Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
1.
Cell Rep ; 36(6): 109504, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1491797

ABSTRACT

Early responses to vaccination are important for shaping both humoral and cellular protective immunity. Dissecting innate vaccine signatures may predict immunogenicity to help optimize the efficacy of mRNA and other vaccine strategies. Here, we characterize the cytokine and chemokine responses to the 1st and 2nd dose of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine in antigen-naive and in previously coronavirus disease 2019 (COVID-19)-infected individuals (NCT04743388). Transient increases in interleukin-15 (IL-15) and interferon gamma (IFN-γ) levels early after boost correlate with Spike antibody levels, supporting their use as biomarkers of effective humoral immunity development in response to vaccination. We identify a systemic signature including increases in IL-15, IFN-γ, and IP-10/CXCL10 after the 1st vaccination, which were enriched by tumor necrosis factor alpha (TNF-α) and IL-6 after the 2nd vaccination. In previously COVID-19-infected individuals, a single vaccination results in both strong cytokine induction and antibody titers similar to the ones observed upon booster vaccination in antigen-naive individuals, a result with potential implication for future public health recommendations.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Chemokine CXCL10/immunology , Interferon-gamma/immunology , Interleukin-15/immunology , SARS-CoV-2/immunology , Adult , Aged , Antibodies, Viral/immunology , COVID-19/metabolism , COVID-19 Vaccines/administration & dosage , Female , Humans , Immunity/immunology , Male , Middle Aged , RNA, Messenger/immunology
2.
Front Immunol ; 12: 654587, 2021.
Article in English | MEDLINE | ID: covidwho-1348485

ABSTRACT

Background: SARS-CoV-2 occurs in the majority of children as COVID-19, without symptoms or with a paucisymptomatic respiratory syndrome, but a small proportion of children develop the systemic Multi Inflammatory Syndrome (MIS-C), characterized by persistent fever and systemic hyperinflammation, with some clinical features resembling Kawasaki Disease (KD). Objective: With this study we aimed to shed new light on the pathogenesis of these two SARS-CoV-2-related clinical manifestations. Methods: We investigated lymphocyte and dendritic cells subsets, chemokine/cytokine profiles and evaluated the neutrophil activity mediators, myeloperoxidase (MPO), and reactive oxygen species (ROS), in 10 children with COVID-19 and 9 with MIS-C at the time of hospital admission. Results: Patients with MIS-C showed higher plasma levels of C reactive protein (CRP), MPO, IL-6, and of the pro-inflammatory chemokines CXCL8 and CCL2 than COVID-19 children. In addition, they displayed higher levels of the chemokines CXCL9 and CXCL10, mainly induced by IFN-γ. By contrast, we detected IFN-α in plasma of children with COVID-19, but not in patients with MIS-C. This observation was consistent with the increase of ISG15 and IFIT1 mRNAs in cells of COVID-19 patients, while ISG15 and IFIT1 mRNA were detected in MIS-C at levels comparable to healthy controls. Moreover, quantification of the number of plasmacytoid dendritic cells (pDCs), which constitute the main source of IFN-α, showed profound depletion of this subset in MIS-C, but not in COVID-19. Conclusions: Our results show a pattern of immune response which is suggestive of type I interferon activation in COVID-19 children, probably related to a recent interaction with the virus, while in MIS-C the immune response is characterized by elevation of the inflammatory cytokines/chemokines IL-6, CCL2, and CXCL8 and of the chemokines CXCL9 and CXL10, which are markers of an active Th1 type immune response. We believe that these immunological events, together with neutrophil activation, might be crucial in inducing the multisystem and cardiovascular damage observed in MIS-C.


Subject(s)
COVID-19/immunology , Chemokine CXCL10/immunology , Chemokine CXCL9/immunology , Dendritic Cells/immunology , Interferon-gamma/immunology , Plasma Cells/immunology , SARS-CoV-2/immunology , Systemic Inflammatory Response Syndrome/immunology , Child , Child, Preschool , Female , Humans , Infant , Male , Retrospective Studies
3.
Viruses ; 13(6)2021 06 03.
Article in English | MEDLINE | ID: covidwho-1259622

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA virus that is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Patients with severe COVID-19 may develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and require mechanical ventilation. Key features of SARS-CoV-2 induced pulmonary complications include an overexpression of pro-inflammatory chemokines and cytokines that contribute to a 'cytokine storm.' In the current study an inflammatory state in Calu-3 human lung epithelial cells was characterized in which significantly elevated transcripts of the immunostimulatory chemokines CXCL9, CXCL10, and CXCL11 were present. Additionally, an increase in gene expression of the cytokines IL-6, TNFα, and IFN-γ was observed. The transcription of CXCL9, CXCL10, IL-6, and IFN-γ was also induced in the lungs of human transgenic angiotensin converting enzyme 2 (ACE2) mice infected with SARS-CoV-2. To elucidate cell signaling pathways responsible for chemokine upregulation in SARS-CoV-2 infected cells, small molecule inhibitors targeting key signaling kinases were used. The induction of CXCL9, CXCL10, and CXCL11 gene expression in response to SARS-CoV-2 infection was markedly reduced by treatment with the AKT inhibitor GSK690693. Samples from COVID-19 positive individuals also displayed marked increases in CXCL9, CXCL10, and CXCL11 transcripts as well as transcripts in the AKT pathway. The current study elucidates potential pathway specific targets for reducing the induction of chemokines that may be contributing to SARS-CoV-2 pathogenesis via hyperinflammation.


Subject(s)
COVID-19/immunology , Chemokine CXCL10/genetics , Chemokine CXCL11/genetics , Chemokine CXCL9/genetics , Proto-Oncogene Proteins c-akt/metabolism , Up-Regulation , Angiotensin-Converting Enzyme 2/genetics , Animals , Cell Line , Chemokine CXCL10/immunology , Chemokine CXCL11/immunology , Chemokine CXCL9/immunology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/immunology , Epithelial Cells/immunology , Epithelial Cells/virology , Female , Humans , Inflammation , Lung/cytology , Mice , Mice, Transgenic , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction/genetics , Signal Transduction/immunology
4.
Front Immunol ; 12: 668507, 2021.
Article in English | MEDLINE | ID: covidwho-1226979

ABSTRACT

SARS-COV-2 virus is responsible for the ongoing devastating pandemic. Since the early phase of the pandemic, the "cytokine-storm" appeared a peculiar aspect of SARS-COV-2 infection which, at least in the severe cases, is responsible for respiratory treat damage and subsequent multi-organ failure. The efforts made in the last few months elucidated that the cytokine-storm results from a complex network involving cytokines/chemokines/infiltrating-immune-cells which orchestrate the aberrant immune response in COVID-19. Clinical and experimental studies aimed at depicting a potential "immune signature" of SARS-COV-2, identified three main "actors," namely the cytokine IL-6, the chemokine CXCL10 and the infiltrating immune cell type macrophages. Although other cytokines, chemokines and infiltrating immune cells are deeply involved and their role should not be neglected, based on currently available data, IL-6, CXCL10, and infiltrating macrophages could be considered prototype factors representing each component of the immune system. It rapidly became clear that a strong and continuous interplay among the three components of the immune response is mandatory in order to produce a severe clinical course of the disease. Indeed, while IL-6, CXCL10 and macrophages alone would not be able to fully drive the onset and maintenance of the cytokine-storm, the establishment of a IL-6/CXCL10/macrophages axis is crucial in driving the sequence of events characterizing this condition. The present review is specifically aimed at overviewing current evidences provided by both in vitro and in vivo studies addressing the issue of the interplay among IL-6, CXCL10 and macrophages in the onset and progression of cytokine storm. SARS-COV-2 infection and the "cytokine storm."


Subject(s)
COVID-19/immunology , Chemokine CXCL10/immunology , Cytokine Release Syndrome/immunology , Interleukin-6/immunology , Macrophages/immunology , COVID-19/complications , COVID-19/virology , Chemokines/immunology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/virology , Cytokines/immunology , Humans , Respiratory System/immunology , Respiratory System/virology , SARS-CoV-2/immunology , SARS-CoV-2/physiology
5.
PLoS Pathog ; 16(12): e1009130, 2020 12.
Article in English | MEDLINE | ID: covidwho-962381

ABSTRACT

The novel coronavirus SARS-CoV-2 is the causative agent of Coronavirus Disease 2019 (COVID-19), a global healthcare and economic catastrophe. Understanding of the host immune response to SARS-CoV-2 is still in its infancy. A 382-nt deletion strain lacking ORF8 (Δ382 herein) was isolated in Singapore in March 2020. Infection with Δ382 was associated with less severe disease in patients, compared to infection with wild-type SARS-CoV-2. Here, we established Nasal Epithelial cells (NECs) differentiated from healthy nasal-tissue derived stem cells as a suitable model for the ex-vivo study of SARS-CoV-2 mediated pathogenesis. Infection of NECs with either SARS-CoV-2 or Δ382 resulted in virus particles released exclusively from the apical side, with similar replication kinetics. Screening of a panel of 49 cytokines for basolateral secretion from infected NECs identified CXCL10 as the only cytokine significantly induced upon infection, at comparable levels in both wild-type and Δ382 infected cells. Transcriptome analysis revealed the temporal up-regulation of distinct gene subsets during infection, with anti-viral signaling pathways only detected at late time-points (72 hours post-infection, hpi). This immune response to SARS-CoV-2 was significantly attenuated when compared to infection with an influenza strain, H3N2, which elicited an inflammatory response within 8 hpi, and a greater magnitude of anti-viral gene up-regulation at late time-points. Remarkably, Δ382 induced a host transcriptional response nearly identical to that of wild-type SARS-CoV-2 at every post-infection time-point examined. In accordance with previous results, Δ382 infected cells showed an absence of transcripts mapping to ORF8, and conserved expression of other SARS-CoV-2 genes. Our findings shed light on the airway epithelial response to SARS-CoV-2 infection, and demonstrate a non-essential role for ORF8 in modulating host gene expression and cytokine production from infected cells.


Subject(s)
COVID-19/virology , Nasal Mucosa/virology , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Viral Proteins/genetics , Chemokine CXCL10/immunology , Epithelial Cells/immunology , Epithelial Cells/metabolism , Epithelial Cells/virology , Host-Pathogen Interactions/physiology , Humans , Kinetics , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Transcriptome , Viral Proteins/immunology , Virus Replication/physiology
6.
Signal Transduct Target Ther ; 5(1): 235, 2020 10 09.
Article in English | MEDLINE | ID: covidwho-841900

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.


Subject(s)
Apoptosis/immunology , Betacoronavirus/pathogenicity , Caspase 8/immunology , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Necroptosis/immunology , Pneumonia, Viral/immunology , Pulmonary Fibrosis/immunology , Animals , COVID-19 , Caspase 8/genetics , Cell Line, Tumor , Chemokine CCL5/genetics , Chemokine CCL5/immunology , Chemokine CXCL10/genetics , Chemokine CXCL10/immunology , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Disease Models, Animal , Epithelial Cells/immunology , Epithelial Cells/pathology , Epithelial Cells/virology , Gene Expression Regulation , Humans , Interleukin-1beta/genetics , Interleukin-1beta/immunology , Interleukin-7/genetics , Interleukin-7/immunology , Interleukin-8/genetics , Interleukin-8/immunology , Lung/immunology , Lung/pathology , Lung/virology , Mice , Mice, Transgenic , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/virology , SARS-CoV-2 , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
7.
Nat Med ; 26(10): 1623-1635, 2020 10.
Article in English | MEDLINE | ID: covidwho-717130

ABSTRACT

Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/immunology , Coronavirus Infections/immunology , Cytokines/immunology , Dendritic Cells/immunology , Pneumonia, Viral/immunology , T-Lymphocytes/immunology , Aged , B-Lymphocyte Subsets/immunology , Basophils/immunology , Betacoronavirus , COVID-19 , Case-Control Studies , Cell Cycle , Chemokine CXCL10/immunology , Chemokines/immunology , Cohort Studies , Coronavirus Infections/blood , Disease Progression , Female , Flow Cytometry , Hospitalization , Humans , Immunologic Memory , Immunophenotyping , Interleukin-10/immunology , Interleukin-6/immunology , Leukocyte Count , Lymphocyte Activation/immunology , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Prognosis , SARS-CoV-2 , Severity of Illness Index , T-Lymphocyte Subsets/immunology , Up-Regulation
8.
Eur Rev Med Pharmacol Sci ; 24(13): 7497-7505, 2020 07.
Article in English | MEDLINE | ID: covidwho-676904

ABSTRACT

OBJECTIVE: The specific mechanism of cytokine storm in COVID-19 infected patients is not clear. This study aims to identify the key genes that cause cytokine storm in COVID-19 infected patients. MATERIALS AND METHODS: We conducted a difference analysis on the GSE147507 data set. The analysis results are combined with immune genes to obtain immune-related genes among the differential genes. Finally, GO enrichment analysis, PPI analysis, core gene identification, and ssGSEA enrichment analysis were performed on the new gene set. RESULTS: A total of 232 differential genes were screened out. After merging with immune genes, a total of 29 immune-related genes were obtained. Further analysis revealed that the genes were enriched in 16 pathways, and the protein interaction network had a total of 29 nodes and 139 edges. After screening, the core gene was CXCL10. The ssGSEA results of CXCL10 showed that CD4 and CD8 immune-related signature were significantly enriched in high CXCL10 expression, and the samples with low CXCL10 expression were significantly enriched with monocytes and DC immune-related signature. CONCLUSIONS: CXCL10 may be a key gene related to the cytokine storm of COVID-19 infection, and it is expected to become the therapeutic target.


Subject(s)
Chemokine CXCL10/genetics , Coronavirus Infections/genetics , Pneumonia, Viral/genetics , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , COVID-19 , Chemokine CXCL10/immunology , Coronavirus Infections/immunology , Humans , Pandemics , Pneumonia, Viral/immunology , Protein Interaction Maps/genetics , Protein Interaction Maps/immunology , SARS-CoV-2
9.
Neuroscientist ; 27(3): 214-221, 2021 06.
Article in English | MEDLINE | ID: covidwho-640850

ABSTRACT

COVID-19 is an ongoing viral pandemic that emerged from East Asia and quickly spread to the rest of the world. SARS-CoV-2 is the virus causing COVID-19. Acute respiratory distress syndrome (ARDS) is definitely one of the main clinically relevant consequences in patients with COVID-19. Starting from the earliest reports of the COVID-19 pandemic, two peculiar neurological manifestations (namely, hyposmia/anosmia and dysgeusia) were reported in a relevant proportion of patients infected by SARS-CoV-2. At present, the physiopathologic mechanisms accounting for the onset of these symptoms are not yet clarified. CXCL10 is a pro-inflammatory chemokine with a well-established role in the COVID-19-related cytokine storm and in subsequent development of ARDS. CXCL10 is also known to be involved in coronavirus-induced demyelination. On these bases, a role for CXCL10 as the common denominator between pulmonary and olfactory dysfunctions could be envisaged. The aim of the present report will be to hypothesize a role for CXCL10 in COVID-19 olfactory dysfunctions. Previous evidences supporting our hypothesis, with special emphasis to the role of CXCL10 in coronavirus-induced demyelination, the anatomical and physiological peculiarity of the olfactory system, and the available data supporting their link during COVID-19 infections, will be overviewed.


Subject(s)
COVID-19/complications , COVID-19/immunology , Chemokine CXCL10/immunology , Olfaction Disorders/immunology , Olfaction Disorders/virology , Animals , Humans , SARS-CoV-2
SELECTION OF CITATIONS
SEARCH DETAIL
...