloid Cells/immunology , Myeloid Cells/metabolism , Organoids/metabolism , Pore Forming Cytotoxic Proteins/genetics , Pore Forming Cytotoxic Proteins/metabolism
9.
Sci Immunol ; 6(60)2021 06 18.
Article in English | MEDLINE | ID: covidwho-1276879

ABSTRACT

The nutrient-sensing mammalian target of rapamycin (mTOR) is integral to cell fate decisions after T cell activation. Sustained mTORC1 activity favors the generation of terminally differentiated effector T cells instead of follicular helper and memory T cells. This is particularly pertinent for T cell responses of older adults who have sustained mTORC1 activation despite dysfunctional lysosomes. Here, we show that lysosome-deficient T cells rely on late endosomes rather than lysosomes as an mTORC1 activation platform, where mTORC1 is activated by sensing cytosolic amino acids. T cells from older adults have an increased expression of the plasma membrane leucine transporter SLC7A5 to provide a cytosolic amino acid source. Hence, SLC7A5 and VPS39 deficiency (a member of the HOPS complex promoting early to late endosome conversion) substantially reduced mTORC1 activities in T cells from older but not young individuals. Late endosomal mTORC1 is independent of the negative-feedback loop involving mTORC1-induced inactivation of the transcription factor TFEB that controls expression of lysosomal genes. The resulting sustained mTORC1 activation impaired lysosome function and prevented lysosomal degradation of PD-1 in CD4+ T cells from older adults, thereby inhibiting their proliferative responses. VPS39 silencing of human T cells improved their expansion to pertussis and to SARS-CoV-2 peptides in vitro. Furthermore, adoptive transfer of CD4+ Vps39-deficient LCMV-specific SMARTA cells improved germinal center responses, CD8+ memory T cell generation, and recall responses to infection. Thus, curtailing late endosomal mTORC1 activity is a promising strategy to enhance T cell immunity.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Endosomes/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , SARS-CoV-2/metabolism , Signal Transduction/genetics , Adoptive Transfer/methods , Adult , Aged , Aged, 80 and over , Animals , Autophagy-Related Proteins/deficiency , Autophagy-Related Proteins/genetics , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , COVID-19/virology , Cells, Cultured , Female , Forkhead Box Protein O1/deficiency , Forkhead Box Protein O1/genetics , Healthy Volunteers , Humans , Large Neutral Amino Acid-Transporter 1/metabolism , Lysosomes/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Signal Transduction/immunology , Transfection , Vesicular Transport Proteins/deficiency , Vesicular Transport Proteins/genetics , Young Adult
10.
Brain Pathol ; 31(5): e12997, 2021 09.
Article in English | MEDLINE | ID: covidwho-1273078

ABSTRACT

The actual role of SARS-CoV-2 in brain damage remains controversial due to lack of matched controls. We aim to highlight to what extent is neuropathology determined by SARS-CoV-2 or by pre-existing conditions. Findings of 9 Coronavirus disease 2019 (COVID-19) cases and 6 matched non-COVID controls (mean age 79 y/o) were compared. Brains were analyzed through immunohistochemistry to detect SARS-CoV-2, lymphocytes, astrocytes, endothelium, and microglia. A semi-quantitative scoring was applied to grade microglial activation. Thal-Braak stages and the presence of small vessel disease were determined in all cases. COVID-19 cases had a relatively short clinical course (0-32 days; mean: 10 days), and did not undergo mechanical ventilation. Five patients with neurocognitive disorder had delirium. All COVID-19 cases showed non-SARS-CoV-2-specific changes including hypoxic-agonal alterations, and a variable degree of neurodegeneration and/or pre-existent SVD. The neuroinflammatory picture was dominated by ameboid CD68 positive microglia, while only scant lymphocytic presence and very few traces of SARS-CoV-2 were detected. Microglial activation in the brainstem was significantly greater in COVID-19 cases (p = 0.046). Instead, microglial hyperactivation in the frontal cortex and hippocampus was clearly associated to AD pathology (p = 0.001), regardless of the SARS-CoV-2 infection. In COVID-19 cases complicated by delirium (all with neurocognitive disorders), there was a significant enhancement of microglia in the hippocampus (p = 0.048). Although higher in cases with both Alzheimer's pathology and COVID-19, cortical neuroinflammation is not related to COVID-19 per se but mostly to pre-existing neurodegeneration. COVID-19 brains seem to manifest a boosting of innate immunity with microglial reinforcement, and adaptive immunity suppression with low number of brain lymphocytes probably related to systemic lymphopenia. Thus, no neuropathological evidence of SARS-CoV-2-specific encephalitis is detectable. The microglial hyperactivation in the brainstem, and in the hippocampus of COVID-19 patients with delirium, appears as a specific topographical phenomenon, and probably represents the neuropathological basis of the "COVID-19 encephalopathic syndrome" in the elderly.


Subject(s)
COVID-19/pathology , Dementia/virology , Microglia/pathology , Nervous System Diseases/virology , Aged , Aged, 80 and over , Astrocytes/pathology , Brain/pathology , COVID-19/psychology , Case-Control Studies , Dementia/pathology , Dementia/psychology , Female , Humans , Male , Nervous System Diseases/pathology , Nervous System Diseases/psychology , SARS-CoV-2/isolation & purification
11.
Acta Virol ; 65(2): 107-114, 2021.
Article in English | MEDLINE | ID: covidwho-1271016

ABSTRACT

Coronavirus disease 2019 (COVID-19) has turned out as one of the worst medical and economic misfortunes across the globe. The etiological agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the Coronaviridae family and represents a disease manifestation from asymptomatic to severe respiratory damage. High transmissibility and contagious nature of the virus helps it to flourish in a large population. The immune system aids to retain the virus, but with accelerated cytokine secretion, it could transform into double edge sword resulting in unrestrained systemic inflammation which might become life-threatening. SARS-CoV-2 sets substantial impact on T-lymphocytes during its course of infection. The number of CD4+ T, CD8+ T, and Treg cells tend to decrease profoundly in case of severe illness. Besides, the virus modulates the CD4+ T/ CD8+ T and Treg/Th17 cells ratio and induces the functional exhaustion of T cells to make them inefficient. T cells define the pathogenesis of severe cases and provide major contributions in antiviral defense. Therefore, the apprehension of T-lymphocytes in SARS-CoV-2 infection would implicate in developing antivirals, disease control, and would broaden the way for vaccine formulation. Thus, the review depicts the significance of T-lymphocytes interaction with SARS-CoV-2. Keywords: SARS-CoV-2; COVID-19; T-lymphocytes; cytokine; inflammation; immune response.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/therapeutic use , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Cytokines/genetics , Humans , T-Lymphocytes
12.
J Biomed Sci ; 28(1): 43, 2021 Jun 07.
Article in English | MEDLINE | ID: covidwho-1261273

ABSTRACT

BACKGROUND: Coronavirus disease 19 (COVID-19) first appeared in the city of Wuhan, in the Hubei province of China. Since its emergence, the COVID-19-causing virus, SARS-CoV-2, has been rapidly transmitted around the globe, overwhelming the medical care systems in many countries and leading to more than 3.3 million deaths. Identification of immunological epitopes on the virus would be highly useful for the development of diagnostic tools and vaccines that will be critical to limiting further spread of COVID-19. METHODS: To find disease-specific B-cell epitopes that correspond to or mimic natural epitopes, we used phage display technology to determine the targets of specific antibodies present in the sera of immune-responsive COVID-19 patients. Enzyme-linked immunosorbent assays were further applied to assess competitive antibody binding and serological detection. VaxiJen, BepiPred-2.0 and DiscoTope 2.0 were utilized for B-cell epitope prediction. PyMOL was used for protein structural analysis. RESULTS: 36 enriched peptides were identified by biopanning with antibodies from two COVID-19 patients; the peptides 4 motifs with consensus residues corresponding to two potential B-cell epitopes on SARS-CoV-2 viral proteins. The putative epitopes and hit peptides were then synthesized for validation by competitive antibody binding and serological detection. CONCLUSIONS: The identified B-cell epitopes on SARS-CoV-2 may aid investigations into COVID-19 pathogenesis and facilitate the development of epitope-based serological diagnostics and vaccines.


Subject(s)
COVID-19 , Epitopes, B-Lymphocyte , Peptide Library , SARS-CoV-2 , Viral Proteins , COVID-19/genetics , COVID-19/immunology , Epitopes, B-Lymphocyte/genetics , Epitopes, B-Lymphocyte/immunology , Humans , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Viral Proteins/genetics , Viral Proteins/immunology
13.
J Immunol ; 206(12): 2900-2908, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1248084

ABSTRACT

The relatively low partial pressure of oxygen, reduced oxygen saturation, and aberrant plasma metabolites in COVID-19 may alter energy metabolism in peripheral immune cells. However, little is known regarding the immunometabolic defects of T cells in COVID-19 patients, which may contribute to the deregulated immune functions of these cells. In this study, we longitudinally characterized the metabolic profiles of resting and activated T cells from acutely infected and convalescent COVID-19 patients by flow cytometry and confirmed the metabolic profiles with a Seahorse analyzer. Non-COVID-19 and healthy subjects were enrolled as controls. We found that ex vivo T cells from acutely infected COVID-19 patients were highly activated and apoptotic and displayed more extensive mitochondrial metabolic dysfunction, especially cells in CD8+ T cell lineages, than those from convalescent COVID-19 patients or healthy controls, but slightly disturbed mitochondrial metabolic activity was observed in non-COVID-19 patients. Importantly, plasma IL-6 and C-reactive protein (CRP) levels positively correlated with mitochondrial mass and negatively correlated with fatty acid uptake in T cells from COVID-19 patients. Additionally, compared with those from healthy controls, in vitro-activated T cells from acutely infected COVID-19 patients showed signs of lower glycolysis, a reduced glycolytic capacity, and a decreased glycolytic reserve, accompanied by lower activation of mTOR signaling. Thus, newly identified defects in T cell mitochondrial metabolic functions and metabolic reprogramming upon activation might contribute to immune deficiency in COVID-19.


Subject(s)
COVID-19 , CD8-Positive T-Lymphocytes , Glycolysis , Humans , SARS-CoV-2
14.
Biomed Hub ; 6(1): 48-58, 2021.
Article in English | MEDLINE | ID: covidwho-1247449

ABSTRACT

We report the disparate clinical progression of a couple infected by SARS-CoV-2 based on their immune checkpoint (IC) levels and immune cell distribution in blood from admission to exitus in patient 1 and from admission to discharge and recovery in patient 2. A detailed clinical follow-up accompanied by a longitudinal analysis of immune phenotypes and IC levels is shown. The continuous increase in the soluble IC ligand galectin-9 (Gal-9) and the increment in T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) protein in T cells in patient 1 suggests an activation of the Gal-9/TIM-3 axis and, subsequently, a potential cell exhaustion in this patient that did not occur in patient 2. Our data indicate that the Gal-9/TIM-3 axis could be a potential target in this clinical setting, along with a patent effector memory T-cell reduction.

15.
Aging Cell ; 20(6): e13372, 2021 06.
Article in English | MEDLINE | ID: covidwho-1247110

ABSTRACT

Severe respiratory viral infectious diseases such as influenza and COVID-19 especially affect the older population. This is partly ascribed to diminished CD8+ T-cell responses a result of aging. The phenotypical diversity of the CD8+ T-cell population has made it difficult to identify the impact of aging on CD8+ T-cell subsets associated with diminished CD8+ T-cell responses. Here we identify a novel human CD8+ T-cell subset characterized by expression of Killer-cell Immunoglobulin-like Receptors (KIR+ ) and CD45RA (RA+ ). These KIR+ RA+ T cells accumulated with age in the blood of healthy individuals (20-82 years of age, n = 50), expressed high levels of aging-related markers of T-cell regulation, and were functionally capable of suppressing proliferation of other CD8+ T cells. Moreover, KIR+ RA+ T cells were a major T-cell subset becoming activated in older adults suffering from an acute respiratory viral infection (n = 36), including coronavirus and influenza virus infection. In addition, older adults with influenza A infection showed that higher activation status of their KIR+ RA+ T cells associated with longer duration of respiratory symptoms. Together, our data indicate that KIR+ RA+ T cells are a unique human T-cell subset with regulatory properties that may explain susceptibility to viral respiratory disease at old age.


Subject(s)
Aging/physiology , CD8-Positive T-Lymphocytes/virology , T-Lymphocyte Subsets/virology , Aged , Aged, 80 and over , COVID-19/immunology , Female , Gene Expression Regulation , Humans , Influenza, Human/immunology , Male , Middle Aged , Receptors, KIR/blood , Receptors, KIR/metabolism , SARS-CoV-2
16.
Immunopharmacol Immunotoxicol ; 43(3): 265-270, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1246577

ABSTRACT

Understanding the exact role of current drugs in Covid-19 disease is essential in the era of global pandemics. Metformin which prescribed as the first-line treatment of type 2 diabetes has beneficial effects on Sars-cov2 infection. These effects are including regulation of immune system, Renin-Angiotensin System and Dipeptidyl Peptidase 4 function in Covid-19 infection. It also activates ACE2, the main receptor of Sars-cov2, in the epithelial cells of respiratory tissue through AMPK signaling and subsequently decreases the rate of viral adhesion. Metformin also declines the adherence of Sars-cov2 to DPP4 (the other receptor of the virus) on T cells. Hence, regulatory effects of metformin on membranous ACE2, and DPP4 can modulate immune reaction against Sars-cov2. Also, immunometabolic effects of metformin on inflammatory cells impair hyper-reactive immune response against the virus through reduction of glycolysis and propagation of mitochondrial oxidation. Metformin also decreases platelet aggravation and risk of thrombosis. In this article, we argue that metformin has beneficial effects on Covid-19 infection in patients with type 2 diabetes and insulin resistance. This opinion should be investigated in future clinical trials.


Subject(s)
COVID-19/drug therapy , Diabetes Mellitus, Type 2 , Drug Repositioning , Insulin Resistance , Metformin/therapeutic use , SARS-CoV-2 , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Humans
17.
J Cell Biochem ; 2021 May 16.
Article in English | MEDLINE | ID: covidwho-1227742

ABSTRACT

CD137 (ILA/4-1BB), a member of tumor necrosis factor receptor superfamily, is one of the most important T cell costimulatory molecules. Interaction of this molecule with its ligand transmits a two-way signal that activates both T lymphocyte and antigen presenting cells. The soluble form of CD137 (sCD137) reduces the activity of its membrane isoform and is associated with T lymphocyte activation-induced cell death. Recombinant CD137-Fc may be used to treat cancers, autoimmune disorders and viral infections. It may also be useful for management of coronavirus infection. The 1276 bp DNA sequence encoded CD137-Fc recombinant protein was prepared and subcloned into lentiviral vector and expressed in transduced CHO-K1 eukaryotic cells. The sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western blot analysis, and enzyme-linked immunosorbent assay analysis results demonstrated that the expression of the 70-kDa CD137-Fc molecule was detectable without any degradation. This study helps to confirm previous research suggesting the use of this recombinant protein as a promising solution for the treatment of virus infections. CD137-Fc fusion protein could also make immunotherapy more effective for some diseases. This product is widely used in novel medical treatments, including cell-based immunotherapy such as dendritic cell, CAR T and CAR NK therapy. Its production and usage in research and treatment is noticeable also in current coronavirus disease 2019 pandemic.

18.
J Immunol ; 206(11): 2527-2535, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1227097

ABSTRACT

The T cell response is an important detection index in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine development. The present study was undertaken to determine the T cell epitopes in the spike (S) protein of SARS-CoV-2 that dominate the T cell responses in SARS-CoV-2-infected patients. PBMCs from rhesus macaques vaccinated with a DNA vaccine encoding the full-length S protein were isolated, and an ELISPOT assay was used to identify the recognized T cell epitopes among a total of 158 18-mer and 10-aa-overlapping peptides spanning the full-length S protein. Six multipeptide-based epitopes located in the S1 region, with four of the six located in the receptor-binding domain, were defined as the most frequently recognized epitopes in macaques. The conservation of the epitopes across species was also verified, and peptide mixtures for T cell response detection were established. Six newly defined T cell epitopes were found in the current study, which may provide a novel potential target for T cell response detection and the diagnosis and vaccine design of SARS-CoV-2 based on multipeptide subunit-based epitopes.


Subject(s)
Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Macaca mulatta
19.
Sci Adv ; 7(19)2021 05.
Article in English | MEDLINE | ID: covidwho-1226702

ABSTRACT

The endoplasmic reticulum (ER) is a central eukaryotic organelle with a tubular network made of hairpin proteins linked by hydrolysis of guanosine triphosphate nucleotides. Among posttranslational modifications initiated at the ER level, glycosylation is the most common reaction. However, our understanding of the impact of glycosylation on the ER structure remains unclear. Here, we show that exostosin-1 (EXT1) glycosyltransferase, an enzyme involved in N-glycosylation, is a key regulator of ER morphology and dynamics. We have integrated multiomics and superresolution imaging to characterize the broad effect of EXT1 inactivation, including the ER shape-dynamics-function relationships in mammalian cells. We have observed that inactivating EXT1 induces cell enlargement and enhances metabolic switches such as protein secretion. In particular, suppressing EXT1 in mouse thymocytes causes developmental dysfunctions associated with the ER network extension. Last, our data illuminate the physical and functional aspects of the ER proteome-glycome-lipidome structure axis, with implications in biotechnology and medicine.


Subject(s)
Endoplasmic Reticulum Stress , Endoplasmic Reticulum , Animals , Endoplasmic Reticulum/metabolism , Glycosylation , Mammals , Mice , Protein Processing, Post-Translational , Protein Transport
20.
Prim Care Diabetes ; 15(4): 713-718, 2021 08.
Article in English | MEDLINE | ID: covidwho-1225362

ABSTRACT

AIM: This study aimed at providing evidence to consider sex differences in interpretations of laboratory parameters of severe COVID-19 patients with diabetes. METHODS: For 118 diabetic patients, laboratory measurements and clinical outcomes were compared between males and females. This study also compared inflammatory ratios obtained from combinations of six inflammatory markers between the two groups. The risk factors for mortality were identified through logistic regression. RESULTS: Males were 54 (45.8%) and females were 64 (54.2%). Males showed a significant increase in ALT (P = 0.003), CRP (P = 0.03), mean platelet volume (MPV)-to-lymphocyte ratio (P = 0.001), and C-reactive protein-to-albumin ratio (P = 0.044), whereas females had a significant increase in lymphocytes (P < 0.005) and MPV (P = 0.01). In all participants, multivariate analysis illustrated that older age, male sex, increased serum total bilirubin, and decreased PO2 were significant independent predictors of mortality (P < 0.05). CONCLUSION: In severe COVID-19 patients with diabetes, there were significant sex differences in many laboratory characteristics with a higher risk of mortality among males.


Subject(s)
Biomarkers/blood , COVID-19/diagnosis , Diabetes Mellitus/diagnosis , Health Status Disparities , Age Factors , Aged , Alanine Transaminase/blood , Bilirubin/blood , C-Reactive Protein/analysis , COVID-19/blood , COVID-19/mortality , Diabetes Mellitus/blood , Diabetes Mellitus/mortality , Female , Humans , Lymphocyte Count , Lymphocytes/metabolism , Male , Mean Platelet Volume , Middle Aged , Predictive Value of Tests , Prognosis , Retrospective Studies , Risk Assessment , Risk Factors , Severity of Illness Index , Sex Factors
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