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1.
Stem Cell Res Ther ; 13(1): 20, 2022 01 15.
Article in English | MEDLINE | ID: covidwho-1638634

ABSTRACT

BACKGROUND: Although 90% of infections with the novel coronavirus 2 (COVID-19) are mild, many patients progress to acute respiratory distress syndrome (ARDS) which carries a high risk of mortality. Given that this dysregulated immune response plays a key role in the pathology of COVID-19, several clinical trials are underway to evaluate the effect of immunomodulatory cell therapy on disease progression. However, little is known about the effect of ARDS associated pro-inflammatory mediators on transplanted stem cell function and survival, and any deleterious effects could undermine therapeutic efficacy. As such, we assessed the impact of inflammatory cytokines on the viability, and paracrine profile (extracellular vesicles) of bone marrow-derived mesenchymal stromal cells, heart-derived cells, and umbilical cord-derived mesenchymal stromal cells. METHODS: All cell products were manufactured and characterized to established clinical release standards by an accredited clinical cell manufacturing facility. Cytokines and Extracellular vesicles in the cell conditioned media were profiled using proteomic array and nanoparticle tracking analysis. Using a survey of the clinical literature, 6 cytotoxic cytokines implicated in the progression of COVID-19 ARDS. Flow cytometry was employed to determine receptor expression of these 6 cytokines in three cell products. Based on clinical survey and flow cytometry data, a cytokine cocktail that mimics cytokine storm seen in COVID-19 ARDS patients was designed and the impact on cytokine cocktail on viability and paracrine secretory ability of cell products were assessed using cell viability and nanoparticle tracking analysis. RESULTS: Flow cytometry revealed the presence of receptors for all cytokines but IL-6, which was subsequently excluded from further experimentation. Despite this widespread expression, exposure of each cell type to individual cytokines at doses tenfold greater than observed clinically or in combination at doses associated with severe ARDS did not alter cell viability or extracellular vesicle character/production in any of the 3 cell products. CONCLUSIONS: The paracrine production and viability of the three leading cell products under clinical evaluation for the treatment of severe COVID-19 ARDS are not altered by inflammatory mediators implicated in disease progression.


Subject(s)
Acute Lung Injury , COVID-19 , Mesenchymal Stem Cell Transplantation , Acute Lung Injury/therapy , Cytokines , Humans , Proteomics , SARS-CoV-2
2.
Zh Nevrol Psikhiatr Im S S Korsakova ; 121(12. Vyp. 2): 69-76, 2021.
Article in Russian | MEDLINE | ID: covidwho-1637642

ABSTRACT

The COVID-19 pandemic had a significant impact on both the incidence of acute cerebral circulatory disorders and the structure of mortality. SARS-CoV-2 increases the risk of both ischemic and hemorrhagic stroke. The key pathogenetic links underlying the development of cerebral stroke in COVID-19 are impaired functioning of angiotensin 2 receptors, accompanied by the accumulation of excess angiotensin 2, endothelial dysfunction, hypercoagulation, hyperproduction of proinflammatory cytokines and oxidative storm. In patients with stroke and COVID-19, the severity of the lesion is associated with a dual mechanism of ischemia - systemic and cerebral. The possibilities of medical correction of systemic disorders associated with coronavirus infection, as well as local ones caused by ischemic or hemorrhagic brain damage, are limited. Substances with antioxidant activity could potentially be effective in patients with stroke and COVID-1.


Subject(s)
COVID-19 , Stroke , Cytokines , Humans , Pandemics , SARS-CoV-2 , Stroke/epidemiology , Stroke/etiology
3.
Cell Mol Life Sci ; 79(1): 65, 2022 Jan 10.
Article in English | MEDLINE | ID: covidwho-1616112

ABSTRACT

Coronavirus disease 2019 (COVID-19), the illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 260 million confirmed infections and 5 million deaths to date. While vaccination is a powerful tool to control pandemic spread, medication to relieve COVID-19-associated symptoms and alleviate disease progression especially in high-risk patients is still lacking. In this study, we explore the suitability of the rapid accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway as a druggable target in the treatment of SARS-CoV-2 infections. We find that SARS-CoV-2 transiently activates Raf/MEK/ERK signaling in the very early infection phase and that ERK1/2 knockdown limits virus replication in cell culture models. We demonstrate that ATR-002, a specific inhibitor of the upstream MEK1/2 kinases which is currently evaluated in clinical trials as an anti-influenza drug, displays strong anti-SARS-CoV-2 activity in cell lines as well as in primary air-liquid-interphase epithelial cell (ALI) cultures, with a safe and selective treatment window. We also observe that ATR-002 treatment impairs the SARS-CoV-2-induced expression of pro-inflammatory cytokines, and thus might prevent COVID-19-associated hyperinflammation, a key player in COVID-19 progression. Thus, our data suggest that the Raf/MEK/ERK signaling cascade may represent a target for therapeutic intervention strategies against SARS-CoV-2 infections and that ATR-002 is a promising candidate for further drug evaluation.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Fenamates/pharmacology , MAP Kinase Signaling System/drug effects , Protein Kinase Inhibitors/pharmacology , SARS-CoV-2/drug effects , A549 Cells , Adult , Animals , COVID-19/metabolism , Cell Line , Cells, Cultured , Chlorocebus aethiops , Cytokines/metabolism , Humans , Inflammation/drug therapy , Inflammation/metabolism , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 1/metabolism , MAP Kinase Kinase 2/antagonists & inhibitors , MAP Kinase Kinase 2/metabolism , SARS-CoV-2/physiology , Vero Cells , Virus Replication/drug effects
4.
Cells ; 10(12)2021 11 30.
Article in English | MEDLINE | ID: covidwho-1613627

ABSTRACT

The COVID-19 pandemic drastically highlighted the vulnerability of the elderly population towards viral and other infectious threats, illustrating that aging is accompanied by dysregulated immune responses currently summarized in terms like inflammaging and immunoparalysis. To gain a better understanding on the underlying mechanisms of the age-associated risk of adverse outcome in individuals experiencing a SARS-CoV-2 infection, we analyzed the impact of age on circulating monocyte phenotypes, activation markers and inflammatory cytokines including interleukin 6 (IL-6), IL-8 and tumor necrosis factor (TNF) in the context of COVID-19 disease progression and outcome in 110 patients. Our data indicate no age-associated differences in peripheral monocyte counts or subset composition. However, age and outcome are associated with differences in monocyte activation status. Moreover, a distinct cytokine pattern of IL-6, IL-8 and TNF in elderly survivors versus non-survivors, which consolidates over the time of hospitalization, suggests that older patients with adverse outcomes experience an inappropriate immune response, reminiscent of an inflammaging driven immunoparalysis. Our study underscores the value, necessity and importance of longitudinal monitoring in elderly COVID-19 patients, as dynamic changes after symptom onset can be observed, which allow for a differentiated insight into confounding factors that impact the complex pathogenesis following an infection with SARS-CoV-2.


Subject(s)
Aging/pathology , COVID-19/blood , COVID-19/pathology , Cytokines/blood , Monocytes/pathology , Acute Disease , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Biomarkers/metabolism , Humans , Longitudinal Studies , Middle Aged , Neutrophils/metabolism , Prospective Studies , SARS-CoV-2 , Young Adult
6.
Int J Biol Sci ; 18(1): 386-408, 2022.
Article in English | MEDLINE | ID: covidwho-1607858

ABSTRACT

Responding to the coronavirus disease 2019 (COVID-19) pandemic has been an unexpected and unprecedented global challenge for humanity in this century. During this crisis, specialists from the laboratories and frontline clinical personnel have made great efforts to prevent and treat COVID-19 by revealing the molecular biological characteristics and epidemic characteristics of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, SARS-CoV-2 has severe consequences for public health, including human respiratory system, immune system, blood circulation system, nervous system, motor system, urinary system, reproductive system and digestive system. In the review, we summarize the physiological and pathological damage of SARS-CoV-2 to these systems and its molecular mechanisms followed by clinical manifestation. Concurrently, the prevention and treatment strategies of COVID-19 will be discussed in preclinical and clinical studies. With constantly unfolding and expanding scientific understanding about COVID-19, the updated information can help applied researchers understand the disease to build potential antiviral drugs or vaccines, and formulate creative therapeutic ideas for combating COVID-19 at speed.


Subject(s)
COVID-19/pathology , COVID-19/therapy , Immunotherapy/methods , SARS-CoV-2 , Animals , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19 Vaccines , Cytokines/metabolism , Female , Humans , Immune System , Immunity, Innate , Immunologic Memory , Male , Mice
7.
J Med Chem ; 65(1): 876-884, 2022 01 13.
Article in English | MEDLINE | ID: covidwho-1606194

ABSTRACT

Coronavirus disease 2019 (COVID-19) pandemic, a global health threat, was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 papain-like cysteine protease (PLpro) was recognized as a promising drug target because of multiple functions in virus maturation and antiviral immune responses. Inhibitor GRL0617 occupied the interferon-stimulated gene 15 (ISG15) C-terminus-binding pocket and showed an effective antiviral inhibition. Here, we described a novel peptide-drug conjugate (PDC), in which GRL0617 was linked to a sulfonium-tethered peptide derived from PLpro-specific substrate LRGG. The EM-C and EC-M PDCs showed a promising in vitro IC50 of 7.40 ± 0.37 and 8.63 ± 0.55 µM, respectively. EC-M could covalently label PLpro active site C111 and display anti-ISGylation activities in cellular assays. The results represent the first attempt to design PDCs composed of stabilized peptide inhibitors and GRL0617 to inhibit PLpro. These novel PDCs provide promising opportunities for antiviral drug design.


Subject(s)
Aniline Compounds/chemistry , Antiviral Agents/metabolism , Benzamides/chemistry , Coronavirus Papain-Like Proteases/metabolism , Drug Design , Naphthalenes/chemistry , Peptides/chemistry , SARS-CoV-2/enzymology , Aniline Compounds/metabolism , Aniline Compounds/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Benzamides/metabolism , Benzamides/pharmacology , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Cell Line , Cell Survival/drug effects , Coronavirus Papain-Like Proteases/chemistry , Cytokines/chemistry , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Naphthalenes/metabolism , Naphthalenes/pharmacology , SARS-CoV-2/isolation & purification , Ubiquitins/chemistry
8.
Assay Drug Dev Technol ; 20(1): 55-62, 2022 01.
Article in English | MEDLINE | ID: covidwho-1603818

ABSTRACT

Cytokine release syndrome, a prominent mechanism of morbidity and mortality in patients with coronavirus disease 2019 (COVID-19), can cause multiple bodily reactions, including excessive release of proinflammatory mediators, with tumor necrosis factor-α (TNF-α) being the most prevalent cytokine combined with persistently elevated D-dimer levels that are indicative of potential thrombotic events, low levels of endogenous nitric oxide (NO) generation, and progressive decrease in hemoglobin production. In our argument, the conceptual repurposing of hydroxyurea (HU) for managing COVID-19 can provide a promising therapeutic option originating from a rich history of investigational antiviral activity. HU as a proposed supportive therapeutic agent for treating COVID-19 can exemplify a successful remedial choice through its anti-inflammatory activity along with an intrinsic propensity to control the circulatory levels of key cytokines including TNF-α. HU has the ability to undergo in vivo NO conversion acting as NO donor together with being a prominent inducer of fetal hemoglobin (HbF) production. The combination of the mentioned two properties allows HU to possess evident capability of protecting against thrombotic events by controlling D-dimer levels. The implication of our hypothetical argument sheds light on the curative potential of HU, which can be strategically harnessed against COVID-19.


Subject(s)
COVID-19 , Hydroxyurea , Cytokine Release Syndrome , Cytokines , Humans , Hydroxyurea/pharmacology , SARS-CoV-2
9.
Sensors (Basel) ; 21(24)2021 Dec 20.
Article in English | MEDLINE | ID: covidwho-1594848

ABSTRACT

Cytokines are proteins secreted by immune cells. They promote cell signal transduction and are involved in cell replication, death, and recovery. Cytokines are immune modulators, but their excessive secretion causes uncontrolled inflammation that attacks normal cells. Considering the properties of cytokines, monitoring the secretion of cytokines in vivo is of great value for medical and biological research. In this review, we offer a report on recent studies for cytokine detection, especially studies on aptasensors using aptamers. Aptamers are single strand nucleic acids that form a stable three-dimensional structure and have been receiving attention due to various characteristics such as simple production methods, low molecular weight, and ease of modification while performing a physiological role similar to antibodies.


Subject(s)
Aptamers, Nucleotide , Biosensing Techniques , Cytokines
10.
J Exp Med ; 219(2)2022 02 07.
Article in English | MEDLINE | ID: covidwho-1594167

ABSTRACT

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


Subject(s)
COVID-19/complications , Hepatitis A Virus Cellular Receptor 2/metabolism , Interferon-gamma/metabolism , Killer Cells, Natural/immunology , Monocytes/metabolism , Receptors, IgG/metabolism , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocytes/immunology , Adolescent , Alveolar Epithelial Cells/pathology , B-Lymphocytes/immunology , Blood Vessels/pathology , COVID-19/immunology , COVID-19/pathology , Cell Proliferation , Child , Cohort Studies , Complement Activation , Cytokines/metabolism , Enterocytes/pathology , Female , Humans , Immunity, Humoral , Inflammation/pathology , Interferon Type I/metabolism , Interleukin-15/metabolism , Lymphocyte Activation/immunology , Male , Receptors, Antigen, T-Cell/metabolism , SARS-CoV-2/immunology , Superantigens/metabolism , Systemic Inflammatory Response Syndrome/pathology
11.
Front Immunol ; 12: 763292, 2021.
Article in English | MEDLINE | ID: covidwho-1581338

ABSTRACT

The cytokine release syndrome has been proposed as the driver of inflammation in coronavirus disease 2019 (COVID-19). However, studies on longitudinal cytokine profiles in patients across the whole severity spectrum of COVID-19 are lacking. In this prospective observational study on adult COVID-19 patients admitted to two Hong Kong public hospitals, cytokine profiling was performed on blood samples taken during early phase (within 7 days of symptom onset) and late phase (8 to 12 days of symptom onset). The primary objective was to evaluate the difference in early and late cytokine profiles among patient groups with different disease severity. The secondary objective was to assess the associations between cytokines and clinical endpoints in critically ill patients. A total of 40 adult patients (mild = 8, moderate = 15, severe/critical = 17) hospitalized with COVID-19 were included in this study. We found 22 cytokines which were correlated with disease severity, as proinflammatory Th1-related cytokines (interleukin (IL)-18, interferon-induced protein-10 (IP-10), monokine-induced by gamma interferon (MIG), and IL-10) and ARDS-associated cytokines (IL-6, monocyte chemoattractant protein-1 (MCP-1), interleukin-1 receptor antagonist (IL-1RA), and IL-8) were progressively elevated with increasing disease severity. Furthermore, 11 cytokines were consistently different in both early and late phases, including seven (growth-regulated oncogene-alpha (GRO-α), IL-1RA, IL-6, IL-8, IL-10, IP-10, and MIG) that increased and four (FGF-2, IL-5, macrophage-derived chemokine (MDC), and MIP-1α) that decreased from mild to severe/critical patients. IL-8, followed by IP-10 and MDC were the best performing early biomarkers to predict disease severity. Among critically ill patients, MCP-1 predicted the duration of mechanical ventilation, highest norepinephrine dose administered, and length of intensive care stay.


Subject(s)
Biomarkers/blood , COVID-19/immunology , Cytokines/blood , Adult , Aged , COVID-19/blood , Cytokines/immunology , Female , Hong Kong , Humans , Male , Middle Aged , Prospective Studies , SARS-CoV-2 , Severity of Illness Index
12.
Front Immunol ; 12: 789735, 2021.
Article in English | MEDLINE | ID: covidwho-1581322

ABSTRACT

Background: The host immune response has a prominent role in the progression and outcome of SARS-CoV-2 infection. Lymphopenia has been described as an important feature of SARS-CoV-2 infection and has been associated with severe disease manifestation. Lymphocyte dysregulation and hyper-inflammation have been shown to be associated with a more severe clinical course; however, a T cell subpopulation whose dysfunction correlate with disease progression has yet to be identify. Methods: We performed an immuno-phenotypic analysis of T cell sub-populations in peripheral blood from patients affected by different severity of COVID-19 (n=60) and undergoing a different clinical evolution. Clinical severity was established based on a modified WHO score considering both ventilation support and respiratory capacity (PaO2/FiO2 ratio). The ability of circulating cells at baseline to predict the probability of clinical aggravation was explored through multivariate regression analyses. Results: The immuno-phenotypic analysis performed by multi-colour flow cytometry confirmed that patients suffering from severe COVID-19 harboured significantly reduced circulating T cell subsets, especially for CD4+ T, Th1, and regulatory T cells. Peripheral T cells also correlated with parameters associated with disease severity, i.e., PaO2/FiO2 ratio and inflammation markers. CD4+ T cell subsets showed an important significant association with clinical evolution, with patients presenting markedly decreased regulatory T cells at baseline having a significantly higher risk of aggravation. Importantly, the combination of gender and regulatory T cells allowed distinguishing between improved and worsened patients with an area under the ROC curve (AUC) of 82%. Conclusions: The present study demonstrates the association between CD4+ T cell dysregulation and COVID-19 severity and progression. Our results support the importance of analysing baseline regulatory T cell levels, since they were revealed able to predict the clinical worsening during hospitalization. Regulatory T cells assessment soon after hospital admission could thus allow a better clinical stratification and patient management.


Subject(s)
COVID-19/epidemiology , COVID-19/immunology , Hospitalization , Lymphocyte Count , SARS-CoV-2/immunology , T-Lymphocytes, Regulatory/immunology , Biomarkers , COVID-19/diagnosis , COVID-19/virology , COVID-19 Serological Testing , Cytokines/blood , Cytokines/metabolism , Disease Progression , Humans , Immunophenotyping , Inflammation Mediators/blood , Inflammation Mediators/metabolism , Prognosis , Public Health Surveillance , ROC Curve , Severity of Illness Index , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/metabolism
13.
Viruses ; 13(12)2021 12 17.
Article in English | MEDLINE | ID: covidwho-1580425

ABSTRACT

BACKGROUND: The SARS-CoV-2 spike protein mediates attachment of the virus to the host cell receptor and fusion between the virus and the cell membrane. The S1 subunit of the spike glycoprotein (S1 protein) contains the angiotensin converting enzyme 2 (ACE2) receptor binding domain. The SARS-CoV-2 variants of concern contain mutations in the S1 subunit. The spike protein is the primary target of neutralizing antibodies generated following infection, and constitutes the viral component of mRNA-based COVID-19 vaccines. METHODS: Therefore, in this work we assessed the effect of exposure (24 h) to 10 nM SARS-CoV-2 recombinant S1 protein on physiologically relevant human bronchial (bro) and alveolar (alv) lung mucosa models cultured at air-liquid interface (ALI) (n = 6 per exposure condition). Corresponding sham exposed samples served as a control. The bro-ALI model was developed using primary bronchial epithelial cells and the alv-ALI model using representative type II pneumocytes (NCI-H441). RESULTS: Exposure to S1 protein induced the surface expression of ACE2, toll like receptor (TLR) 2, and TLR4 in both bro-ALI and alv-ALI models. Transcript expression analysis identified 117 (bro-ALI) and 97 (alv-ALI) differentially regulated genes (p ≤ 0.01). Pathway analysis revealed enrichment of canonical pathways such as interferon (IFN) signaling, influenza, coronavirus, and anti-viral response in the bro-ALI. Secreted levels of interleukin (IL) 4 and IL12 were significantly (p < 0.05) increased, whereas IL6 decreased in the bro-ALI. In the case of alv-ALI, enriched terms involving p53, APRIL (a proliferation-inducing ligand) tight junction, integrin kinase, and IL1 signaling were identified. These terms are associated with lung fibrosis. Further, significantly (p < 0.05) increased levels of secreted pro-inflammatory cytokines IFNγ, IL1ꞵ, IL2, IL4, IL6, IL8, IL10, IL13, and tumor necrosis factor alpha were detected in alv-ALI, whereas IL12 was decreased. Altered levels of these cytokines are also associated with lung fibrotic response. CONCLUSIONS: In conclusion, we observed a typical anti-viral response in the bronchial model and a pro-fibrotic response in the alveolar model. The bro-ALI and alv-ALI models may serve as an easy and robust platform for assessing the pathogenicity of SARS-CoV-2 variants of concern at different lung regions.


Subject(s)
Lung/metabolism , Respiratory Mucosa/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Bronchi/metabolism , Cytokines/metabolism , Gene Expression Profiling , Humans , Models, Biological , Protein Interaction Domains and Motifs , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 4/metabolism
14.
Theranostics ; 12(1): 290-306, 2022.
Article in English | MEDLINE | ID: covidwho-1579955

ABSTRACT

Coronavirus disease 2019 (COVID19), caused by SARS-CoV-2, is a complex disease, with a variety of clinical manifestations ranging from asymptomatic infection or mild cold-like symptoms to more severe cases requiring hospitalization and critical care. The most severe presentations seem to be related with a delayed, deregulated immune response leading to exacerbated inflammation and organ damage with close similarities to sepsis. Methods: In order to improve the understanding on the relation between host immune response and disease course, we have studied the differences in the cellular (monocytes, CD8+ T and NK cells) and soluble (cytokines, chemokines and immunoregulatory ligands) immune response in blood between Healthy Donors (HD), COVID19 and a group of patients with non-COVID19 respiratory tract infections (NON-COV-RTI). In addition, the immune response profile has been analyzed in COVID19 patients according to disease severity. Results: In comparison to HDs and patients with NON-COV-RTI, COVID19 patients show a heterogeneous immune response with the presence of both activated and exhausted CD8+ T and NK cells characterised by the expression of the immune checkpoint LAG3 and the presence of the adaptive NK cell subset. An increased frequency of adaptive NK cells and a reduction of NK cells expressing the activating receptors NKp30 and NKp46 correlated with disease severity. Although both activated and exhausted NK cells expressing LAG3 were increased in moderate/severe cases, unsupervised cell clustering analyses revealed a more complex scenario with single NK cells expressing more than one immune checkpoint (PD1, TIM3 and/or LAG3). A general increased level of inflammatory cytokines and chemokines was found in COVID19 patients, some of which like IL18, IL1RA, IL36B and IL31, IL2, IFNα and TNFα, CXCL10, CCL2 and CCL8 were able to differentiate between COVID19 and NON-COV-RTI and correlated with bad prognosis (IL2, TNFα, IL1RA, CCL2, CXCL10 and CXCL9). Notably, we found that soluble NKG2D ligands from the MIC and ULBPs families were increased in COVID19 compared to NON-COV-RTI and correlated with disease severity. Conclusions: Our results provide a detailed comprehensive analysis of the presence of activated and exhausted CD8+T, NK and monocyte cell subsets as well as extracellular inflammatory factors beyond cytokines/chemokines, specifically associated to COVID19. Importantly, multivariate analysis including clinical, demographical and immunological experimental variables have allowed us to reveal specific immune signatures to i) differentiate COVID19 from other infections and ii) predict disease severity and the risk of death.


Subject(s)
COVID-19/blood , COVID-19/immunology , Adult , Aged , Aged, 80 and over , Biomarkers/blood , CD8-Positive T-Lymphocytes/virology , COVID-19/mortality , Case-Control Studies , Chemokines/blood , Cytokines/blood , Female , Hospitalization , Humans , Killer Cells, Natural/virology , Logistic Models , Male , Middle Aged , Monocytes/virology , Prospective Studies , Respiratory Tract Infections/blood , Respiratory Tract Infections/immunology , Severity of Illness Index
15.
Signal Transduct Target Ther ; 6(1): 420, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1585885

ABSTRACT

COVID-19 is identified as a zoonotic disease caused by SARS-CoV-2, which also can cross-transmit to many animals but not mice. Genetic modifications of SARS-CoV-2 or mice enable the mice susceptible to viral infection. Although neither is the natural situation, they are currently utilized to establish mouse infection models. Here we report a direct contact transmission of SARS-CoV-2 variant B.1.351 in wild-type mice. The SARS-CoV-2 (B.1.351) replicated efficiently and induced significant pathological changes in lungs and tracheas, accompanied by elevated proinflammatory cytokines in the lungs and sera. Mechanistically, the receptor-binding domain (RBD) of SARS-CoV-2 (B.1.351) spike protein turned to a high binding affinity to mouse angiotensin-converting enzyme 2 (mACE2), allowing the mice highly susceptible to SARS-CoV-2 (B.1.351) infection. Our work suggests that SARS-CoV-2 (B.1.351) expands the host range and therefore increases its transmission route without adapted mutation. As the wild house mice live with human populations quite closely, this possible transmission route could be potentially risky. In addition, because SARS-CoV-2 (B.1.351) is one of the major epidemic strains and the mACE2 in laboratory-used mice is naturally expressed and regulated, the SARS-CoV-2 (B.1.351)/mice could be a much convenient animal model system to study COVID-19 pathogenesis and evaluate antiviral inhibitors and vaccines.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/transmission , Host-Pathogen Interactions/genetics , Receptors, Virus/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , COVID-19/immunology , COVID-19/virology , Cytokines/genetics , Cytokines/immunology , Disease Models, Animal , Gene Expression , HEK293 Cells , Host-Pathogen Interactions/immunology , Humans , Lung/pathology , Lung/virology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Protein Binding , Protein Domains , Receptors, Virus/immunology , SARS-CoV-2/classification , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/immunology , Virus Replication
17.
Rev Med Virol ; 31(6): e2221, 2021 11.
Article in English | MEDLINE | ID: covidwho-1575100

ABSTRACT

The current pandemic caused by SARS-CoV-2 virus infection is known as Covid-19 (coronavirus disease 2019). This disease can be asymptomatic or can affect multiple organ systems. Damage induced by the virus is related to dysfunctional activity of the immune system, but the activity of molecules such as C-reactive protein (CRP) as a factor capable of inducing an inflammatory status that may be involved in the severe evolution of the disease, has not been extensively evaluated. A systematic review was performed using the NCBI-PubMed database to find articles related to Covid-19 immunity, inflammatory response, and CRP published from December 2019 to December 2020. High levels of CRP were found in patients with severe evolution of Covid-19 in which several organ systems were affected and in patients who died. CRP activates complement, induces the production of pro-inflammatory cytokines and induces apoptosis which, together with the inflammatory status during the disease, can lead to a severe outcome. Several drugs can decrease the level or block the effect of CRP and might be useful in the treatment of Covid-19. From this review it is reasonable to conclude that CRP is a factor that can contribute to severe evolution of Covid-19 and that the use of drugs able to lower CRP levels or block its activity should be evaluated in randomized controlled clinical trials.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , C-Reactive Protein/antagonists & inhibitors , COVID-19/drug therapy , Complement System Proteins/immunology , Cytokine Release Syndrome/drug therapy , SARS-CoV-2/pathogenicity , ADAM17 Protein/antagonists & inhibitors , ADAM17 Protein/genetics , ADAM17 Protein/immunology , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Biomarkers/blood , C-Reactive Protein/genetics , C-Reactive Protein/immunology , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Celecoxib/therapeutic use , Complement System Proteins/genetics , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Cytokines/antagonists & inhibitors , Cytokines/genetics , Cytokines/immunology , Disease Progression , Doxycycline/therapeutic use , Gene Expression Regulation , Humans , Randomized Controlled Trials as Topic , Severity of Illness Index , Survival Analysis
18.
Life Sci ; 284: 119201, 2021 Nov 01.
Article in English | MEDLINE | ID: covidwho-1574805

ABSTRACT

BACKGROUND: Cytokine storm is the exaggerated immune response often observed in viral infections. It is also intimately linked with the progression of COVID-19 disease as well as associated complications and mortality. Therefore, targeting the cytokine storm might help in reducing COVID-19-associated health complications. The number of COVID-19 associated deaths (as of January 15, 2021; https://www.worldometers.info/coronavirus/) in the USA is high (1199/million) as compared to countries like India (110/million). Although the reason behind this is not clear, spices may have some role in explaining this difference. Spices and herbs are used in different traditional medicines, especially in countries such as India to treat various chronic diseases due to their potent antioxidant and anti-inflammatory properties. AIM: To evaluate the literature available on the anti-inflammatory properties of spices which might prove beneficial in the prevention and treatment of COVID-19 associated cytokine storm. METHOD: A detailed literature search has been conducted on PubMed for collecting information pertaining to the COVID-19; the history, origin, key structural features, and mechanism of infection of SARS-CoV-2; the repurposed drugs in use for the management of COVID-19, and the anti-inflammatory role of spices to combat COVID-19 associated cytokine storm. KEY FINDINGS: The literature search resulted in numerous in vitro, in vivo and clinical trials that have reported the potency of spices to exert anti-inflammatory effects by regulating crucial molecular targets for inflammation. SIGNIFICANCE: As spices are derived from Mother Nature and are inexpensive, they are relatively safer to consume. Therefore, their anti-inflammatory property can be exploited to combat the cytokine storm in COVID-19 patients. This review thus focuses on the current knowledge on the role of spices for the treatment of COVID-19 through suppression of inflammation-linked cytokine storm.


Subject(s)
COVID-19/pathology , Cytokines/metabolism , Inflammation/pathology , Spices , COVID-19/epidemiology , COVID-19/virology , Cytokine Release Syndrome/pathology , Humans , SARS-CoV-2/physiology
19.
Front Cell Infect Microbiol ; 11: 624483, 2021.
Article in English | MEDLINE | ID: covidwho-1574395

ABSTRACT

The immune response type organized against viral infection is determinant in the prognosis of some infections. This work has aimed to study Th polarization in acute COVID-19 and its possible association with the outcome through an observational prospective study. Fifty-eight COVID-19 patients were recruited in the Medicine Department of the hospital "12 de Octubre," 55 patients remaining after losses to follow-up. Four groups were established according to maximum degree of disease progression. T-helper cell percentages and phenotypes, analyzed by flow cytometer, and serum cytokines levels, analyzed by Luminex, were evaluated when the microbiological diagnosis (acute phase) of the disease was obtained. Our study found a significant reduction of %Th1 and %Th17 cells with higher activated %Th2 cells in the COVID-19 patients compared with reference population. A higher percent of senescent Th2 cells was found in the patients who died than in those who survived. Senescent Th2 cell percentage was an independent risk factor for death (OR: 13.88) accompanied by the numbers of total lymphocytes (OR: 0.15) with an AUC of 0.879. COVID-19 patients showed a profile of pro-inflammatory serum cytokines compared to controls, with higher levels of IL-2, IL-6, IL-15, and IP-10. IL-10 and IL-13 were also elevated in patients compared to controls. Patients who did not survive presented significantly higher levels of IL-15 than those who recovered. No significant differences were observed according to disease progression groups. The study has shown that increased levels of IL-15 and a high Th2 response are associated with a fatal outcome of the disease.


Subject(s)
COVID-19/immunology , SARS-CoV-2/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Helper-Inducer/immunology , Adult , Aged , COVID-19/blood , COVID-19/pathology , Cytokines/blood , Disease Progression , Female , Humans , Immunity , Male , Middle Aged , Multivariate Analysis , Prospective Studies , Th1 Cells/immunology , Th17 Cells/immunology , Th2 Cells/immunology
20.
Rev Med Virol ; 31(5): 1-13, 2021 09.
Article in English | MEDLINE | ID: covidwho-1574011

ABSTRACT

Coronavirus disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is now pandemic. While most Covid-19 patients will experience mild symptoms, a small proportion will develop severe disease, which could be fatal. Clinically, Covid-19 patients manifest fever with dry cough, fatigue and dyspnoea, and in severe cases develop into acute respiratory distress syndrome (ARDS), sepsis and multi-organ failure. These severe patients are characterized by hyperinflammation with highly increased pro-inflammatory cytokines including IL-6, IL-17 and TNF-alpha as well as C-reactive protein, which are accompanied by decreased lymphocyte counts. Clinical evidence supports that gut microbiota dysregulation is common in Covid-19 and plays a key role in the pathogenesis of Covid-19. In this narrative review, we summarize the roles of intestinal dysbiosis in Covid-19 pathogenesis and posit that the associated mechanisms are being mediated by gut bacterial metabolites. Based on this premise, we propose possible clinical implications. Various risk factors could be causal for severe Covid-19, and these include advanced age, concomitant chronic disease, SARS-CoV-2 infection of enterocytes, use of antibiotics and psychological distress. Gut dysbiosis is associated with risk factors and severe Covid-19 due to decreased commensal microbial metabolites, which cause reduced anti-inflammatory mechanisms and chronic low-grade inflammation. The preconditioned immune dysregulation enables SARS-CoV-2 infection to progress to an uncontrolled hyperinflammatory response. Thus, a pre-existing gut microbiota that is diverse and abundant could be beneficial for the prevention of severe Covid-19, and supplementation with commensal microbial metabolites may facilitate and augment the treatment of severe Covid-19.


Subject(s)
Bacteria/metabolism , COVID-19/microbiology , Gastrointestinal Microbiome , Animals , Bacteria/classification , Bacteria/genetics , Bacteria/isolation & purification , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Cytokines/genetics , Cytokines/immunology , Dysbiosis/genetics , Dysbiosis/immunology , Dysbiosis/microbiology , Dysbiosis/virology , Humans , SARS-CoV-2/genetics , SARS-CoV-2/physiology
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