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1.
Genes Immun ; 23(1): 51-56, 2022 02.
Article in English | MEDLINE | ID: covidwho-1585868

ABSTRACT

Toll-like receptors (TLR) are crucial components in the initiation of innate immune responses to a variety of pathogens, triggering the production of pro-inflammatory cytokines and type I and II interferons, which are responsible for innate antiviral responses. Among the different TLRs, TLR7 recognizes several single-stranded RNA viruses including SARS-CoV-2. We and others identified rare loss-of-function variants in X-chromosomal TLR7 in young men with severe COVID-19 and with no prior history of major chronic diseases, that were associated with impaired TLR7 signaling as well as type I and II IFN responses. Here, we performed RNA sequencing to investigate transcriptome variations following imiquimod stimulation of peripheral blood mononuclear cells isolated from patients carrying previously identified hypomorphic, hypofunctional, and loss-of-function TLR7 variants. Our investigation revealed a profound impairment of the TLR7 pathway in patients carrying loss-of-function variants. Of note, a failure in IFNγ upregulation following stimulation was also observed in cells harboring the hypofunctional and hypomorphic variants. We also identified new TLR7 variants in severely affected male patients for which a functional characterization of the TLR7 pathway was performed demonstrating a decrease in mRNA levels in the IFNα, IFNγ, RSAD2, ACOD1, IFIT2, and CXCL10 genes.


Subject(s)
COVID-19 , Toll-Like Receptor 7 , Cytokines/metabolism , Down-Regulation , Humans , Leukocytes, Mononuclear/metabolism , Male , SARS-CoV-2 , Toll-Like Receptor 7/genetics , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 8/genetics , Toll-Like Receptor 8/metabolism
2.
Front Immunol ; 12: 756262, 2021.
Article in English | MEDLINE | ID: covidwho-1551507

ABSTRACT

A male sex bias has emerged in the COVID-19 pandemic, fitting to the sex-biased pattern in other viral infections. Males are 2.84 times more often admitted to the ICU and mortality is 1.39 times higher as a result of COVID-19. Various factors play a role in this, and novel studies suggest that the gene-dose of Toll-Like Receptor (TLR) 7 could contribute to the sex-skewed severity. TLR7 is one of the crucial pattern recognition receptors for SARS-CoV-2 ssRNA and the gene-dose effect is caused by X chromosome inactivation (XCI) escape. Female immune cells with TLR7 XCI escape have biallelic TLR7 expression and produce more type 1 interferon (IFN) upon TLR7 stimulation. In COVID-19, TLR7 in plasmacytoid dendritic cells is one of the pattern recognition receptors responsible for IFN production and a delayed IFN response has been associated with immunopathogenesis and mortality. Here, we provide a hypothesis that females may be protected to some extend against severe COVID-19, due to the biallelic TLR7 expression, allowing them to mount a stronger and more protective IFN response early after infection. Studies exploring COVID-19 treatment via the TLR7-mediated IFN pathway should consider this sex difference. Various factors such as age, sex hormones and escape modulation remain to be investigated concerning the TLR7 gene-dose effect.


Subject(s)
COVID-19/mortality , Gene Dosage/genetics , Interferon Type I/biosynthesis , Toll-Like Receptor 7/genetics , Toll-Like Receptor 7/metabolism , COVID-19/drug therapy , COVID-19/pathology , Chromosomes, Human, X/genetics , Critical Care/statistics & numerical data , Dendritic Cells/immunology , Female , Humans , Interferon Type I/immunology , Male , RNA, Viral/genetics , Receptors, Pattern Recognition/genetics , Receptors, Pattern Recognition/metabolism , Risk Factors , SARS-CoV-2/immunology , Sex Factors , Signal Transduction/immunology , X Chromosome Inactivation/genetics
3.
Dermatology ; 237(6): 847-856, 2021.
Article in English | MEDLINE | ID: covidwho-1398749

ABSTRACT

BACKGROUND: The innate immune system is recognized as an essential aspect of COVID-19 pathogenesis. Toll-like receptors (TLRs) are important in inducing antiviral response, triggering downstream production of interferons (IFNs). Certain loss-of-function variants in TLR7 are associated with increased COVID-19 disease severity, and imiquimod (ImiQ) is known to have immunomodulating effects as an agonist of TLR7. Given that topical imiquimod (topImiQ) is indicated for various dermatologic conditions, it is necessary for dermatologists to understand the interplay between innate immunity mechanisms and the potential role of ImiQ in COVID-19, with a particular focus on TLR7. SUMMARY: Our objective was to survey recent peer-reviewed scientific literature in the PubMed database, examine relevant evidence, and elucidate the relationships between IFNs, TLR7, the innate immune system, and topImiQ in the context of COVID-19. Despite limited studies on this topic, current evidence supports the critical role of TLRs in mounting a strong immune response against COVID-19. Of particular interest to dermatologists, topImiQ can result in systemic upregulation of the immune system via activation of TLR7. Key Message: Given the role of TLR7 in the systemic activation of the immune system, ImiQ, as a ligand of the TLR7 receptor, may have potential therapeutic benefit as a topical immunomodulatory treatment for COVID-19.


Subject(s)
COVID-19/prevention & control , Imiquimod/administration & dosage , Immunity, Innate , Interferons/administration & dosage , SARS-CoV-2 , Toll-Like Receptor 7/metabolism , Up-Regulation/drug effects , Adjuvants, Immunologic/pharmacology , Administration, Topical , Animals , Antiviral Agents/administration & dosage , COVID-19/epidemiology , COVID-19/metabolism , Humans
4.
PLoS Pathog ; 17(9): e1009878, 2021 09.
Article in English | MEDLINE | ID: covidwho-1394563

ABSTRACT

SARS-CoV-2 fine-tunes the interferon (IFN)-induced antiviral responses, which play a key role in preventing coronavirus disease 2019 (COVID-19) progression. Indeed, critically ill patients show an impaired type I IFN response accompanied by elevated inflammatory cytokine and chemokine levels, responsible for cell and tissue damage and associated multi-organ failure. Here, the early interaction between SARS-CoV-2 and immune cells was investigated by interrogating an in vitro human peripheral blood mononuclear cell (PBMC)-based experimental model. We found that, even in absence of a productive viral replication, the virus mediates a vigorous TLR7/8-dependent production of both type I and III IFNs and inflammatory cytokines and chemokines, known to contribute to the cytokine storm observed in COVID-19. Interestingly, we observed how virus-induced type I IFN secreted by PBMC enhances anti-viral response in infected lung epithelial cells, thus, inhibiting viral replication. This type I IFN was released by plasmacytoid dendritic cells (pDC) via an ACE-2-indipendent but Neuropilin-1-dependent mechanism. Viral sensing regulates pDC phenotype by inducing cell surface expression of PD-L1 marker, a feature of type I IFN producing cells. Coherently to what observed in vitro, asymptomatic SARS-CoV-2 infected subjects displayed a similar pDC phenotype associated to a very high serum type I IFN level and induction of anti-viral IFN-stimulated genes in PBMC. Conversely, hospitalized patients with severe COVID-19 display very low frequency of circulating pDC with an inflammatory phenotype and high levels of chemokines and pro-inflammatory cytokines in serum. This study further shed light on the early events resulting from the interaction between SARS-CoV-2 and immune cells occurring in vitro and confirmed ex vivo. These observations can improve our understanding on the contribution of pDC/type I IFN axis in the regulation of the anti-viral state in asymptomatic and severe COVID-19 patients.


Subject(s)
COVID-19/immunology , Dendritic Cells/classification , Interferon Type I/metabolism , SARS-CoV-2/immunology , Adult , Aged, 80 and over , Asymptomatic Infections , Cell Line, Tumor , Dendritic Cells/immunology , Dendritic Cells/virology , Epithelial Cells/cytology , Female , Hospitalization , Humans , Interferon Type I/immunology , Lung/cytology , Male , Middle Aged , Neuropilin-1/metabolism , Phenotype , Severity of Illness Index , Toll-Like Receptor 7/metabolism
5.
J Innate Immun ; 13(6): 345-358, 2021.
Article in English | MEDLINE | ID: covidwho-1245277

ABSTRACT

Regulation of proinflammatory cytokine expression is critical in the face of single-stranded RNA (ssRNA) virus infections. Many viruses, including coronavirus and influenza virus, wreak havoc on the control of cytokine expression, leading to the formation of detrimental cytokine storms. Understanding the regulation and interplay between inflammatory cytokines is critical to the identification of targets involved in controlling the induction of cytokine expression. In this study, we focused on how the antiviral cytokine interleukin-27 (IL-27) regulates signal transduction downstream of Toll-like receptor 7 (TLR7) and TLR8 ligation, which recognize endosomal single-stranded RNA. Given that IL-27 alters bacterial-sensing TLR expression on myeloid cells and can inhibit replication of single-stranded RNA viruses, we investigated whether IL-27 affects expression and function of TLR7 and TLR8. Analysis of IL-27-treated THP-1 monocytic cells and THP-1-derived macrophages revealed changes in mRNA and protein expression of TLR7 and TLR8. Although treatment with IL-27 enhanced TLR7 expression, only TLR8-mediated cytokine secretion was amplified. Furthermore, we demonstrated that imiquimod, a TLR7 agonist, inhibited cytokine and chemokine production induced by a TLR8 agonist, TL8-506. Delineating the immunomodulatory role of IL-27 on TLR7 and TLR8 responses provides insight into how myeloid cell TLR-mediated responses are regulated during virus infection.


Subject(s)
Interleukin-27/immunology , Macrophages/immunology , Monocytes/immunology , Toll-Like Receptor 7/immunology , Toll-Like Receptor 8/immunology , Cytokines/immunology , Humans , Immunomodulation , Inflammation , RNA, Messenger/metabolism , Signal Transduction , THP-1 Cells , Toll-Like Receptor 7/genetics , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 8/genetics , Toll-Like Receptor 8/metabolism
6.
Front Immunol ; 12: 635018, 2021.
Article in English | MEDLINE | ID: covidwho-1211810

ABSTRACT

Objective: Bacterial and viral infectious triggers are linked to spondyloarthritis (SpA) including psoriatic arthritis (PsA) development, likely via dendritic cell activation. We investigated spinal entheseal plasmacytoid dendritic cells (pDCs) toll-like receptor (TLR)-7 and 9 activation and therapeutic modulation, including JAK inhibition. We also investigated if COVID-19 infection, a potent TLR-7 stimulator triggered PsA flares. Methods: Normal entheseal pDCs were characterized and stimulated with imiquimod and CpG oligodeoxynucleotides (ODN) to evaluate TNF and IFNα production. NanoString gene expression assay of total pDCs RNA was performed pre- and post- ODN stimulation. Pharmacological inhibition of induced IFNα protein was performed with Tofacitinib and PDE4 inhibition. The impact of SARS-CoV2 viral infection on PsA flares was evaluated. Results: CD45+HLA-DR+CD123+CD303+CD11c- entheseal pDCs were more numerous than blood pDCs (1.9 ± 0.8% vs 0.2 ± 0.07% of CD45+ cells, p=0.008) and showed inducible IFNα and TNF protein following ODN/imiquimod stimulation and were the sole entheseal IFNα producers. NanoString data identified 11 significantly upregulated differentially expressed genes (DEGs) including TNF in stimulated pDCs. Canonical pathway analysis revealed activation of dendritic cell maturation, NF-κB signaling, toll-like receptor signaling and JAK/STAT signaling pathways following ODN stimulation. Both tofacitinib and PDE4i strongly attenuated ODN induced IFNα. DAPSA scores elevations occurred in 18 PsA cases with SARS-CoV2 infection (9.7 ± 4 pre-infection and 35.3 ± 7.5 during infection). Conclusion: Entheseal pDCs link microbes to TNF/IFNα production. SARS-CoV-2 infection is associated with PsA Flares and JAK inhibition suppressed activated entheseal plasmacytoid dendritic Type-1 interferon responses as pointers towards a novel mechanism of PsA and SpA-related arthropathy.


Subject(s)
Arthritis, Psoriatic/complications , COVID-19/complications , Dendritic Cells/metabolism , Interferon-alpha/metabolism , Janus Kinases/antagonists & inhibitors , Adjuvants, Immunologic/pharmacology , Adult , Aged , COVID-19/genetics , COVID-19/metabolism , Computational Biology , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Dendritic Cells/drug effects , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Humans , Imiquimod/pharmacology , Janus Kinases/metabolism , Male , Middle Aged , NF-kappa B/metabolism , Oligonucleotides/pharmacology , Phosphodiesterase 4 Inhibitors/pharmacology , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Signal Transduction/drug effects , Signal Transduction/genetics , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 9/metabolism , Transcriptome , Tumor Necrosis Factor-alpha/metabolism
7.
Int Immunopharmacol ; 96: 107671, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1227634

ABSTRACT

Chlorogenic acid (CGA) is a phenolic compound that has been well studied for its antiviral, anti-inflammatory and immune stimulating properties. This research was aimed to focus on the antiviral properties of CGA on infectious bronchitis virus (IBV) in vivo and in vitro for the very first time. The outcome of in vitro experiments validated that, out of five previously reported antiviral components, CGA significantly reduced the relative mRNA expression of IBV-N in CEK cells. At high concentration (400 mg/kg), CGA supplementation reduced IBV-N mRNA expression levels and ameliorated the injury in trachea and lungs. The mRNA expression levels of IL-6, IL-1ß, IL-12, and NF-κB were considerably turned down, but IL-22 and IL-10 were enhanced in trachea. However, CGA-H treatment had considerably increased the expression levels of MDA5, MAVS, TLR7, MyD88, IRF7, IFN-ß and IFN-α both in trachea and lungs. Moreover, CGA-H notably induced the CD3+, CD3+ CD4+ and CD4+/CD8+ proliferation and significantly increased the IgA, IgG, and IgM levels in the serum. In conclusion, these results showed that at high concentration CGA is a strong anti-IBV compound that can effectively regulate the innate immunity through MDA5, TLR7 and NF-κB signaling pathways and have the potential to induce the cell mediated and humoral immune response in IBV infected chickens.


Subject(s)
Chlorogenic Acid/pharmacology , Coronavirus Infections/drug therapy , Gammacoronavirus/drug effects , Interferon-Induced Helicase, IFIH1/metabolism , NF-kappa B/metabolism , Toll-Like Receptor 7/metabolism , Animals , Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , Cells, Cultured , Chickens , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Models, Animal , Gammacoronavirus/immunology , Gammacoronavirus/isolation & purification , Immunity, Innate , Interferon-Induced Helicase, IFIH1/genetics , NF-kappa B/genetics , Toll-Like Receptor 7/genetics
8.
J Ethnopharmacol ; 275: 114063, 2021 Jul 15.
Article in English | MEDLINE | ID: covidwho-1164034

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang-Yinhua-Jiedu Granules (FFYH) optimized from a Yin-Qiao-San, as traditional Chinese medicine (TCM), was used to treat influenza and upper respiratory tract infection and was recommended for the prevention and treatment of SARS in 2003 and current COVID-19 in Anhui Province in 2020. AIM OF STUDY: In the clinical studies, FFYH was very effective for the treatment of influenza, but the mechanism of action against influenza A virus remains unclear. In the present study, we investigated the antiviral effect of FFYH against influenza A virus in vitro and vivo. Moreover, the potential mechanism of FFYH against influenza A virus in vivo was investigated for the first time. MATERIALS AND METHODS: CPE inhibition assay and HA assay were used to evaluate the in vitro antiviral effects of FFYH against influenza A virus H1N1, H3N2, H5N1, H7N9 and H9N2. Mice were used to evaluate the antiviral effect of FFYH in vivo with ribavirin and lianhuaqingwen as positive controls. RT-PCR was used to quantify the mRNA transcription of TNF-α, IL-6, IFN-γ, IP10, and IL-1ß mRNA. ELISA was used to examine the expression of inflammatory factors such as TNF-α, IL-6, IFN-γ, IP10, and IL-1ß in sera. The blood parameters were analyzed with auto hematology analyzer. Moreover, the potential mechanism of FFYH against influenza A virus in vivo was also investigated. RESULTS: FFYH showed a broad-spectrum of antiviral activity against H1N1, H3N2, H5N1, H7N9, and H9N2 influenza A viruses. Furthermore, FFYH dose-dependently increased the survival rate, significantly prolonged the median survival time of mice, and markedly reduced lung injury caused by influenza A virus. Also, FFYH significantly improve the sick signs, food taken, weight loss, blood parameters, lung index, and lung pathological changes. Moreover, FFYH could markedly inhibit the inflammatory cytokine expression of TNF-α, IL-6, IFN-γ, IP10, IL-10, and IL-1ß mRNA or protein via inhibition of the TLR7/MyD88/NF-κB signaling pathway in vivo. CONCLUSION: FFYH not only showed a broad-spectrum of anti-influenza virus activity in vitro, but also exhibited a significant protective effect against lethal influenza virus infection in vivo. Furthermore, our results indicated that the in vivo antiviral effect of FFYH against influenza virus may be attributed to suppressing the expression of inflammatory cytokines via regulating the TLR7/MyD88/NF-κB signaling pathway. These findings provide evidence for the clinical treatment of influenza A virus infection with FFYH.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , Drugs, Chinese Herbal/pharmacology , Influenza A virus/drug effects , Lung/drug effects , Membrane Glycoproteins/metabolism , Myeloid Differentiation Factor 88/metabolism , Orthomyxoviridae Infections/drug therapy , Toll-Like Receptor 7/metabolism , A549 Cells , Animals , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Dogs , Host-Pathogen Interactions , Humans , Inflammation Mediators/metabolism , Influenza A virus/pathogenicity , Lung/immunology , Lung/metabolism , Lung/virology , Madin Darby Canine Kidney Cells , Mice, Inbred ICR , NF-kappa B/metabolism , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae Infections/virology , Signal Transduction , Virus Replication/drug effects
9.
J Interferon Cytokine Res ; 40(12): 549-554, 2020 12.
Article in English | MEDLINE | ID: covidwho-990532

ABSTRACT

Coronavirus disease 2019 (COVID-19) has spread rapidly and become a pandemic. Caused by a novel human coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe COVID-19 is characterized by cytokine storm syndromes due to innate immune activation. Primary immunodeficiency (PID) cases represent a special patient population whose impaired immune system might make them susceptible to severe infections, posing a higher risk to COVID-19, but this could also lead to suppressed inflammatory responses and cytokine storm. It remains an open question as to whether the impaired immune system constitutes a predisposing or protective factor for PID patients when facing SARS-CoV-2 infection. After literature review, it was found that, similar to other patient populations with different comorbidities, PID patients may be susceptible to SARS-CoV-2 infection. Their varied immune status, however, may lead to different disease severity and outcomes after SARS-CoV-2 infection. PID patients with deficiency in antiviral innate immune signaling [eg, Toll-like receptor (TLR)3, TLR7, or interferon regulatory factor 7 (IRF7)] or interferon signaling (IFNAR2) may be linked to severe COVID-19. Because of its anti-infection, anti-inflammatory, and immunomodulatory effects, routine intravenous immunoglobulin therapy may provide some protective effects to the PID patients.


Subject(s)
COVID-19/complications , COVID-19/immunology , Immune System , Inflammation , Primary Immunodeficiency Diseases/complications , Primary Immunodeficiency Diseases/immunology , Comorbidity , Disease Susceptibility , Humans , Immunity, Innate , Immunoglobulins, Intravenous/metabolism , Interferon Regulatory Factor-7/metabolism , Pandemics , Receptor, Interferon alpha-beta/metabolism , Risk , Toll-Like Receptor 3/metabolism , Toll-Like Receptor 7/metabolism
10.
Infect Genet Evol ; 85: 104507, 2020 11.
Article in English | MEDLINE | ID: covidwho-731865

ABSTRACT

The COVID-19 pandemic highlighted healthcare disparities in multiple countries. As such morbidity and mortality vary significantly around the globe between populations and ethnic groups. Underlying medical conditions and environmental factors contribute higher incidence in some populations and a genetic predisposition may play a role for severe cases with respiratory failure. Here we investigated whether genetic variation in the key genes for viral entry to host cells-ACE2 and TMPRSS2-and sensing of viral genomic RNAs (i.e., TLR3/7/8) could explain the variation in incidence across diverse ethnic groups. Overall, these genes are under strong selection pressure and have very few nonsynonymous variants in all populations. Genetic determinant for the binding affinity between SARS-CoV-2 and ACE2 does not show significant difference between populations. Non-genetic factors are likely to contribute differential population characteristics affected by COVID-19. Nonetheless, a systematic mutagenesis study on the receptor binding domain of ACE2 is required to understand the difference in host-viral interaction across populations.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Toll-Like Receptors/genetics , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Binding Sites , Humans , Mutagenesis, Site-Directed , Protein Binding , Protein Domains , Selection, Genetic , Serine Endopeptidases/metabolism , Toll-Like Receptor 3/chemistry , Toll-Like Receptor 3/genetics , Toll-Like Receptor 3/metabolism , Toll-Like Receptor 7/chemistry , Toll-Like Receptor 7/genetics , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 8/chemistry , Toll-Like Receptor 8/genetics , Toll-Like Receptor 8/metabolism , Toll-Like Receptors/chemistry , Toll-Like Receptors/metabolism , Virus Internalization
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