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1.
Nat Commun ; 12(1): 5376, 2021 09 10.
Article in English | MEDLINE | ID: covidwho-1402068

ABSTRACT

Natural killer (NK) cells are important early responders against viral infections. Changes in metabolism are crucial to fuel NK cell responses, and altered metabolism is linked to NK cell dysfunction in obesity and cancer. However, very little is known about the metabolic requirements of NK cells during acute retroviral infection and their importance for antiviral immunity. Here, using the Friend retrovirus mouse model, we show that following infection NK cells increase nutrient uptake, including amino acids and iron, and reprogram their metabolic machinery by increasing glycolysis and mitochondrial metabolism. Specific deletion of the amino acid transporter Slc7a5 has only discrete effects on NK cells, but iron deficiency profoundly impaires NK cell antiviral functions, leading to increased viral loads. Our study thus shows the requirement of nutrients and metabolism for the antiviral activity of NK cells, and has important implications for viral infections associated with altered iron levels such as HIV and SARS-CoV-2.


Subject(s)
Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Retroviridae Infections/immunology , Animals , Bone Marrow , COVID-19 , Cytokines , HIV , HIV Infections , Large Neutral Amino Acid-Transporter 1/genetics , Large Neutral Amino Acid-Transporter 1/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondria , Retroviridae , Retroviridae Infections/virology , SARS-CoV-2 , Viral Load
2.
Nat Commun ; 12(1): 4854, 2021 08 11.
Article in English | MEDLINE | ID: covidwho-1354099

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56dimCD57+ natural killer (NK) cells and exhausted CD8+ T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8+ T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Systemic Inflammatory Response Syndrome/immunology , Transcriptome/immunology , Adolescent , CD56 Antigen/metabolism , CD57 Antigens/metabolism , CD8-Positive T-Lymphocytes/metabolism , COVID-19/genetics , Child , Child, Preschool , Down-Regulation , Female , Humans , Infant , Infant, Newborn , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Male , Mucocutaneous Lymph Node Syndrome/genetics , Mucocutaneous Lymph Node Syndrome/immunology , SARS-CoV-2/pathogenicity , Systemic Inflammatory Response Syndrome/genetics , Young Adult
3.
PLoS One ; 16(8): e0255608, 2021.
Article in English | MEDLINE | ID: covidwho-1344157

ABSTRACT

BACKGROUND: The diversity in the clinical course of COVID-19 has been related to differences in innate and adaptative immune response mechanisms. Natural killer (NK) lymphocytes are critical protagonists of human host defense against viral infections. It would seem that reduced circulating levels of these cells have an impact on COVID-19 progression and severity. Their activity is strongly regulated by killer-cell immuno-globulin-like receptors (KIRs) expressed on the NK cell surface. The present study's focus was to investigate the impact of KIRs and their HLA Class I ligands on SARS-CoV-2 infection. METHODS: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 396 Sardinian patients with SARS-CoV-2 infection. Comparisons were made between 2 groups of patients divided according to disease severity: 240 patients were symptomatic or paucisymptomatic (Group A), 156 hospitalized patients had severe disease (Group S). The immunogenetic characteristics of patients were also compared to a population group of 400 individuals from the same geographical areas. RESULTS: Substantial differences were obtained for KIR genes, KIR haplotypes and KIR-HLA ligand combinations when comparing patients of Group S to those of Group A. Patients in Group S had a statistically significant higher frequency of the KIR A/A haplotype compared to patients in Group A [34.6% vs 23.8%, OR = 1.7 (95% CI 1.1-2.6); P = 0.02, Pc = 0.04]. Moreover, the KIR2DS2/HLA C1 combination was poorly represented in the group of patients with severe symptoms compared to those of the asymptomatic-paucisymptomatic group [33.3% vs 50.0%, OR = 0.5 (95% CI 0.3-0.8), P = 0.001, Pc = 0.002]. Multivariate analysis confirmed that, regardless of the sex and age of the patients, the latter genetic variable correlated with a less severe disease course [ORM = 0.4 (95% CI 0.3-0.7), PM = 0.0005, PMC = 0.005]. CONCLUSIONS: The KIR2DS2/HLA C1 functional unit resulted to have a strong protective effect against the adverse outcomes of COVID-19. Combined to other well known factors such as advanced age, male sex and concomitant autoimmune diseases, this marker could prove to be highly informative of the disease course and thus enable the timely intervention needed to reduce the mortality associated with the severe forms of SARS-CoV-2 infection. However, larger studies in other populations as well as experimental functional studies will be needed to confirm our findings and further pursue the effect of KIR receptors on NK cell immune-mediated response to SARS-Cov-2 infection.


Subject(s)
COVID-19/immunology , Killer Cells, Natural/immunology , Receptors, KIR/immunology , Adult , Aged , COVID-19/metabolism , Case-Control Studies , Female , Gene Frequency/genetics , Genes, MHC Class I/immunology , Genetic Predisposition to Disease , HLA-C Antigens/genetics , Haplotypes/genetics , Humans , Immunity/immunology , Immunogenetics/methods , Killer Cells, Natural/metabolism , Ligands , Male , Middle Aged , Receptors, KIR/genetics , Receptors, KIR/metabolism , SARS-CoV-2/pathogenicity , Severity of Illness Index
4.
J Infect Dis ; 224(2): 229-240, 2021 07 15.
Article in English | MEDLINE | ID: covidwho-1310926

ABSTRACT

BACKGROUND: Etiopathogenesis of the clinical variability of the coronavirus disease 2019 (COVID-19) remains mostly unknown. In this study, we investigate the role of killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen class-I (HLA-I) interactions in the susceptibility and severity of COVID-19. METHODS: We performed KIR and HLA-I genotyping and natural killer cell (NKc) receptors immunophenotyping in 201 symptomatic patients and 210 noninfected controls. RESULTS: The NKcs with a distinctive immunophenotype, suggestive of recent activation (KIR2DS4low CD16low CD226low CD56high TIGIThigh NKG2Ahigh), expanded in patients with severe COVID-19. This was associated with a higher frequency of the functional A-telomeric activating KIR2DS4 in severe versus mild and/or moderate patients and controls (83.7%, 55.7% and 36.2%, P < 7.7 × 10-9). In patients with mild and/or moderate infection, HLA-B*15:01 was associated with higher frequencies of activating B-telomeric KIR3DS1 compared with patients with other HLA-B*15 subtypes and noninfected controls (90.9%, 42.9%, and 47.3%; P < .002; Pc = 0.022). This strongly suggests that HLA-B*15:01 specifically presenting severe acute respiratory syndrome coronavirus 2 peptides could form a neoligand interacting with KIR3DS1. Likewise, a putative neoligand for KIR2DS4 could arise from other HLA-I molecules presenting severe acute respiratory syndrome coronavirus 2 peptides expressed on infected an/or activated lung antigen-presenting cells. CONCLUSIONS: Our results support a crucial role of NKcs in the clinical variability of COVID-19 with specific KIR/ligand interactions associated with disease severity.


Subject(s)
COVID-19/genetics , Genetic Predisposition to Disease/genetics , Receptors, KIR/genetics , Aged , COVID-19/immunology , COVID-19/pathology , Cross-Sectional Studies , Female , Genotype , HLA Antigens/genetics , HLA Antigens/metabolism , Humans , Immunophenotyping , Killer Cells, Natural/metabolism , Male , Middle Aged , Prospective Studies , Receptors, KIR/metabolism , SARS-CoV-2 , Severity of Illness Index
5.
Int J Mol Sci ; 22(13)2021 Jun 29.
Article in English | MEDLINE | ID: covidwho-1288903

ABSTRACT

The vulnerability of humankind to SARS-CoV-2 in the absence of a pre-existing immunity, the unpredictability of the infection outcome, and the high transmissibility, broad tissue tropism, and ability to exploit and subvert the immune response pose a major challenge and are likely perpetuating the COVID-19 pandemic. Nevertheless, this peculiar infectious scenario provides researchers with a unique opportunity for studying, with the latest immunological techniques and understandings, the immune response in SARS-CoV-2 naïve versus recovered subjects as well as in SARS-CoV-2 vaccinees. Interestingly, the current understanding of COVID-19 indicates that the combined action of innate immune cells, cytokines, and chemokines fine-tunes the outcome of SARS-CoV-2 infection and the related immunopathogenesis. Indeed, the emerging picture clearly shows that the excessive inflammatory response against this virus is among the main causes of disease severity in COVID-19 patients. In this review, the innate immune response to SARS-CoV-2 infection is described not only in light of its capacity to influence the adaptive immune response towards a protective phenotype but also with the intent to point out the multiple strategies exploited by SARS-CoV-2 to antagonize host antiviral response and, finally, to outline inborn errors predisposing individuals to COVID-19 disease severity.


Subject(s)
COVID-19/pathology , Immunity, Innate , COVID-19/immunology , COVID-19/virology , Chemokines/metabolism , Cytokines/metabolism , Host-Pathogen Interactions , Humans , Killer Cells, Natural/cytology , Killer Cells, Natural/metabolism , Monocytes/cytology , Monocytes/metabolism , SARS-CoV-2/isolation & purification , Severity of Illness Index
6.
Nat Commun ; 12(1): 3501, 2021 06 09.
Article in English | MEDLINE | ID: covidwho-1263489

ABSTRACT

The characteristics of COVID-19 patients with persistent SARS-CoV-2 infection are not yet well described. Here, we compare the clinical and molecular features of patients with long duration of viral shedding (LDs) with those from patients with short duration patients (SDs), and healthy donors (HDs). We find that several cytokines and chemokines, such as interleukin (IL)-2, tumor necrosis factor (TNF) and lymphotoxin α (LT-α) are present at lower levels in LDs than SDs. Single-cell RNA sequencing shows that natural killer (NK) cells and CD14+ monocytes are reduced, while regulatory T cells are increased in LDs; moreover, T and NK cells in LDs are less activated than in SDs. Importantly, most cells in LDs show reduced expression of ribosomal protein (RP) genes and related pathways, with this inversed correlation between RP levels and infection duration further validated in 103 independent patients. Our results thus indicate that immunosuppression and low RP expression may be related to the persistence of the viral infection in COVID-19 patients.


Subject(s)
COVID-19/immunology , SARS-CoV-2/pathogenicity , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , COVID-19/virology , Cytokines/blood , Gene Expression Profiling , Humans , Killer Cells, Natural/metabolism , Killer Cells, Natural/pathology , Leukocytes, Mononuclear/pathology , Lymphocyte Activation/genetics , Lymphocyte Subsets/metabolism , Lymphocyte Subsets/pathology , Ribosomal Proteins/genetics , SARS-CoV-2/isolation & purification , Signal Transduction/genetics , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , Virus Shedding
7.
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
8.
Neuropeptides ; 89: 102159, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1225350

ABSTRACT

T cells of aged people, and of patients with either cancer or severe infections (including COVID-19), are often exhausted, senescent and dysfunctional, leading to increased susceptibilities, complications and mortality. Neurotransmitters and Neuropeptides bind their receptors in T cells, and induce multiple beneficial T cell functions. Yet, T cells of different people vary in the expression levels of Neurotransmitter and Neuropeptide receptors, and in the magnitude of the corresponding effects. Therefore, we performed an individual-based study on T cells of 3 healthy subjects, and 3 Hepatocellular Carcinoma (HCC) patients. HCC usually develops due to chronic inflammation. The inflamed liver induces reduction and inhibition of CD4+ T cells and Natural Killer (NK) cells. Immune-based therapies for HCC are urgently needed. We tested if selected Neurotransmitters and Neuropeptides decrease the key checkpoint protein PD-1 in human T cells, and increase proliferation and killing of HCC cells. First, we confirmed human T cells express all dopamine receptors (DRs), and glutamate receptors (GluRs): AMPA-GluR3, NMDA-R and mGluR. Second, we discovered that either Dopamine, Glutamate, GnRH-II, Neuropeptide Y and/or CGRP (10nM), as well as DR and GluR agonists, induced the following effects: 1. Decreased significantly both %PD-1+ T cells and PD-1 expression level per cell (up to 60% decrease, within 1 h only); 2. Increased significantly the number of T cells that proliferated in the presence of HCC cells (up to 7 fold increase), 3. Increased significantly T cell killing of HCC cells (up to 2 fold increase). 4. Few non-conventional combinations of Neurotransmitters and Neuropeptides had surprising synergistic beneficial effects. We conclude that Dopamine, Glutamate, GnRH-II, Neuropeptide Y and CGRP, alone or in combinations, can decrease % PD-1+ T cells and PD-1 expression per cell, in T cells of both healthy subjects and HCC patients, and increase their proliferation in response to HCC cells and killing of HCC cells. Yet, testing T cells of many more cancer patients is absolutely needed. Based on these findings and previous ones, we designed a novel "Personalized Adoptive Neuro-Immunotherapy", calling for validation of safety and efficacy in clinical trials.


Subject(s)
Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Cell Proliferation/drug effects , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Neuropeptides/pharmacology , Neurotransmitter Agents/pharmacology , Programmed Cell Death 1 Receptor/biosynthesis , Programmed Cell Death 1 Receptor/genetics , T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/metabolism , COVID-19/complications , Carcinoma, Hepatocellular/pathology , Dopamine/pharmacology , Dopamine Agonists/pharmacology , Humans , Immunotherapy , Killer Cells, Natural/metabolism , Liver Neoplasms/pathology , Receptors, Glutamate/drug effects , Receptors, Neuropeptide/metabolism , Receptors, Neurotransmitter/metabolism
9.
Front Immunol ; 12: 655934, 2021.
Article in English | MEDLINE | ID: covidwho-1156126

ABSTRACT

COVID-19 manifests with a wide diversity of clinical phenotypes characterized by dysfunctional and exaggerated host immune responses. Many results have been described on the status of the immune system of patients infected with SARS-CoV-2, but there are still aspects that have not been fully characterized or understood. In this study, we have analyzed a cohort of patients with mild, moderate and severe disease. We performed flow cytometric studies and correlated the data with the clinical characteristics and clinical laboratory values of the patients. Both conventional and unsupervised data analyses concluded that patients with severe disease are characterized, among others, by a higher state of activation in all T cell subsets (CD4, CD8, double negative and T follicular helper cells), higher expression of perforin and granzyme B in cytotoxic cells, expansion of adaptive NK cells and the accumulation of activated and immature dysfunctional monocytes which are identified by a low expression of HLA-DR and an intriguing shift in the expression pattern of CD300 receptors. More importantly, correlation analysis showed a strong association between the alterations in the immune cells and the clinical signs of severity. These results indicate that patients with severe COVID-19 have a broad perturbation of their immune system, and they will help to understand the immunopathogenesis of COVID-19.


Subject(s)
COVID-19/immunology , Cytotoxicity, Immunologic , Killer Cells, Natural/immunology , Lymphocyte Activation , Monocytes/immunology , Receptors, Immunologic/blood , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Aged , COVID-19/blood , COVID-19/diagnosis , COVID-19/virology , Case-Control Studies , Cross-Sectional Studies , Female , Flow Cytometry , Host-Pathogen Interactions , Humans , Immunophenotyping , Killer Cells, Natural/metabolism , Killer Cells, Natural/virology , Male , Middle Aged , Monocytes/metabolism , Monocytes/virology , Phenotype , Severity of Illness Index , T-Lymphocytes/metabolism , T-Lymphocytes/virology
10.
Int J Mol Sci ; 22(6)2021 Mar 15.
Article in English | MEDLINE | ID: covidwho-1136499

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality across the world, with no current effective treatments available. Recent studies suggest the possibility of a cytokine storm associated with severe COVID-19, similar to the biochemical profile seen in hemophagocytic lymphohistiocytosis (HLH), raising the question of possible benefits that could be derived from targeted immunosuppression in severe COVID-19 patients. We reviewed the literature regarding the diagnosis and features of HLH, particularly secondary HLH, and aimed to identify gaps in the literature to truly clarify the existence of a COVID-19 associated HLH. Diagnostic criteria such as HScore or HLH-2004 may have suboptimal performance in identifying COVID-19 HLH-like presentations, and criteria such as soluble CD163, NK cell activity, or other novel biomarkers may be more useful in identifying this entity.


Subject(s)
COVID-19/complications , COVID-19/diagnosis , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/etiology , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Humans , Killer Cells, Natural/metabolism , Receptors, Cell Surface/metabolism , Receptors, Interleukin-2/metabolism , Sepsis/etiology
11.
Sci Signal ; 14(673)2021 03 09.
Article in English | MEDLINE | ID: covidwho-1127536

ABSTRACT

IL-1ß is a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19, and IL-1ß blockade with anakinra and canakinumab during COVID-19 infection has entered clinical trials. Using mass cytometry of human peripheral blood mononuclear cells, we identified effector memory CD4+ T cells and CD4-CD8low/-CD161+ T cells, specifically those positive for the chemokine receptor CCR6, as the circulating immune subtypes with the greatest response to IL-1ß. This response manifested as increased phosphorylation and, thus, activation of the proinflammatory transcription factor NF-κB and was also seen in other subsets, including CD11c+ myeloid dendritic cells, classical monocytes, two subsets of natural killer cells (CD16-CD56brightCD161- and CD16-CD56dimCD161+), and lineage- (Lin-) cells expressing CD161 and CD25. IL-1ß also induced a rapid but less robust increase in the phosphorylation of the kinase p38 as compared to that of NF-κB in most of these immune cell subsets. Prolonged IL-1ß stimulation increased the phosphorylation of the transcription factor STAT3 and to a lesser extent that of STAT1 and STAT5 across various immune cell types. IL-1ß-induced production of IL-6 likely led to the activation of STAT1 and STAT3 at later time points. Interindividual heterogeneity and inhibition of STAT activation by anakinra raise the possibility that assays measuring NF-κB phosphorylation in response to IL-1ß in CCR6+ T cell subtypes could identify those patients at higher risk of cytokine storm and most likely to benefit from IL-1ß-neutralizing therapies.


Subject(s)
COVID-19/immunology , Interleukin-1beta/blood , T-Lymphocyte Subsets/immunology , COVID-19/blood , COVID-19/complications , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Flow Cytometry , Humans , Interleukin-1beta/pharmacology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Monocytes/classification , Monocytes/immunology , Monocytes/metabolism , NF-kappa B/blood , Pandemics , Phosphorylation , Receptors, CCR6/blood , SARS-CoV-2 , STAT Transcription Factors/blood , STAT Transcription Factors/immunology , Signal Transduction/immunology , T-Lymphocyte Subsets/metabolism , p38 Mitogen-Activated Protein Kinases/blood
12.
Cell ; 184(7): 1836-1857.e22, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1077815

ABSTRACT

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56dimCD16hi NK cells linked positively to circulating interleukin (IL)-15. CD8+ T cell activation was apparent without signs of exhaustion. Although cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery versus fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.


Subject(s)
COVID-19/immunology , Cytokines/metabolism , Dendritic Cells/metabolism , Gene Expression/immunology , Killer Cells, Natural/metabolism , Severity of Illness Index , Adult , Aged , Aged, 80 and over , Biomarkers/metabolism , COVID-19/mortality , Case-Control Studies , Dendritic Cells/cytology , Female , Humans , Killer Cells, Natural/cytology , Longitudinal Studies , Male , Middle Aged , Transcriptome/immunology , Young Adult
13.
Nat Immunol ; 22(1): 86-98, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065906

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for an unprecedented global pandemic of COVID-19. Animal models are urgently needed to study the pathogenesis of COVID-19 and to screen vaccines and treatments. We show that African green monkeys (AGMs) support robust SARS-CoV-2 replication and develop pronounced respiratory disease, which may more accurately reflect human COVID-19 cases than other nonhuman primate species. SARS-CoV-2 was detected in mucosal samples, including rectal swabs, as late as 15 days after exposure. Marked inflammation and coagulopathy in blood and tissues were prominent features. Transcriptome analysis demonstrated stimulation of interferon and interleukin-6 pathways in bronchoalveolar lavage samples and repression of natural killer cell- and T cell-associated transcripts in peripheral blood. Despite a slight waning in antibody titers after primary challenge, enhanced antibody and cellular responses contributed to rapid clearance after re-challenge with an identical strain. These data support the utility of AGM for studying COVID-19 pathogenesis and testing medical countermeasures.


Subject(s)
COVID-19/immunology , Disease Models, Animal , Reinfection/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Animals , Antibodies, Viral/immunology , COVID-19/epidemiology , COVID-19/virology , Chlorocebus aethiops , Epidemics/prevention & control , Gene Expression/genetics , Gene Expression/immunology , Gene Expression Profiling , Humans , Interferons/genetics , Interferons/immunology , Interferons/metabolism , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Reinfection/virology , SARS-CoV-2/physiology , T-Lymphocytes/metabolism , T-Lymphocytes/virology
14.
J Cell Physiol ; 236(4): 2413-2429, 2021 04.
Article in English | MEDLINE | ID: covidwho-745433

ABSTRACT

Mesenchymal stem cells (MSCs) are mesenchymal precursors of various origins, with well-known immunomodulatory effects. Natural killer (NK) cells, the major cells of the innate immune system, are critical for the antitumor and antiviral defenses; however, in certain cases, they may be the main culprits in the pathogenesis of some NK-related conditions such as autoimmunities and hematological malignancies. On the other hand, these cells seem to be the major responders in beneficial phenomena like graft versus leukemia. Substantial data suggest that MSCs can variably affect NK cells and can be affected by these cells. Accordingly, acquiring a profound understanding of the crosstalk between MSCs and NK cells and the involved mechanisms seems to be a necessity to develop therapeutic approaches based on such interactions. Therefore, in this study, we made a thorough review of the existing literature on the interactions between MSCs and NK cells with a focus on the underlying mechanisms. The current knowledge herein suggests that MSCs possess a great potential to be used as tools for therapeutic targeting of NK cells in disease context and that preconditioning of MSCs, as well as their genetic manipulation before administration, may provide a wider variety of options in terms of eliciting more specific and desirable therapeutic outcomes. Nevertheless, our knowledge regarding the effects of MSCs on NK cells is still in its infancy, and further studies with well-defined conditions are warranted herein.


Subject(s)
Cell Communication , Killer Cells, Natural/metabolism , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/metabolism , Animals , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Autoimmune Diseases/surgery , Genetic Therapy , Humans , Killer Cells, Natural/immunology , Mesenchymal Stem Cells/immunology , Neoplasms/immunology , Neoplasms/metabolism , Neoplasms/surgery , Phenotype , Signal Transduction , Tumor Microenvironment
15.
Biomed Res Int ; 2020: 7570981, 2020.
Article in English | MEDLINE | ID: covidwho-961169

ABSTRACT

To investigate the immune status of people who previously had COVID-19 infections, we recruited two-week postrecovery patients and analyzed circulating cytokine and lymphocyte subsets. We measured levels of total lymphocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD56+ NK cells and the serum concentrations of interleukin- (IL-) 1, IL-4, IL-6, IL-8, IL-10, transforming growth factor beta (TGF-ß), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) by flow cytometry. We found that in most postrecovery patients, levels of total lymphocytes (66.67%), CD3+ T cells (54.55%), CD4+ T cells (54.55%), CD8+ T cells (81.82%), CD19+ B cells (69.70%), and CD56+ NK cells (51.52%) remained lower than normal, whereas most patients showed normal levels of IL-2 (100%), IL-4 (80.88%), IL-6 (79.41%), IL-10 (98.53%), TNF-α (89.71%), IFN-γ (100%), and IL-17 (97.06%). Compared to healthy controls, two-week postrecovery patients had significantly lower absolute numbers of total lymphocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD56+ NK cells, along with significantly higher levels of IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and IL-17. Among postrecovery patients, T cells, particularly CD4+ T cells, were positively correlated with CD19+ B cell counts. Additionally, CD8+ T cells were positively correlated with CD4+ T cells and IL-2 levels, and IL-6 positively correlated with TNF-α and IFN-γ. These correlations were not observed in healthy controls. By ROC curve analysis, postrecovery decreases in lymphocyte subsets and increases in cytokines were identified as independent predictors of rehabilitation efficacy. These findings indicate that the immune system gradually recovers following COVID-19 infection; however, the sustained hyperinflammatory response for more than 14 days suggests a need to continue medical observation following discharge from the hospital. Longitudinal studies of a larger cohort of recovered patients are needed to fully understand the consequences of the infection.


Subject(s)
CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , COVID-19 , Cytokines , Killer Cells, Natural , Lymphocyte Subsets , SARS-CoV-2 , Adult , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , COVID-19/blood , COVID-19/immunology , Cytokines/blood , Cytokines/immunology , Female , Humans , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Lymphocyte Subsets/immunology , Lymphocyte Subsets/metabolism , Male , SARS-CoV-2/immunology , SARS-CoV-2/metabolism
16.
Sci Rep ; 10(1): 17718, 2020 10 19.
Article in English | MEDLINE | ID: covidwho-880700

ABSTRACT

COVID-19 has been widely spreading. We aimed to examine adaptive immune cells in non-severe patients with persistent SARS-CoV-2 shedding. 37 non-severe patients with persistent SARS-CoV-2 presence that were transferred to Zhongnan hospital of Wuhan University were retrospectively recruited to the PP (persistently positive) group, which was further allocated to PPP group (n = 19) and PPN group (n = 18), according to their testing results after 7 days (N = negative). Epidemiological, demographic, clinical and laboratory data were collected and analyzed. Data from age- and sex-matched non-severe patients at disease onset (PA [positive on admission] patients, n = 37), and lymphocyte subpopulation measurements from matched 54 healthy subjects were extracted for comparison (HC). Compared with PA patients, PP patients had much improved laboratory findings. The absolute numbers of CD3+ T cells, CD4+ T cells, and NK cells were significantly higher in PP group than that in PA group, and were comparable to that in healthy controls. PPP subgroup had markedly reduced B cells and T cells compared to PPN group and healthy subjects. Finally, paired results of these lymphocyte subpopulations from 10 PPN patients demonstrated that the number of T cells and B cells significantly increased when the SARS-CoV-2 tests turned negative. Persistent SARS-CoV-2 presence in non-severe COVID-19 patients is associated with reduced numbers of adaptive immune cells. Monitoring lymphocyte subpopulations could be clinically meaningful in identifying fully recovered COVID-19 patients.


Subject(s)
B-Lymphocytes/cytology , Coronavirus Infections/pathology , Pneumonia, Viral/pathology , T-Lymphocytes/cytology , Adult , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Betacoronavirus/isolation & purification , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , COVID-19 , Case-Control Studies , Coronavirus Infections/immunology , Coronavirus Infections/virology , Female , Humans , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Male , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
17.
Cell ; 183(4): 982-995.e14, 2020 11 12.
Article in English | MEDLINE | ID: covidwho-756809

ABSTRACT

Initially, children were thought to be spared from disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a month into the epidemic, a novel multisystem inflammatory syndrome in children (MIS-C) emerged. Herein, we report on the immune profiles of nine MIS-C cases. All MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with intact neutralization capability. Cytokine profiling identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1), and mucosal immune dysregulation (IL-17A, CCL20, and CCL28). Immunophenotyping of peripheral blood revealed reductions of non-classical monocytes, and subsets of NK and T lymphocytes, suggesting extravasation to affected tissues. Finally, profiling the autoantigen reactivity of MIS-C plasma revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal, and immune-cell antigens. All patients were treated with anti-IL-6R antibody and/or IVIG, which led to rapid disease resolution.


Subject(s)
Inflammation/pathology , Systemic Inflammatory Response Syndrome/pathology , Adolescent , Antibodies, Viral/blood , Autoantibodies/blood , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , COVID-19 , Chemokine CCL3/metabolism , Child , Child, Preschool , Coronavirus Infections/complications , Coronavirus Infections/pathology , Coronavirus Infections/virology , Female , Humans , Immunity, Humoral , Infant , Infant, Newborn , Inflammation/metabolism , Interleukin-17/metabolism , Interleukin-18/metabolism , Killer Cells, Natural/cytology , Killer Cells, Natural/metabolism , Male , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Young Adult
18.
Int J Mol Sci ; 21(17)2020 Sep 01.
Article in English | MEDLINE | ID: covidwho-742800

ABSTRACT

When facing an acute viral infection, our immune systems need to function with finite precision to enable the elimination of the pathogen, whilst protecting our bodies from immune-related damage. In many instances however this "perfect balance" is not achieved, factors such as ageing, cancer, autoimmunity and cardiovascular disease all skew the immune response which is then further distorted by viral infection. In SARS-CoV-2, although the vast majority of COVID-19 cases are mild, as of 24 August 2020, over 800,000 people have died, many from the severe inflammatory cytokine release resulting in extreme clinical manifestations such as acute respiratory distress syndrome (ARDS) and hemophagocytic lymphohistiocytosis (HLH). Severe complications are more common in elderly patients and patients with cardiovascular diseases. Natural killer (NK) cells play a critical role in modulating the immune response and in both of these patient groups, NK cell effector functions are blunted. Preliminary studies in COVID-19 patients with severe disease suggests a reduction in NK cell number and function, resulting in decreased clearance of infected and activated cells, and unchecked elevation of tissue-damaging inflammation markers. SARS-CoV-2 infection skews the immune response towards an overwhelmingly inflammatory phenotype. Restoration of NK cell effector functions has the potential to correct the delicate immune balance required to effectively overcome SARS-CoV-2 infection.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Susceptibility/immunology , Host-Pathogen Interactions/immunology , Immunity, Innate , Killer Cells, Natural/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Autoimmunity , COVID-19 , Coronavirus Infections/metabolism , Humans , Immunomodulation , Killer Cells, Natural/metabolism , Pandemics , Pneumonia, Viral/metabolism , SARS-CoV-2
19.
Hum Immunol ; 81(10-11): 588-595, 2020.
Article in English | MEDLINE | ID: covidwho-712293

ABSTRACT

Coronavirus Disease 2019 (COVID-19) is a dangerous global threat that has no clinically approved treatment yet. Bioinformatics represent an outstanding approach to reveal key immunogenic regions in viral proteins. Here, five severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-structural proteins (NSPs) (NSP7, NSP8, NSP9, NSP12, and NSP13) were screened to identify potential human leukocyte antigen (HLA) binding peptides. These peptides showed robust viral antigenicity, immunogenicity, and a marked interaction with HLA alleles. Interestingly, several peptides showed affinity by HLA class I (HLA-I) alleles that commonly activates to natural killer (NK) cells. Notably, HLA biding peptides are conserved among SARS-CoV-2, severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle Eastern respiratory syndrome coronavirus (MERS-CoV). Interestingly, HLA-I and HLA class II (HLA-II) binding peptides induced humoral and cell-mediated responses after in silico vaccination. These results may open further in vitro and in vivo investigations to develop novel therapeutic strategies against coronaviral infections.


Subject(s)
Betacoronavirus/immunology , Conserved Sequence/immunology , Coronavirus Infections/immunology , HLA Antigens/immunology , Pneumonia, Viral/immunology , Viral Nonstructural Proteins/immunology , Amino Acid Sequence , Betacoronavirus/genetics , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/blood , Coronavirus Infections/prevention & control , Coronavirus Infections/therapy , Coronavirus Infections/virology , HLA Antigens/metabolism , Humans , Immunity, Cellular/immunology , Immunity, Humoral/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/immunology , Molecular Docking Simulation , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/therapy , Pneumonia, Viral/virology , SARS Virus/genetics , SARS Virus/immunology , SARS-CoV-2 , Vaccines, Subunit/immunology , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Viral Vaccines/immunology
20.
Nat Immunol ; 21(9): 1107-1118, 2020 09.
Article in English | MEDLINE | ID: covidwho-710376

ABSTRACT

In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ effector-GNLY (granulysin), CD8+ effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.


Subject(s)
Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , Betacoronavirus/immunology , Coronavirus Infections/immunology , Interferon Type I/metabolism , Pneumonia, Viral/immunology , Receptors, Immunologic/metabolism , Adolescent , Adult , Aged , Antigens, CD/genetics , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/genetics , Antigens, Differentiation, T-Lymphocyte/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , COVID-19 , Cohort Studies , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Female , GPI-Linked Proteins/genetics , GPI-Linked Proteins/immunology , GPI-Linked Proteins/metabolism , Humans , Interferon Type I/genetics , Interferon Type I/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , RNA-Seq , Receptors, Immunologic/genetics , Receptors, Immunologic/immunology , SARS-CoV-2 , Severity of Illness Index , Single-Cell Analysis
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