scholarly journals Cell-intrinsic Innate Immune Responses against Chikungunya Virus in a Human Ex Vivo Synovial Fibroblast Model

2020 ◽  
Author(s):  
Fabian Pott ◽  
Richard J. P. Brown ◽  
Elena Neumann ◽  
Thomas Pietschmann ◽  
Christine Goffinet
Keyword(s):  
Chikungunya Virus ◽  
Cell Model ◽  
Ex Vivo ◽  
Antiviral Treatment ◽  
Treatment Strategies ◽  
Synovial Fibroblasts ◽  
International Travel ◽  
Type I ◽  
Insect Vector ◽  
Chikv Infection

AbstractIn recent years, newly and re-emerging arboviruses including Chikungunya virus (CHIKV), have caused growing concern due to expansion of insect vector ranges, mediated by the exponential increase in international travel and accelerating climate change. Due to the absence of specific antiviral treatment strategies and a protective vaccine, over 2 million CHIKV cases have been reported since 2005. Long-term morbidity after CHIKV infection includes debilitating chronic joint pain, which has associated health, social, individual, and economic impact. Here, we analyzed the early cell-intrinsic response to CHIKV infection in primary human synovial fibroblasts. This cell type represents a potential source of polyarthralgia induced by CHIKV infection. Synovial fibroblasts from healthy donors and osteoarthritic patients were similarly permissive to CHIKV infection. We observed a CHIKV infection-induced transcriptional profile that consisted in upregulation of several hundred interferon-stimulated genes, in addition to transcription factor-encoding genes and effector genes of proinflammatory pathways. In contrast, IL-6, which mediates chronic synovitis by stimulating neutrophil and macrophage infiltration into the joints, was barely secreted by CHIKV-infected fibroblasts. Finally, the cell-intrinsic response to interferon type I and III treatment of synovial fibroblasts differed from that of immortalized model cell lines. In synovial fibroblasts, CHIKV replication was impaired by IFN-α administered post-infection. In summary, primary human synovial fibroblasts serve as bona-fide ex vivo primary cell model of CHIKV infection and provide a valuable platform for studies of joint tissue-associated aspects of CHIKV immunopathogenesis.

scholarly journals Overproduction of IL-6 and Type-I IFN in a Lethal Case of Chikungunya Virus Infection in an Elderly Man During the 2017 Italian Outbreak

2018 ◽  
Vol 5 (11) ◽  
Author(s):  
Francesca Colavita ◽  
Serena Vita ◽  
Eleonora Lalle ◽  
Fabrizio Carletti ◽  
Licia Bordi ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
Strong Increase ◽  
Type I ◽  
Type I Ifn ◽  
Chikv Infection ◽  
Clinical Presentations ◽  
Abnormal Pattern ◽  
Disease Analysis

Abstract Chikungunya fever is caused by Chikungunya virus (CHIKV) and is generally considered a self-limiting disease. However, severe clinical presentations with a high mortality rate have been reported in association with underlying medical conditions. This study reports the molecular characterization of the virus and an abnormal pattern of circulating cytokines in a unique lethal CHIKV case during the 2017 outbreak in Italy, which involved an elderly patient with underlying cardiac disease. Analysis of inflammatory cytokines revealed a strong increase of interferon (IFN)-α and IFN-β, as well as interleukin-6, suggesting a possible role of type-I IFN in the cytokine storm, which may be correlated with unfavorable prognosis of CHIKV infection.

scholarly journals Pro chondrogenic effect of mesenchymal stromal cell-based treatment of chondral defects under physioxia in a novel ex vivo organ model

2020 ◽  
Author(s):  
Andrea Schwab ◽  
Alexa Buß ◽  
Oliver Pullig ◽  
Franziska Ehlicke
Keyword(s):  
Cartilage Repair ◽  
Ex Vivo ◽  
Knee Injuries ◽  
Treatment Strategies ◽  
Collagen Type I ◽  
Cartilage Defects ◽  
Type I ◽  
Full Thickness ◽  
Secondary Osteoarthritis ◽  
Chondral Defects

AbstractObjectiveHigh failure rates of (trauma induced) knee injuries highlight the need to improve current treatment strategies aiming to decrease the number of secondary osteoarthritis developed by patients in later stage [1-3]. In this controlled laboratory study the stimulative effect of mesenchymal stromal cells (MSC) on chondrocyte (CHON) extracellular matrix production was investigated in an ex vivo cartilage defect model (chondral vs. full thickness defects) cultured under normoxic (20 % O2) and physioxic (2 % O2) conditions.DesignPorcine CHON or co-culture of 20 % CHON and 80 % MSC (MIX) were embedded in collagen type I hydrogel, implanted into 4 mm diameter cartilage defects of osteochondral explants and cultured with tissue specific media without addition of TGF-β under normoxia and physioxia. Chondral defects were induced automatically, while full thickness defects were created with biopsy punch. After 28 days of culture, samples were histologically processed, and treatments outcome was evaluated using international cartilage repair society (ICRS)-II scoring.ResultsUnder physioxic conditions, cartilage repair scoring results of the MIX treatment (chondral 8.67 ± 2.42, full thickness 5.67 ± 1.21) were close to those of CHON treatment (chondral 8.17 ± 0.75, full thickness 7.33 ± 1.21). Overall, scoring results were higher in physioxia compared to normoxia conditions in chondral defects, but less or no prevalent for full thickness defects.ConclusionCo-culture of CHON with MSC represents a promising approach to stimulate chondrogenic repair and tissue formation in our ex vivo model and reduces total amount of CHON needed for cell-based treatment.

scholarly journals Macrophage scavenger receptor 1 controls Chikungunya virus infection through autophagy

2020 ◽  
Author(s):  
Long Yang ◽  
Tingting Geng ◽  
Guang Yang ◽  
Jinzhu Ma ◽  
Leilei Wang ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
Scavenger Receptor ◽  
Type I ◽  
Chikv Infection ◽  
Viral Loads ◽  
Macrophage Scavenger Receptor ◽  
Modified Low Density Lipoproteins ◽  
Wd40 Domain ◽  
Antiviral Role ◽  
Increased Susceptibility

AbstractMacrophage scavenger receptor 1 (MSR1) mediates the endocytosis of modified low-density lipoproteins and plays an important antiviral role. However, the molecular mechanism underlying MSR1 antiviral actions remains elusive. Herein, we report that MSR1 activates autophagy to restrict infection of Chikungunya virus (CHIKV), an arthritogenic alphavirus that causes acute and chronic crippling arthralgia. Msr1 expression was rapidly upregulated after CHIKV infection in mice. Msr1 knockout mice had elevated viral loads and increased susceptibility to CHIKV arthritis along with a normal type I IFN response. Induction of LC3 lipidation by CHIKV, a marker of autophagy, was reduced in Msr1-/- cells. Mechanistically, MSR1 interacted with ATG12 through its cytoplasmic tail and this interaction was enhanced by CHIKV nsP1 protein. MSR1 repressed CHIKV replication through ATG5-ATG12-ATG16L1 and this was dependent on the FIP200-and-WIPI2-binding domain, but not the WD40 domain of ATG16L1. Our results elucidate an antiviral role for MSR1 involving the autophagic function of ATG5-ATG12-ATG16L1.

scholarly journals Quercetin can reduce viral RNA level of O’nyong-nyong virus and resulting innate immune cytokine responses in cultured human synovial fibroblasts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Axelle Septembre-Malaterre ◽  
Yosra Bedoui ◽  
Claude Giry ◽  
Philippe Gasque ◽  
Pascale Guiraud ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Secretion ◽  
Chikungunya Virus ◽  
Antiviral Treatment ◽  
Synovial Fibroblasts ◽  
Chronic Arthritis ◽  
Innate Immune ◽  
Viral Rna ◽  
Inflammatory Status ◽  
Cytokine Responses

AbstractO’nyong-nyong virus is an alphavirus closely related to chikungunya virus, causing arthralgia, rash and fever. Alphaviruses mainly target synovial fibroblasts and persists in the joints of patients, possibly leading to chronic arthritis. To date, no specific antiviral treatment is available for ONNV infection and induced-inflammation. Primary human synovial fibroblasts cells were used to assess infection by ONNV and the resulting cytokine responses. Phenolics (gallic acid, caffeic acid and chlorogenic acid, curcumin and quercetin) and a curcuminoids-rich extract from turmeric were tested for their antiviral and anti-inflammatory capacities. We showed that infection occurred in HSF cells and increased gene expression and protein secretion of two major proinflammatory CCL-2 and IL-1β markers. In ONNV-infected HSF cells (MOI 1), we found that non-cytotoxic concentrations of phenolics (10 µM) reduced the level of viral RNA (E1, E2, nsP1, nsP2) and downregulated CCL-2 and IL-1β expression and secretion. These results highlighted the high value of the flavonol quercetin to reduce viral RNA levels and inflammatory status induced by ONNV in HSF cells.

scholarly journals Distinct Roles of Interferon Alpha and Beta in Controlling Chikungunya Virus Replication and Modulating Neutrophil-Mediated Inflammation

2019 ◽  
Vol 94 (1) ◽  
Author(s):  
Lindsey E. Cook ◽  
Marissa C. Locke ◽  
Alissa R. Young ◽  
Kristen Monte ◽  
Matthew L. Hedberg ◽  
...  
Keyword(s):  
Immune Response ◽  
Chikungunya Virus ◽  
Biological Activities ◽  
Neutrophil Infiltration ◽  
Type I Interferons ◽  
Type I ◽  
Functional Variation ◽  
Chikv Infection ◽  
Blocking Antibody ◽  
Type I Ifns

ABSTRACT Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-β (IFN-β knockout [IFN-β-KO] mice or mice treated with an IFN-β-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice treated with a pan-IFN-α-blocking antibody). Mice lacking either IFN-α or IFN-β developed severe clinical disease following infection with CHIKV, with a marked increase in foot swelling compared to wild-type mice. Virological analysis revealed that mice lacking IFN-α sustained elevated infection in the infected ankle and in distant tissues. In contrast, IFN-β-KO mice displayed minimal differences in viral burdens within the ankle or at distal sites and instead had an altered cellular immune response. Mice lacking IFN-β had increased neutrophil infiltration into musculoskeletal tissues, and depletion of neutrophils in IFN-β-KO but not IRF7-KO mice mitigated musculoskeletal disease caused by CHIKV. Our findings suggest disparate roles for the IFN subtypes during CHIKV infection, with IFN-α limiting early viral replication and dissemination and IFN-β modulating neutrophil-mediated inflammation. IMPORTANCE Type I interferons (IFNs) possess a range of biological activity and protect against a number of viruses, including alphaviruses. Despite signaling through a shared receptor, there are established biochemical and functional differences among the IFN subtypes. The significance of our research is in demonstrating that IFN-α and IFN-β both have protective roles during acute chikungunya virus (CHIKV) infection but do so by distinct mechanisms. IFN-α limits CHIKV replication and dissemination, whereas IFN-β protects from CHIKV pathogenesis by limiting inflammation mediated by neutrophils. Our findings support the premise that the IFN subtypes have distinct biological activities in the antiviral response.

scholarly journals Macrophage scavenger receptor 1 controls Chikungunya virus infection through autophagy in mice

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Long Yang ◽  
Tingting Geng ◽  
Guang Yang ◽  
Jinzhu Ma ◽  
Leilei Wang ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
Scavenger Receptor ◽  
Type I ◽  
Chikv Infection ◽  
Viral Loads ◽  
Macrophage Scavenger Receptor ◽  
Modified Low Density Lipoproteins ◽  
Wd40 Domain ◽  
Antiviral Role ◽  
Increased Susceptibility

Abstract Macrophage scavenger receptor 1 (MSR1) mediates the endocytosis of modified low-density lipoproteins and plays an important antiviral role. However, the molecular mechanism underlying MSR1 antiviral actions remains elusive. We report that MSR1 activates autophagy to restrict infection of Chikungunya virus (CHIKV), an arthritogenic alphavirus that causes acute and chronic crippling arthralgia. Msr1 expression was rapidly upregulated after CHIKV infection in mice. Msr1 knockout mice had elevated viral loads and increased susceptibility to CHIKV arthritis along with a normal type I IFN response. Induction of LC3 lipidation by CHIKV, a marker of autophagy, was reduced in Msr1−/− cells. Mechanistically, MSR1 interacted with ATG12 through its cytoplasmic tail and this interaction was enhanced by CHIKV nsP1 protein. MSR1 repressed CHIKV replication through ATG5-ATG12-ATG16L1 and this was dependent on the FIP200-and-WIPI2-binding domain, but not the WD40 domain of ATG16L1. Our results elucidate an antiviral role for MSR1 involving the autophagic function of ATG5-ATG12-ATG16L1.

scholarly journals Organometallic Complex Strongly Impairs Chikungunya Virus Entry to the Host Cells

2020 ◽  
Vol 11 ◽  
Author(s):  
Débora Moraes de Oliveira ◽  
Igor de Andrade Santos ◽  
Daniel Oliveira Silva Martins ◽  
Yasmim Garcia Gonçalves ◽  
Léia Cardoso-Sousa ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
Hydrophobic Interactions ◽  
Therapeutic Potential ◽  
Virus Entry ◽  
Antiviral Treatment ◽  
Host Cells ◽  
Virus Infectivity ◽  
Chloride Salt ◽  
Organometallic Complex ◽  
Chikv Infection

Chikungunya fever is a disease caused by the Chikungunya virus (CHIKV) that is transmitted by the bite of the female of Aedes sp. mosquito. The symptoms include fever, muscle aches, skin rash, and severe joint pains. The disease may develop into a chronic condition and joint pain for months or years. Currently, there is no effective antiviral treatment against CHIKV infection. Treatments based on natural compounds have been widely studied, as many drugs were produced by using natural molecules and their derivatives. Alpha-phellandrene (α-Phe) is a naturally occurring organic compound that is a ligand for ruthenium, forming the organometallic complex [Ru2Cl4(p-cymene)2] (RcP). Organometallic complexes have shown promising as candidate molecules to a new generation of compounds that presented relevant biological properties, however, there is a lack of knowledge concerning the anti-CHIKV activity of these complexes. The present work evaluated the effects of the RcP and its precursors, the hydrate ruthenium(III) chloride salt (RuCl3⋅xH2O) (Ru) and α-Phe, on CHIKV infection in vitro. To this, BHK-21 cells were infected with CHIKV-nanoluciferase (CHIKV-nanoluc), a viral construct harboring the nanoluciferase reporter gene, at the presence or absence of the compounds for 16 h. Cytotoxicity and impact on infectivity were analyzed. The results demonstrated that RcP exhibited a strong therapeutic potential judged by the selective index > 40. Antiviral effects of RcP on different stages of the CHIKV replicative cycle were investigated; the results showed that it affected early stages of virus infection reducing virus replication by 77% at non-cytotoxic concentrations. Further assays demonstrated the virucidal activity of the compound that completely blocked virus infectivity. In silico molecular docking calculations suggested different binding interactions between aromatic rings of RcP and the loop of amino acids of the E2 envelope CHIKV glycoprotein mainly through hydrophobic interactions. Additionally, infrared spectroscopy spectral analysis indicated interactions of RcP with CHIKV glycoproteins. These data suggest that RcP may act on CHIKV particles, disrupting virus entry to the host cells. Therefore, RcP may represent a strong candidate for the development of anti-CHIKV drugs.

scholarly journals Inhibition of Chikungunya Virus Replication by Harringtonine, a Novel Antiviral That Suppresses Viral Protein Expression

2012 ◽  
Vol 57 (1) ◽  
pp. 155-167 ◽  
Author(s):  
Parveen Kaur ◽  
Meerra Thiruchelvan ◽  
Regina Ching Hua Lee ◽  
Huixin Chen ◽  
Karen Caiyun Chen ◽  
...  
Keyword(s):  
Protein Expression ◽  
Viral Entry ◽  
Viral Protein ◽  
Sindbis Virus ◽  
Chikungunya Virus ◽  
Early Stage ◽  
Antiviral Treatment ◽  
Chikv Infection ◽  
Viral Protein Synthesis ◽  
Viral Protein Expression

ABSTRACTChikungunya virus (CHIKV) is a mosquito-transmitted virus that has reemerged as a significant public health threat in the last decade. Since the 2005-2006 chikungunya fever epidemic in the Indian Ocean island of La Réunion, millions of people in more than 40 countries have been infected. Despite this, there is currently no antiviral treatment for chikungunya infection. In this study, an immunofluorescence-based screening platform was developed to identify potential inhibitors of CHIKV infection. A primary screen was performed using a highly purified natural product compound library, and 44 compounds exhibiting ≥70% inhibition of CHIKV infection were identified as positive hits. Among these, four were selected for dose-dependent inhibition assays to confirm their anti-CHIKV activity. Harringtonine, a cephalotaxine alkaloid, displayed potent inhibition of CHIKV infection (50% effective concentration [EC50] = 0.24 μM) with minimal cytotoxicity and was selected for elucidation of its antiviral mechanism. Time-of-addition studies, cotreatment assays, and direct transfection of viral genomic RNA indicated that harringtonine inhibited an early stage of the CHIKV replication cycle which occurred after viral entry into cells. In addition, quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses indicated that harringtonine affects CHIKV RNA production as well as viral protein expression. Treatment of harringtonine against Sindbis virus, a related alphavirus, suggested that harringtonine could inhibit other alphaviruses. This study suggests for the first time that harringtonine exerts its antiviral effects by inhibiting CHIKV viral protein synthesis.

An Integrated Chikungunya Virus Database to Facilitate Therapeutic Analysis: ChkVDb

2019 ◽  
Vol 14 (4) ◽  
pp. 323-332 ◽  
Author(s):  
Priya Narang ◽  
Mehak Dangi ◽  
Deepak Sharma ◽  
Alka Khichi ◽  
Anil Kumar Chhillar
Keyword(s):  
Side Effects ◽  
Chikungunya Virus ◽  
Cpg Island ◽  
Antiviral Treatment ◽  
Current Treatment ◽  
T Cell Epitopes ◽  
Entire Genome ◽  
Viral Pathogen ◽  
Related Data ◽  
Codon Context

Background: Chikungunya infection flare-ups have manifested in nations of Africa, Asia, and Europe including Indian and Pacific seas. It causes fever and different side effects include muscle torment, migraine, sickness, exhaustion and rash. It has turned into another, startling general medical issue in numerous tropical African and Asian countries and is presently being viewed as a genuine risk. No antiviral treatment or vaccine is yet available for this ailment. The current treatment is centered just on mitigating its side effects. Objective: The objective was to encourage the study on this viral pathogen, by the development of a database dedicated to Chikungunya Virus, that annotates and unifies the related data from various resources. associations while known disease-lncRNA associations are required only. Method: It undertook a consolidated approach for Chikungunya Virus genomic, proteomic, phylogenetics and therapeutic learning, involving the entire genome sequences and their annotation utilizing different in silico tools. Annotation included the information for CpG Island, usage bias, codon context and phylogenetic analysis at both the genome and proteome levels. Results: This database incorporates information of 41 strains of virus causing Chikungunya infection that can be accessed conveniently as well as downloaded effortlessly. Therapeutics section of this database contains data about B and T cell Epitopes, siRNAs and miRNAs that can be used as potential therapeutic targets. Conclusion: This database can be explored by specialists and established researchers around the world to assist their research on this non-treatable virus. It is a public database available from “www.chkv.in”.</P>

Sign in / Sign up

Export Citation Format

Share Document