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1.
Immunity ; 55(3): 423-441.e9, 2022 03 08.
Article in English | MEDLINE | ID: covidwho-1693372

ABSTRACT

Cell death plays an important role during pathogen infections. Here, we report that interferon-γ (IFNγ) sensitizes macrophages to Toll-like receptor (TLR)-induced death that requires macrophage-intrinsic death ligands and caspase-8 enzymatic activity, which trigger the mitochondrial apoptotic effectors, BAX and BAK. The pro-apoptotic caspase-8 substrate BID was dispensable for BAX and BAK activation. Instead, caspase-8 reduced pro-survival BCL-2 transcription and increased inducible nitric oxide synthase (iNOS), thus facilitating BAX and BAK signaling. IFNγ-primed, TLR-induced macrophage killing required iNOS, which licensed apoptotic caspase-8 activity and reduced the BAX and BAK inhibitors, A1 and MCL-1. The deletion of iNOS or caspase-8 limited SARS-CoV-2-induced disease in mice, while caspase-8 caused lethality independent of iNOS in a model of hemophagocytic lymphohistiocytosis. These findings reveal that iNOS selectively licenses programmed cell death, which may explain how nitric oxide impacts disease severity in SARS-CoV-2 infection and other iNOS-associated inflammatory conditions.


Subject(s)
COVID-19/immunology , Caspase 8/metabolism , Interferon-gamma/metabolism , Lymphohistiocytosis, Hemophagocytic/immunology , Macrophages/immunology , Mitochondria/metabolism , SARS-CoV-2/physiology , Animals , Caspase 8/genetics , Cells, Cultured , Cytotoxicity, Immunologic , Humans , Interferon-gamma/genetics , Macrophage Activation , Mice , Mice, Inbred C57BL , Mice, Knockout , Nitric Oxide Synthase Type II/metabolism , Pathogen-Associated Molecular Pattern Molecules/immunology , Signal Transduction , bcl-2 Homologous Antagonist-Killer Protein/genetics , bcl-2 Homologous Antagonist-Killer Protein/metabolism , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism
3.
Cytokine ; 143: 155525, 2021 07.
Article in English | MEDLINE | ID: covidwho-1628419

ABSTRACT

Interferon gamma (IFN-γ) is a crucial cytokine in host immune response to hepatitis B virus (HBV) infection. This study aimed to determine whether a functional polymorphism +874T/A in IFN-γ gene linked to high and low producer phenotypes [IFN-γ (+874Thigh â†’ Alow)] may alter the outcomes of chronic HBV infection in Tunisian population. The +874T/A was analysed by ARMS-PCR method in the group of 200 patients chronically infected with HBV and 200 healthy controls. We observed that minor +874A allele, minor +874AA and +874TA genotypes were significantly more frequent in the chronic hepatitis B group in comparison to the control group [49 vs. 31%, P < 10-4; 24 vs. 13%, P < 10-4; 52 vs. 38%, P < 10-4; respectively]. Besides, they were associated with susceptibility to hepatitis B infection [OR = 2.15, 3.87 and 2.84, respectively]. The minor +874A allele and +874AA genotype were statistically more representative in the sub-group of patients with high viral DNA load when compared with the sub-group of patients with low HBV DNA load [(57% vs. 43%, P = 0.003, OR = 1.79); (33% vs. 14%, P = 0.003, OR = 3.59), respectively]. Collectively, our study suggests an association between the IFN-γ +874T/A SNP and persistence of HBV by the enhancement of HBV DNA replication.


Subject(s)
DNA Replication , Genetic Association Studies , Genetic Predisposition to Disease , Hepatitis B virus/physiology , Hepatitis B, Chronic/genetics , Interferon-gamma/genetics , Polymorphism, Single Nucleotide/genetics , Virus Replication/physiology , Adult , Alleles , Case-Control Studies , DNA, Viral/genetics , Female , Gene Frequency/genetics , Hepatitis B, Chronic/virology , Humans , Male , Viral Load/genetics
4.
Nutrients ; 13(11)2021 Nov 12.
Article in English | MEDLINE | ID: covidwho-1512522

ABSTRACT

BACKGROUND: We aimed to establish an acute treatment protocol to increase serum vitamin D, evaluate the effectiveness of vitamin D3 supplementation, and reveal the potential mechanisms in COVID-19. METHODS: We retrospectively analyzed the data of 867 COVID-19 cases. Then, a prospective study was conducted, including 23 healthy individuals and 210 cases. A total of 163 cases had vitamin D supplementation, and 95 were followed for 14 days. Clinical outcomes, routine blood biomarkers, serum levels of vitamin D metabolism, and action mechanism-related parameters were evaluated. RESULTS: Our treatment protocol increased the serum 25OHD levels significantly to above 30 ng/mL within two weeks. COVID-19 cases (no comorbidities, no vitamin D treatment, 25OHD <30 ng/mL) had 1.9-fold increased risk of having hospitalization longer than 8 days compared with the cases with comorbidities and vitamin D treatment. Having vitamin D treatment decreased the mortality rate by 2.14 times. The correlation analysis of specific serum biomarkers with 25OHD indicated that the vitamin D action in COVID-19 might involve regulation of INOS1, IL1B, IFNg, cathelicidin-LL37, and ICAM1. CONCLUSIONS: Vitamin D treatment shortened hospital stay and decreased mortality in COVID-19 cases, even in the existence of comorbidities. Vitamin D supplementation is effective on various target parameters; therefore, it is essential for COVID-19 treatment.


Subject(s)
COVID-19/drug therapy , SARS-CoV-2 , Vitamin D/administration & dosage , Antimicrobial Cationic Peptides/blood , Antimicrobial Cationic Peptides/genetics , Antimicrobial Cationic Peptides/metabolism , COVID-19/complications , COVID-19/mortality , Dietary Supplements , Gene Expression Regulation/drug effects , Humans , Intercellular Adhesion Molecule-1/blood , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/metabolism , Interferon-gamma/blood , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-1beta/blood , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Nitric Oxide Synthase Type II/blood , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Prospective Studies , Retrospective Studies , Vitamin D/blood , Vitamin D/pharmacology , Vitamins/administration & dosage , Vitamins/pharmacology
5.
Int J Mol Sci ; 22(20)2021 Oct 18.
Article in English | MEDLINE | ID: covidwho-1470894

ABSTRACT

Infection caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in many cases is accompanied by the release of a large amount of proinflammatory cytokines in an event known as "cytokine storm", which is associated with severe coronavirus disease 2019 (COVID-19) cases and high mortality. The excessive production of proinflammatory cytokines is linked, inter alia, to the enhanced activity of receptors capable of recognizing the conservative regions of pathogens and cell debris, namely TLRs, TREM-1 and TNFR1. Here we report that peptides derived from innate immunity protein Tag7 inhibit activation of TREM-1 and TNFR1 receptors during acute inflammation. Peptides from the N-terminal fragment of Tag7 bind only to TREM-1, while peptides from the C-terminal fragment interact solely with TNFR1. Selected peptides are capable of inhibiting the production of proinflammatory cytokines both in peripheral blood mononuclear cells (PBMCs) from healthy donors and in vivo in the mouse model of acute lung injury (ALI) by diffuse alveolar damage (DAD). Treatment with peptides significantly decreases the infiltration of mononuclear cells to lungs in animals with DAD. Our findings suggest that Tag7-derived peptides might be beneficial in terms of the therapy or prevention of acute lung injury, e.g., for treating COVID-19 patients with severe pulmonary lesions.


Subject(s)
Acute Lung Injury/pathology , Cytokines/chemistry , Peptides/metabolism , Receptors, Tumor Necrosis Factor, Type I/metabolism , Triggering Receptor Expressed on Myeloid Cells-1/metabolism , Acute Lung Injury/metabolism , Animals , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Humans , Interferon-gamma/genetics , Interferon-gamma/metabolism , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/pharmacology , Lung/metabolism , Lung/pathology , Lymphocyte Activation/drug effects , Male , Mice , Mice, Inbred ICR , Peptides/chemistry , Peptides/pharmacology , Protein Binding , Receptors, Tumor Necrosis Factor, Type I/antagonists & inhibitors , Triggering Receptor Expressed on Myeloid Cells-1/antagonists & inhibitors
8.
Mol Ther ; 29(6): 1970-1983, 2021 06 02.
Article in English | MEDLINE | ID: covidwho-1386766

ABSTRACT

A self-transcribing and replicating RNA (STARR)-based vaccine (LUNAR-COV19) has been developed to prevent SARS-CoV-2 infection. The vaccine encodes an alphavirus-based replicon and the SARS-CoV-2 full-length spike glycoprotein. Translation of the replicon produces a replicase complex that amplifies and prolongs SARS-CoV-2 spike glycoprotein expression. A single prime vaccination in mice led to robust antibody responses, with neutralizing antibody titers increasing up to day 60. Activation of cell-mediated immunity produced a strong viral antigen-specific CD8+ T lymphocyte response. Assaying for intracellular cytokine staining for interferon (IFN)γ and interleukin-4 (IL-4)-positive CD4+ T helper (Th) lymphocytes as well as anti-spike glycoprotein immunoglobulin G (IgG)2a/IgG1 ratios supported a strong Th1-dominant immune response. Finally, single LUNAR-COV19 vaccination at both 2 µg and 10 µg doses completely protected human ACE2 transgenic mice from both mortality and even measurable infection following wild-type SARS-CoV-2 challenge. Our findings collectively suggest the potential of LUNAR-COV19 as a single-dose vaccine.


Subject(s)
Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/administration & dosage , Alphavirus/genetics , Alphavirus/immunology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , COVID-19 Vaccines/biosynthesis , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Female , Gene Expression , Humans , Immunity, Cellular/drug effects , Immunity, Humoral/drug effects , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-4/genetics , Interleukin-4/immunology , Mice , Mice, Transgenic , Replicon/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Th1 Cells/drug effects , Th1 Cells/immunology , Th1 Cells/virology , Transgenes , Treatment Outcome , Vaccination/methods , Vaccines, Synthetic/biosynthesis , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology
9.
J Infect Dis ; 224(5): 777-782, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1381012

ABSTRACT

We analyzed plasma levels of interferons (IFNs) and cytokines, and expression of IFN-stimulated genes in peripheral blood mononuclear cells in patients with coronavirus disease 2019 of varying disease severity. Patients hospitalized with mild disease exhibited transient type I IFN responses, while intensive care unit patients had prolonged type I IFN responses. Type II IFN responses were compromised in intensive care unit patients. Type III IFN responses were induced in the early phase of infection, even in convalescent patients. These results highlight the importance of early type I and III IFN responses in controlling coronavirus disease 2019 progression.


Subject(s)
COVID-19/immunology , Interferon Type I/immunology , Interferon-gamma/immunology , Interferons/immunology , COVID-19/blood , Chemokines/blood , Cytokines/blood , Humans , Interferon Type I/blood , Interferon Type I/genetics , Interferon-gamma/blood , Interferon-gamma/genetics , Interferons/blood , Leukocytes, Mononuclear/immunology , SARS-CoV-2/isolation & purification
10.
Front Immunol ; 12: 693054, 2021.
Article in English | MEDLINE | ID: covidwho-1334935

ABSTRACT

Advanced age is associated with severe symptoms and death upon SARS-CoV-2 infection. Virus-specific CD8+ T-cell responses have shown to be protective toward critical COVID-19 manifestations, suggesting that suboptimal cellular immunity may contribute to the age-pattern of the disease. The induction of a CD8+ T-cell response against an emerging pathogen like SARS-CoV-2 relies on the activation of naive T cells. To investigate whether the primary CD8+ T-cell response against this virus is defective in advanced age, we used an in vitro approach to prime SARS-CoV-2-specific naive CD8+ T cells from healthy, unexposed donors of different age groups. Compared to younger adults, older individuals display a poor SARS-CoV-2-specific T-cell priming capacity in terms of both magnitude and quality of the response. In addition, older subjects recognize a lower number of epitopes. Our results implicate that immune aging is associated with altered primary SARS-CoV-2-specific CD8+ T-cell responses.


Subject(s)
Aging/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Adult , Aged , Antigens, Viral/immunology , Cells, Cultured , Enzyme-Linked Immunospot Assay , Epitopes, T-Lymphocyte/immunology , Gene Expression Regulation , Healthy Volunteers , Humans , Interferon-gamma/genetics , Interferon-gamma/metabolism , Lymphocyte Activation , Middle Aged , Peptides/immunology , Young Adult
11.
J Biol Chem ; 296: 100630, 2021.
Article in English | MEDLINE | ID: covidwho-1333548

ABSTRACT

Unchecked inflammation can result in severe diseases with high mortality, such as macrophage activation syndrome (MAS). MAS and associated cytokine storms have been observed in COVID-19 patients exhibiting systemic hyperinflammation. Interleukin-18 (IL-18), a proinflammatory cytokine belonging to the IL-1 family, is elevated in both MAS and COVID-19 patients, and its level is known to correlate with the severity of COVID-19 symptoms. IL-18 binds its specific receptor IL-1 receptor 5 (IL-1R5, also known as IL-18 receptor alpha chain), leading to the recruitment of the coreceptor, IL-1 receptor 7 (IL-1R7, also known as IL-18 receptor beta chain). This heterotrimeric complex then initiates downstream signaling, resulting in systemic and local inflammation. Here, we developed a novel humanized monoclonal anti-IL-1R7 antibody to specifically block the activity of IL-18 and its inflammatory signaling. We characterized the function of this antibody in human cell lines, in freshly obtained peripheral blood mononuclear cells (PBMCs) and in human whole blood cultures. We found that the anti-IL-1R7 antibody significantly suppressed IL-18-mediated NFκB activation, reduced IL-18-stimulated IFNγ and IL-6 production in human cell lines, and reduced IL-18-induced IFNγ, IL-6, and TNFα production in PBMCs. Moreover, the anti-IL-1R7 antibody significantly inhibited LPS- and Candida albicans-induced IFNγ production in PBMCs, as well as LPS-induced IFNγ production in whole blood cultures. Our data suggest that blocking IL-1R7 could represent a potential therapeutic strategy to specifically modulate IL-18 signaling and may warrant further investigation into its clinical potential for treating IL-18-mediated diseases, including MAS and COVID-19.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/pharmacology , Immunologic Factors/pharmacology , Interleukin-18/genetics , Receptors, Interleukin-18/genetics , Anti-Inflammatory Agents/metabolism , Antibodies, Monoclonal/biosynthesis , Antibodies, Neutralizing/biosynthesis , COVID-19/drug therapy , Candida albicans/growth & development , Candida albicans/pathogenicity , Gene Expression Regulation , HEK293 Cells , Humans , Immunologic Factors/biosynthesis , Inflammation , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-18/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/microbiology , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Macrophage Activation Syndrome/drug therapy , NF-kappa B/genetics , NF-kappa B/immunology , Primary Cell Culture , Receptors, Interleukin-18/antagonists & inhibitors , Receptors, Interleukin-18/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
13.
Int J Mol Sci ; 22(14)2021 Jul 13.
Article in English | MEDLINE | ID: covidwho-1308364

ABSTRACT

Children with the new coronavirus disease 2019 (COVID-19) have milder symptoms and a better prognosis than adult patients. Several investigations assessed type I, II, and III interferon (IFN) signatures in SARS-CoV-2 infected adults, however no data are available for pediatric patients. TRIM28 and SETDB1 regulate the transcription of multiple genes involved in the immune response as well as of human endogenous retroviruses (HERVs). Exogenous viral infections can trigger the activation of HERVs, which in turn can induce inflammatory and immune reactions. Despite the potential cross-talks between SARS-CoV-2 infection and TRIM28, SETDB1, and HERVs, information on their expressions in COVID-19 patients is lacking. We assessed, through a PCR real time Taqman amplification assay, the transcription levels of six IFN-I stimulated genes, IFN-II and three of its sensitive genes, three IFN-lIIs, as well as of TRIM28, SETDB1, pol genes of HERV-H, -K, and -W families, and of env genes of Syncytin (SYN)1, SYN2, and multiple sclerosis-associated retrovirus (MRSV) in peripheral blood from COVID-19 children and in control uninfected subjects. Higher expression levels of IFN-I and IFN-II inducible genes were observed in 36 COVID-19 children with mild or moderate disease as compared to uninfected controls, whereas their concentrations decreased in 17 children with severe disease and in 11 with multisystem inflammatory syndrome (MIS-C). Similar findings were found for the expression of TRIM-28, SETDB1, and every HERV gene. Positive correlations emerged between the transcriptional levels of type I and II IFNs, TRIM28, SETDB1, and HERVs in COVID-19 patients. IFN-III expressions were comparable in each group of subjects. This preserved induction of IFN-λs could contribute to the better control of the infection in children as compared to adults, in whom IFN-III deficiency has been reported. The upregulation of IFN-I, IFN-II, TRIM28, SETDB1, and HERVs in children with mild symptoms, their declines in severe cases or with MIS-C, and the positive correlations of their transcription in SARS-CoV-2-infected children suggest that they may play important roles in conditioning the evolution of the infection.


Subject(s)
COVID-19/epidemiology , COVID-19/metabolism , Endogenous Retroviruses/metabolism , SARS-CoV-2/isolation & purification , Severity of Illness Index , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Child , Endogenous Retroviruses/genetics , Female , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Humans , Interferon Type I/genetics , Interferon Type I/metabolism , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interferons/genetics , Interferons/metabolism , Italy/epidemiology , Male , Tripartite Motif-Containing Protein 28/genetics , Tripartite Motif-Containing Protein 28/metabolism
14.
J Infect Dis ; 224(5): 777-782, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1243489

ABSTRACT

We analyzed plasma levels of interferons (IFNs) and cytokines, and expression of IFN-stimulated genes in peripheral blood mononuclear cells in patients with coronavirus disease 2019 of varying disease severity. Patients hospitalized with mild disease exhibited transient type I IFN responses, while intensive care unit patients had prolonged type I IFN responses. Type II IFN responses were compromised in intensive care unit patients. Type III IFN responses were induced in the early phase of infection, even in convalescent patients. These results highlight the importance of early type I and III IFN responses in controlling coronavirus disease 2019 progression.


Subject(s)
COVID-19/immunology , Interferon Type I/immunology , Interferon-gamma/immunology , Interferons/immunology , COVID-19/blood , Chemokines/blood , Cytokines/blood , Humans , Interferon Type I/blood , Interferon Type I/genetics , Interferon-gamma/blood , Interferon-gamma/genetics , Interferons/blood , Leukocytes, Mononuclear/immunology , SARS-CoV-2/isolation & purification
15.
Int J Mol Sci ; 22(10)2021 May 15.
Article in English | MEDLINE | ID: covidwho-1236794

ABSTRACT

Acute lung injury (ALI) afflicts approximately 200,000 patients annually and has a 40% mortality rate. The COVID-19 pandemic has massively increased the rate of ALI incidence. The pathogenesis of ALI involves tissue damage from invading microbes and, in severe cases, the overexpression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). This study aimed to develop a therapy to normalize the excess production of inflammatory cytokines and promote tissue repair in the lipopolysaccharide (LPS)-induced ALI. Based on our previous studies, we tested the insulin-like growth factor I (IGF-I) and BTP-2 therapies. IGF-I was selected, because we and others have shown that elevated inflammatory cytokines suppress the expression of growth hormone receptors in the liver, leading to a decrease in the circulating IGF-I. IGF-I is a growth factor that increases vascular protection, enhances tissue repair, and decreases pro-inflammatory cytokines. It is also required to produce anti-inflammatory 1,25-dihydroxyvitamin D. BTP-2, an inhibitor of cytosolic calcium, was used to suppress the LPS-induced increase in cytosolic calcium, which otherwise leads to an increase in proinflammatory cytokines. We showed that LPS increased the expression of the primary inflammatory mediators such as toll like receptor-4 (TLR-4), IL-1ß, interleukin-17 (IL-17), TNF-α, and interferon-γ (IFN-γ), which were normalized by the IGF-I + BTP-2 dual therapy in the lungs, along with improved vascular gene expression markers. The histologic lung injury score was markedly elevated by LPS and reduced to normal by the combination therapy. In conclusion, the LPS-induced increases in inflammatory cytokines, vascular injuries, and lung injuries were all improved by IGF-I + BTP-2 combination therapy.


Subject(s)
Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Anilides/pharmacology , Cytokines/metabolism , Gene Expression Regulation/drug effects , Insulin-Like Growth Factor I/pharmacology , Thiadiazoles/pharmacology , Acute Lung Injury/pathology , Acute Lung Injury/virology , Anilides/therapeutic use , Animals , COVID-19/complications , Calcium/metabolism , Calcium Channels/metabolism , Cytokines/genetics , Disease Models, Animal , Female , Gene Expression Regulation/genetics , Immunohistochemistry , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor I/therapeutic use , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-17/genetics , Interleukin-17/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lipopolysaccharides/toxicity , Mice , Mice, Inbred C57BL , Signal Transduction/drug effects , Signal Transduction/genetics , Thiadiazoles/therapeutic use , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
16.
J Int Med Res ; 49(3): 3000605211002695, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1145418

ABSTRACT

Over the past several decades, studies have demonstrated the existence of bi-directional relationships between periodontal disease and systemic conditions. Periodontitis is a polymicrobial and multifactorial disease involving both host and environmental factors. Tissue destruction is primarily associated with hyperresponsiveness of the host resulting in release of inflammatory mediators. Pro-inflammatory cytokines play a major role in bacterial stimulation and tissue destruction. In addition, these cytokines are thought to underlie the associations between periodontitis and systemic conditions. Current research suggests that increased release of cytokines from host cells, referred to as the cytokine storm, is associated with disease progression in patients with coronavirus disease 2019 (COVID-19). An intersection between periodontitis and pulmonary disease is biologically plausible. Hence, we reviewed the evidence linking COVID-19, cytokines, and periodontal disease. Plaque control is essential to prevent exchange of bacteria between the mouth and the lungs, reducing the risk of lung disease. Understanding these associations may help identify individuals at high risk and deliver appropriate care at early stages.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Dental Plaque/immunology , Host-Pathogen Interactions/immunology , Periodontitis/immunology , SARS-CoV-2/pathogenicity , Stress, Psychological/immunology , COVID-19/complications , COVID-19/genetics , COVID-19/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/virology , Dental Plaque/complications , Dental Plaque/genetics , Dental Plaque/virology , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Humans , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-10/genetics , Interleukin-10/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Lung/immunology , Lung/pathology , Lung/virology , Pathogen-Associated Molecular Pattern Molecules/immunology , Pathogen-Associated Molecular Pattern Molecules/metabolism , Periodontitis/complications , Periodontitis/genetics , Periodontitis/virology , SARS-CoV-2/immunology , Signal Transduction , Stress, Psychological/complications , Stress, Psychological/genetics , Stress, Psychological/virology , Tooth/immunology , Tooth/pathology , Tooth/virology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
17.
J Mol Cell Biol ; 13(3): 197-209, 2021 07 06.
Article in English | MEDLINE | ID: covidwho-1145182

ABSTRACT

Although millions of patients have clinically recovered from COVID-19, little is known about the immune status of lymphocytes in these individuals. In this study, the peripheral blood mononuclear cells of a clinically recovered (CR) cohort were comparatively analyzed with those of an age- and sex-matched healthy donor cohort. We found that CD8+ T cells in the CR cohort had higher numbers of effector T cells and effector memory T cells but lower Tc1 (IFN-γ+), Tc2 (IL-4+), and Tc17 (IL-17A+) cell frequencies. The CD4+ T cells of the CR cohort were decreased in frequency, especially the central memory T cell subset. Moreover, CD4+ T cells in the CR cohort showed lower programmed cell death protein 1 (PD-1) expression and had lower frequencies of Th1 (IFN-γ+), Th2 (IL-4+), Th17 (IL-17A+), and circulating follicular helper T (CXCR5+PD-1+) cells. Accordingly, the proportion of isotype-switched memory B cells (IgM-CD20hi) among B cells in the CR cohort showed a significantly lower proportion, although the level of the activation marker CD71 was elevated. For CD3-HLA-DR- lymphocytes in the CR cohort, in addition to lower levels of IFN-γ, granzyme B and T-bet, the correlation between T-bet and IFN-γ was not observed. Additionally, by taking into account the number of days after discharge, all the phenotypes associated with reduced function did not show a tendency toward recovery within 4‒11 weeks. The remarkable phenotypic alterations in lymphocytes in the CR cohort suggest that  severe acute respiratory syndrome coronavirus 2 infection profoundly affects lymphocytes and potentially results in dysfunction even after clinical recovery.


Subject(s)
CD8-Positive T-Lymphocytes/virology , COVID-19/blood , Leukocytes, Mononuclear/virology , SARS-CoV-2/pathogenicity , Adult , Aged , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , COVID-19/epidemiology , COVID-19/pathology , COVID-19/virology , Cell Lineage/genetics , Cell Lineage/immunology , Female , Gene Expression Regulation/immunology , Granzymes/genetics , Humans , Interferon-gamma/genetics , Leukocytes, Mononuclear/pathology , Male , Middle Aged , T-Box Domain Proteins/genetics , Th1 Cells/immunology , Th1 Cells/virology , Th17 Cells/immunology , Th17 Cells/virology , Th2 Cells/immunology , Th2 Cells/virology
18.
Cells ; 10(3)2021 03 02.
Article in English | MEDLINE | ID: covidwho-1125490

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) that has resulted in the current pandemic. The lack of highly efficacious antiviral drugs that can manage this ongoing global emergency gives urgency to establishing a comprehensive understanding of the molecular pathogenesis of SARS-CoV-2. We characterized the role of the nucleocapsid protein (N) of SARS-CoV-2 in modulating antiviral immunity. Overexpression of SARS-CoV-2 N resulted in the attenuation of retinoic acid inducible gene-I (RIG-I)-like receptor-mediated interferon (IFN) production and IFN-induced gene expression. Similar to the SARS-CoV-1 N protein, SARS-CoV-2 N suppressed the interaction between tripartate motif protein 25 (TRIM25) and RIG-I. Furthermore, SARS-CoV-2 N inhibited polyinosinic: polycytidylic acid [poly(I:C)]-mediated IFN signaling at the level of Tank-binding kinase 1 (TBK1) and interfered with the association between TBK1 and interferon regulatory factor 3 (IRF3), subsequently preventing the nuclear translocation of IRF3. We further found that both type I and III IFN production induced by either the influenza virus lacking the nonstructural protein 1 or the Zika virus were suppressed by the SARS-CoV-2 N protein. Our findings provide insights into the molecular function of the SARS-CoV-2 N protein with respect to counteracting the host antiviral immune response.


Subject(s)
Coronavirus Nucleocapsid Proteins/metabolism , DEAD Box Protein 58/metabolism , Interferons/metabolism , Receptors, Immunologic/metabolism , SARS-CoV-2/metabolism , DEAD Box Protein 58/genetics , Host-Pathogen Interactions/genetics , Humans , Interferon Regulatory Factor-3/genetics , Interferon Regulatory Factor-3/metabolism , Interferon Type I/genetics , Interferon Type I/metabolism , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interferons/genetics , Orthomyxoviridae/genetics , Orthomyxoviridae/metabolism , Phosphoproteins/metabolism , Poly C/pharmacology , Poly I/pharmacology , Promoter Regions, Genetic , /metabolism , Receptors, Immunologic/genetics , SARS-CoV-2/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Transcription Factors/metabolism , Tripartite Motif Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Up-Regulation , Zika Virus/genetics , Zika Virus/metabolism
19.
JCI Insight ; 6(1)2021 01 11.
Article in English | MEDLINE | ID: covidwho-1027164

ABSTRACT

Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.


Subject(s)
COVID-19/immunology , COVID-19/mortality , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Anti-Bacterial Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , Biomarkers , COVID-19/genetics , COVID-19/therapy , Calgranulin B/genetics , Calgranulin B/immunology , Case-Control Studies , Chemokine CCL2/genetics , Chemokine CCL2/immunology , Chemokine CXCL9/genetics , Chemokine CXCL9/immunology , Enzyme Inhibitors/therapeutic use , Female , Ferritins/genetics , Ferritins/immunology , Gene Expression Profiling , Humans , Hydroxychloroquine/therapeutic use , Immunologic Factors/therapeutic use , Interferon Type I/genetics , Interferon Type I/immunology , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-1 Receptor-Like 1 Protein/genetics , Interleukin-1 Receptor-Like 1 Protein/immunology , Interleukin-10/genetics , Interleukin-10/immunology , Interleukin-15/genetics , Interleukin-15/immunology , Interleukin-2/genetics , Interleukin-2/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Lactoferrin/genetics , Lactoferrin/immunology , Lipocalin-2/genetics , Lipocalin-2/immunology , Male , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/immunology , Middle Aged , Multivariate Analysis , NF-kappa B/genetics , NF-kappa B/immunology
20.
J Med Virol ; 92(10): 2114-2123, 2020 10.
Article in English | MEDLINE | ID: covidwho-777547

ABSTRACT

The present study provides the first multiepitope vaccine construct using the 3CL hydrolase protein of SARS-CoV-2. The coronavirus 3CL hydrolase (Mpro) enzyme is essential for proteolytic maturation of the virus. This study was based on immunoinformatics and structural vaccinology strategies. The design of the multiepitope vaccine was built using helper T-cell and cytotoxic T-cell epitopes from the 3CL hydrolase protein along with an adjuvant to enhance immune response; these are joined to each other by short peptide linkers. The vaccine also carries potential B-cell linear epitope regions, B-cell discontinuous epitopes, and interferon-γ-inducing epitopes. Epitopes of the constructed multiepitope vaccine were found to be antigenic, nonallergic, nontoxic, and covering large human populations worldwide. The vaccine construct was modeled, validated, and refined by different programs to achieve a high-quality three-dimensional structure. The resulting high-quality model was applied for conformational B-cell epitope selection and docking analyses with toll-like receptor-3 for understanding the capability of the vaccine to elicit an immune response. In silico cloning and codon adaptation were also performed with the pET-19b plasmid vector. The designed multiepitope peptide vaccine may prompt the development of a vaccine to control SARS-CoV-2 infection.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Coronavirus 3C Proteases/immunology , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Toll-Like Receptor 3/immunology , Amino Acid Sequence , Binding Sites , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/genetics , Cloning, Molecular/methods , Computational Biology/methods , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/genetics , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/genetics , Genetic Vectors/chemistry , Genetic Vectors/immunology , HLA Antigens/chemistry , HLA Antigens/genetics , HLA Antigens/immunology , Humans , Immunity, Innate/drug effects , Immunogenicity, Vaccine , Interferon-gamma/genetics , Interferon-gamma/immunology , Molecular Docking Simulation , Protein Binding , Protein Interaction Domains and Motifs , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , T-Lymphocytes, Cytotoxic/chemistry , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/virology , T-Lymphocytes, Helper-Inducer/chemistry , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/virology , Toll-Like Receptor 3/chemistry , Toll-Like Receptor 3/genetics , User-Computer Interface , Vaccines, Subunit
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