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Pratap SinghRaman A, Kumar D, Kumari K, Jain P, Bahadur I, Abedigamba OP, Preetam A, Singh P. Computational Insights for Interactions between nsP2 and nsP3 of CHIKV and Hormones through DFT Computations and Molecular Dynamics Simulations. Chem Biodivers 2024; 21:e202401241. [PMID: 39137144 DOI: 10.1002/cbdv.202401241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 08/11/2024] [Accepted: 08/13/2024] [Indexed: 08/15/2024]
Abstract
The non-structural protein (nsP2 & nsP3) of the Chikungunya virus (CHIKV) is responsible for the transmission of viral infection. The main role of non-structural proteins are involved in the transcription process at an early stage of the infection. In this work, authors have studied the impact of nsP2 and nsP3 of CHIKV on hormones present in the human body using a computational approach. The ten hormones of chemical properties such as 4-Androsterone-2,17-dione, aldosterone, androsterone, corticosterone, cortisol, cortisone, estradiol, estrone, progesterone and testosterone were taken as a potency. From the molecular docking, the binding energy of the complexes is estimated, and cortisone was found to be the highest negative binding energy (-6.57 kcal/mol) with the nsP2 and corticosterone with the nsP3 (-6.47 kcal/mol). This is based on the interactions between hormones and nsP2/nsP3, which are types of noncovalent intermolecular interactions categorized into three types: electrostatic interactions, van der Waals (vdW) interactions, and hydrogen-bonding (H-bonding) interactions. To validate the docking results, additional molecular dynamics simulations and MM-GBSA methods were performed. The change in enthalpy, entropy, and free energy were calculated using MM-GBSA methods. The nsP2 and nsP3 of CHIKV interact strongly with the cortisone and corticosterone with free energy changes of -20.55 & -36.08 kcal/mol, respectively. Methods: The crystal structures of 3TKR and 3GPO proteins of nsP2 and nsP3 were extracted from the RCSB Protein Data Bank. Initially, unnecessary atoms like extra cations or anions and missing explicit hydrogen atoms were removed and added from the native domain of nsP2 and nsP3. The alignment of coordinated in the native domain was performed using Chimera and Notepad++ tools. The molecular docking of protein and ligand was performed usingAutoDock tool; it is essential for the prediction of the orientation of the ligand into the cavity of the target protein based on binding affinity. Based on thermodynamic parameters, MD Simulations were employed to calculate the change in binding free energies of various complexes followed by a change in enthalpy and entropy with time. According to MD production, the CPPTAJ and PTRAJ programs were used to analyse the trajectories, such as dynamic stability (RMSD), residual fluctuation (RMSF), compatibility, and hydrogen bonds of the newly formed complexes. After that, the Density Functional Theory (DFT) were used to calculate the electronic properties of selected molecules by Gaussian 16 on applying the B3LYP method with the 6-311G (d, p) basis set.
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Affiliation(s)
| | - Durgesh Kumar
- Department of Chemistry, Maitreyi College, University of Delhi, New Delhi, India
| | - Kamlesh Kumari
- Department of Zoology, University of Delhi, Delhi, India
| | - Pallavi Jain
- Department of Chemistry, SRM Institute of Science & Technology, NCR Campus, Modinagar, Ghaziabad, India
| | - Indra Bahadur
- Department of Chemistry, Material Science, Innovation and Modelling (MaSIM) Research Focus Area, North-West University (Mafikeng Campus), Private Bag X2046, Mmabatho, 2735, South Africa
| | | | - Amreeta Preetam
- Department of Applied Science, Bharati Vidyapeeth's College of Engineering, Delhi, India
| | - Prashant Singh
- Department of Chemistry, Atma Ram Sanatan Dharma College, University of Delhi, Delhi, India
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Taylor M, Rayner JO. Immune Response to Chikungunya Virus: Sex as a Biological Variable and Implications for Natural Delivery via the Mosquito. Viruses 2023; 15:1869. [PMID: 37766276 PMCID: PMC10538149 DOI: 10.3390/v15091869] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 08/30/2023] [Accepted: 09/01/2023] [Indexed: 09/29/2023] Open
Abstract
Chikungunya virus (CHIKV) is a mosquito-borne virus with significant public health implications around the world. Climate change, as well as rapid urbanization, threatens to expand the population range of Aedes vector mosquitoes globally, increasing CHIKV cases worldwide in return. Epidemiological data suggests a sex-dependent response to CHIKV infection. In this review, we draw attention to the importance of studying sex as a biological variable by introducing epidemiological studies from previous CHIKV outbreaks. While the female sex appears to be a risk factor for chronic CHIKV disease, the male sex has recently been suggested as a risk factor for CHIKV-associated death; however, the underlying mechanisms for this phenotype are unknown. Additionally, we emphasize the importance of including mosquito salivary components when studying the immune response to CHIKV. As with other vector-transmitted pathogens, CHIKV has evolved to use these salivary components to replicate more extensively in mammalian hosts; however, the response to natural transmission of CHIKV has not been fully elucidated.
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Affiliation(s)
| | - Jonathan O. Rayner
- Department of Microbiology & Immunology, Whiddon College of Medicine, University of South Alabama, Mobile, AL 36688, USA;
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Montero Morales L, Barbas Del Buey JF, Alonso García M, Iñigo Martínez J, Cenamor Largo N, Jiménez Bueno S, Arce Arnáez A. Authors' response: Bias in the vaccine effectiveness estimates of one-dose post-exposure prophylaxis against mpox. Euro Surveill 2023; 28:2300442. [PMID: 37616117 PMCID: PMC10451012 DOI: 10.2807/1560-7917.es.2023.28.34.2300442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 08/24/2023] [Indexed: 08/25/2023] Open
Affiliation(s)
- Laura Montero Morales
- Directorate General of Public Health, Regional Ministry of Health of Madrid, Madrid, Spain
| | | | - Marcos Alonso García
- Directorate General of Public Health, Regional Ministry of Health of Madrid, Madrid, Spain
| | - Jesús Iñigo Martínez
- Directorate General of Public Health, Regional Ministry of Health of Madrid, Madrid, Spain
| | - Noelia Cenamor Largo
- Directorate General of Public Health, Regional Ministry of Health of Madrid, Madrid, Spain
| | - Susana Jiménez Bueno
- Directorate General of Public Health, Regional Ministry of Health of Madrid, Madrid, Spain
| | - Araceli Arce Arnáez
- Directorate General of Public Health, Regional Ministry of Health of Madrid, Madrid, Spain
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Neupane B, Acharya D, Nazneen F, Gonzalez-Fernandez G, Flynt AS, Bai F. Interleukin-17A Facilitates Chikungunya Virus Infection by Inhibiting IFN-α2 Expression. Front Immunol 2020; 11:588382. [PMID: 33304351 PMCID: PMC7701120 DOI: 10.3389/fimmu.2020.588382] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 10/19/2020] [Indexed: 12/27/2022] Open
Abstract
Interferons (IFNs) are the key components of innate immunity and are crucial for host defense against viral infections. Here, we report a novel role of interleukin-17A (IL-17A) in inhibiting IFN-α2 expression thus promoting chikungunya virus (CHIKV) infection. CHIKV infected IL-17A deficient (Il17a-/- ) mice expressed a higher level of IFN-α2 and developed diminished viremia and milder footpad swelling in comparison to wild-type (WT) control mice, which was also recapitulated in IL-17A receptor-deficient (Il17ra-/- ) mice. Interestingly, IL-17A selectively blocked IFN-α2 production during CHIKV, but not West Nile virus (WNV) or Zika virus (ZIKV), infections. Recombinant IL-17A treatment inhibited CHIKV-induced IFN-α2 expression and enhanced CHIKV replication in both human and mouse cells. We further found that IL-17A inhibited IFN-α2 production by modulating the expression of Interferon Regulatory Factor-5 (IRF-5), IRF-7, IFN-stimulated gene 49 (ISG-49), and Mx1 expression during CHIKV infection. Neutralization of IL-17A in vitro leads to the increase of the expression of these antiviral molecules and decrease of CHIKV replication. Collectively, these results suggest a novel function of IL-17A in inhibiting IFN-α2-mediated antiviral responses during CHIKV infection, which may have broad implications in viral infections and other inflammatory diseases.
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Affiliation(s)
- Biswas Neupane
- Department of Cell and Molecular Biology, Center for Molecular and Cellular Biosciences, The University of Southern Mississippi, Hattiesburg, MS, United States
| | - Dhiraj Acharya
- Department of Cell and Molecular Biology, Center for Molecular and Cellular Biosciences, The University of Southern Mississippi, Hattiesburg, MS, United States
| | - Farzana Nazneen
- Department of Cell and Molecular Biology, Center for Molecular and Cellular Biosciences, The University of Southern Mississippi, Hattiesburg, MS, United States
| | - Gabriel Gonzalez-Fernandez
- Department of Cell and Molecular Biology, Center for Molecular and Cellular Biosciences, The University of Southern Mississippi, Hattiesburg, MS, United States
| | - Alex Sutton Flynt
- Department of Cell and Molecular Biology, Center for Molecular and Cellular Biosciences, The University of Southern Mississippi, Hattiesburg, MS, United States
| | - Fengwei Bai
- Department of Cell and Molecular Biology, Center for Molecular and Cellular Biosciences, The University of Southern Mississippi, Hattiesburg, MS, United States
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Kumar N, Barua S, Riyesh T, Chaubey KK, Rawat KD, Khandelwal N, Mishra AK, Sharma N, Chandel SS, Sharma S, Singh MK, Sharma DK, Singh SV, Tripathi BN. Complexities in Isolation and Purification of Multiple Viruses from Mixed Viral Infections: Viral Interference, Persistence and Exclusion. PLoS One 2016; 11:e0156110. [PMID: 27227480 PMCID: PMC4881941 DOI: 10.1371/journal.pone.0156110] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 05/09/2016] [Indexed: 11/18/2022] Open
Abstract
Successful purification of multiple viruses from mixed infections remains a challenge. In this study, we investigated peste des petits ruminants virus (PPRV) and foot-and-mouth disease virus (FMDV) mixed infection in goats. Rather than in a single cell type, cytopathic effect (CPE) of the virus was observed in cocultured Vero/BHK-21 cells at 6th blind passage (BP). PPRV, but not FMDV could be purified from the virus mixture by plaque assay. Viral RNA (mixture) transfection in BHK-21 cells produced FMDV but not PPRV virions, a strategy which we have successfully employed for the first time to eliminate the negative-stranded RNA virus from the virus mixture. FMDV phenotypes, such as replication competent but noncytolytic, cytolytic but defective in plaque formation and, cytolytic but defective in both plaque formation and standard FMDV genome were observed respectively, at passage level BP8, BP15 and BP19 and hence complicated virus isolation in the cell culture system. Mixed infection was not found to induce any significant antigenic and genetic diversity in both PPRV and FMDV. Further, we for the first time demonstrated the viral interference between PPRV and FMDV. Prior transfection of PPRV RNA, but not Newcastle disease virus (NDV) and rotavirus RNA resulted in reduced FMDV replication in BHK-21 cells suggesting that the PPRV RNA-induced interference was specifically directed against FMDV. On long-term coinfection of some acute pathogenic viruses (all possible combinations of PPRV, FMDV, NDV and buffalopox virus) in Vero cells, in most cases, one of the coinfecting viruses was excluded at passage level 5 suggesting that the long-term coinfection may modify viral persistence. To the best of our knowledge, this is the first documented evidence describing a natural mixed infection of FMDV and PPRV. The study not only provides simple and reliable methodologies for isolation and purification of two epidemiologically and economically important groups of viruses, but could also help in establishing better guidelines for trading animals that could transmit further infections and epidemics in disease free nations.
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Affiliation(s)
- Naveen Kumar
- Division of Animal Health, ICAR-Central Institute for Research on Goats, Makhdoom, Mathura, India
- National Centre for Veterinary Type Culture Collections, ICAR-National Research Centre on Equines, Hisar, Haryana, India
- * E-mail:
| | - Sanjay Barua
- National Centre for Veterinary Type Culture Collections, ICAR-National Research Centre on Equines, Hisar, Haryana, India
| | - Thachamvally Riyesh
- National Centre for Veterinary Type Culture Collections, ICAR-National Research Centre on Equines, Hisar, Haryana, India
| | - Kundan K. Chaubey
- Division of Animal Health, ICAR-Central Institute for Research on Goats, Makhdoom, Mathura, India
| | - Krishan Dutt Rawat
- National Centre for Veterinary Type Culture Collections, ICAR-National Research Centre on Equines, Hisar, Haryana, India
| | - Nitin Khandelwal
- National Centre for Veterinary Type Culture Collections, ICAR-National Research Centre on Equines, Hisar, Haryana, India
| | - Anil K. Mishra
- Division of Animal Health, ICAR-Central Institute for Research on Goats, Makhdoom, Mathura, India
| | - Nitika Sharma
- Division of Animal Health, ICAR-Central Institute for Research on Goats, Makhdoom, Mathura, India
| | - Surender S. Chandel
- National Centre for Veterinary Type Culture Collections, ICAR-National Research Centre on Equines, Hisar, Haryana, India
| | - Shalini Sharma
- Department of Veterinary Physiology and Biochemistry, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar, Haryana, India
| | - Manoj K. Singh
- Division of Animal Health, ICAR-Central Institute for Research on Goats, Makhdoom, Mathura, India
| | - Dinesh K. Sharma
- Division of Animal Health, ICAR-Central Institute for Research on Goats, Makhdoom, Mathura, India
| | - Shoor V. Singh
- Division of Animal Health, ICAR-Central Institute for Research on Goats, Makhdoom, Mathura, India
| | - Bhupendra N. Tripathi
- National Centre for Veterinary Type Culture Collections, ICAR-National Research Centre on Equines, Hisar, Haryana, India
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Yu Z, Predina JD, Cheng G. Refractoriness of interferon-beta signaling through NOD1 pathway in mouse respiratory epithelial cells using the anticancer xanthone compound. World J Biol Chem 2013; 4:18-29. [PMID: 23710296 PMCID: PMC3652647 DOI: 10.4331/wjbc.v4.i2.18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Revised: 03/19/2013] [Accepted: 04/29/2013] [Indexed: 02/05/2023] Open
Abstract
AIM: To explore the possibility that nucleotide oligomerization domain 1 (NOD1) pathway involved in refractoriness of interferon-β signaling in mouse respiratory epithelial cells induced by the anticancer xanthone compound, 5,6-dimethylxanthenone-4-acetic acid (DMXAA).
METHODS: C10 mouse bronchial epithelial cells were grown in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal bovine serum, 2 mmol/L glutamine, 100 units/mL penicillin, 100 g/mL streptomycin. Pathogen-free female BALB/c mice were used to explore the mechanisms of refractoriness of interferon-signaling. Mouse thioglycollate-elicited peritoneal macrophages, bone marrow derived macrophages and bone marrow derived dendritic cells were collected and cultured. The amount of interferon (IFN)-inducible protein-10 (IP10/CXCL10), macrophage chemotactic protein (MCP1/CCL2) and interleukin (IL)-6 secreted by cells activated by DMXAA was quantified using enzyme-linked immunosorbent assay kits according to the instructions of the manufacturers. Total RNA was isolated from cells or nasal epithelium with RNeasy Plus Mini Kit, and cDNA was synthesized. Gene expression was checked using Applied Biosystems StepOne Real-Time Polymerase Chain Reaction System. Transfection of small interfering RNA (siRNA) control, NOD1 duplexed RNA oligonucleotides, and high-mobility group box 1/2/3 (HMGB1/2/3) siRNA was performed using siRNA transfection reagent.
RESULTS: DMXAA activates IFN-β pathway with high level of IFN-β dependent antiviral genes including 2’, 5’-oligoadenylate synthetase 1 and myxovirus resistance 1 in mouse thioglycollate-elicited peritoneal macrophages, bone marrow derived macrophages and bone marrow derived dendritic cells. Activation of IFN-β by DMXAA involved in NOD1, but not HMGB1/2/3 signal pathway demonstrated by siRNA. NOD1 pathway plays an important role in refractoriness of IFN-β signaling induced by DMXAA in mouse C10 respiratory epithelial cells and BALB/c mice nasal epithelia. These data indicate that DMXAA is not well adapted to the intrinsic properties of IFN-β signaling. Approaches to restore sensitivity of IFN-β signaling by find other xanthone compounds may function similarly, could enhance the efficacy of protection from influenza pneumonia and potentially in other respiratory viral infections.
CONCLUSION: NOD1 pathway may play an important role in refractoriness of IFN-β signaling in mouse respiratory epithelial cells induced by DMXAA.
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Tang BL. The cell biology of Chikungunya virus infection. Cell Microbiol 2012; 14:1354-1363. [PMID: 22686853 DOI: 10.1111/j.1462-5822.2012.01825.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Revised: 05/31/2012] [Accepted: 06/04/2012] [Indexed: 11/29/2022]
Abstract
Chikungunya virus (CHIKV) infection causes a disease which appears to affect multiple cell types and tissues. The acute phase is manifested by a non-fatal febrile illness, polyarthralgia and maculopapular rashes in adults, but with recurrent arthralgia that may linger for months during convalescence. The issue of cellular and tissue tropism of CHIKV has elicited interest primarily because of this lingering incapacitating chronic joint pain, as well as clear encephalopathy in severe cases among neonates during the re-emergence of the virus in recent epidemics. The principle cell types productively infected by CHIKV are skin fibroblasts, epithelial cells and lymphoid tissues. There is controversy as to whether CHIKV productively infects haematopoietic cells and neurones/glia. CHIKV infection triggers rapid and robust innate immune responses which quickly clears the acute phase infection. However, significant acute as well as chronic infection of less obvious cell types, such as monocytes, neurones/glia or even CNS neural progenitors may conceivably occur. There is therefore a need to ascertain the full range potential of CHIKV tropism, fully understand the cellular responses triggered during the acute the convalescent phases, and explore possible cell types that might be the source of chronic problems associated with CHIKV infection.
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Affiliation(s)
- Bor Luen Tang
- Department of Biochemistry, Yong Loo Lin School of Medicine and NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore 117597, Singapore.
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Clavarino G, Cláudio N, Couderc T, Dalet A, Judith D, Camosseto V, Schmidt EK, Wenger T, Lecuit M, Gatti E, Pierre P. Induction of GADD34 is necessary for dsRNA-dependent interferon-β production and participates in the control of Chikungunya virus infection. PLoS Pathog 2012; 8:e1002708. [PMID: 22615568 PMCID: PMC3355096 DOI: 10.1371/journal.ppat.1002708] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2011] [Accepted: 04/03/2012] [Indexed: 01/08/2023] Open
Abstract
Nucleic acid sensing by cells is a key feature of antiviral responses, which generally result in type-I Interferon production and tissue protection. However, detection of double-stranded RNAs in virus-infected cells promotes two concomitant and apparently conflicting events. The dsRNA-dependent protein kinase (PKR) phosphorylates translation initiation factor 2-alpha (eIF2α) and inhibits protein synthesis, whereas cytosolic DExD/H box RNA helicases induce expression of type I-IFN and other cytokines. We demonstrate that the phosphatase-1 cofactor, growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a), an important component of the unfolded protein response (UPR), is absolutely required for type I-IFN and IL-6 production by mouse embryonic fibroblasts (MEFs) in response to dsRNA. GADD34 expression in MEFs is dependent on PKR activation, linking cytosolic microbial sensing with the ATF4 branch of the UPR. The importance of this link for anti-viral immunity is underlined by the extreme susceptibility of GADD34-deficient fibroblasts and neonate mice to Chikungunya virus infection. Nucleic acids detection by multiple molecular sensors results in type-I interferon production, which protects cells and tissues from viral infections. At the intracellular level, the detection of double-stranded RNA by one of these sensors, the dsRNA-dependent protein kinase also leads to the profound inhibition of protein synthesis. We describe here that the inducible phosphatase 1 co-factor Ppp1r15a/GADD34, a well known player in the endoplasmic reticulum unfolded protein response (UPR), is activated during double-stranded RNA detection and is absolutely necessary to allow cytokine production in cells exposed to poly I:C or Chikungunya virus. Our data shows that the cellular response to nucleic acids can reveal unanticipated connections between innate immunity and fundamental stress pathways, such as the ATF4 branch of the UPR.
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Affiliation(s)
- Giovanna Clavarino
- Centre d'Immunologie de Marseille-Luminy, UM2, Aix-Marseille Université, Marseille, France
- INSERM, U1104, Marseille, France
- CNRS, UMR 7280, Marseille, France
| | - Nuno Cláudio
- Centre d'Immunologie de Marseille-Luminy, UM2, Aix-Marseille Université, Marseille, France
- INSERM, U1104, Marseille, France
- CNRS, UMR 7280, Marseille, France
| | - Thérèse Couderc
- Institut Pasteur, ‘Microbes and host barriers’ Group, Paris, France
- Inserm, Equipe avenir U604, Paris, France
| | - Alexandre Dalet
- Centre d'Immunologie de Marseille-Luminy, UM2, Aix-Marseille Université, Marseille, France
- INSERM, U1104, Marseille, France
- CNRS, UMR 7280, Marseille, France
| | - Delphine Judith
- Institut Pasteur, ‘Microbes and host barriers’ Group, Paris, France
- Inserm, Equipe avenir U604, Paris, France
| | - Voahirana Camosseto
- Centre d'Immunologie de Marseille-Luminy, UM2, Aix-Marseille Université, Marseille, France
- INSERM, U1104, Marseille, France
- CNRS, UMR 7280, Marseille, France
| | - Enrico K. Schmidt
- Centre d'Immunologie de Marseille-Luminy, UM2, Aix-Marseille Université, Marseille, France
- INSERM, U1104, Marseille, France
- CNRS, UMR 7280, Marseille, France
| | - Till Wenger
- Centre d'Immunologie de Marseille-Luminy, UM2, Aix-Marseille Université, Marseille, France
- INSERM, U1104, Marseille, France
- CNRS, UMR 7280, Marseille, France
| | - Marc Lecuit
- Institut Pasteur, ‘Microbes and host barriers’ Group, Paris, France
- Inserm, Equipe avenir U604, Paris, France
- Université Paris Descartes, Hôpital Necker-Enfants malades, Service des Maladies Infectieuses et Tropicales, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Evelina Gatti
- Centre d'Immunologie de Marseille-Luminy, UM2, Aix-Marseille Université, Marseille, France
- INSERM, U1104, Marseille, France
- CNRS, UMR 7280, Marseille, France
- * E-mail: (EG) (EG); (PP) (PP)
| | - Philippe Pierre
- Centre d'Immunologie de Marseille-Luminy, UM2, Aix-Marseille Université, Marseille, France
- INSERM, U1104, Marseille, France
- CNRS, UMR 7280, Marseille, France
- * E-mail: (EG) (EG); (PP) (PP)
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Hussain KM, Chu JJH. Insights into the interplay between chikungunya virus and its human host. Future Virol 2011. [DOI: 10.2217/fvl.11.101] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chikungunya virus (CHIKV) is a re-emerging arbovirus known to cause chronic arthritis with rare cases of neurological and hepatic complications. Nevertheless, infections with CHIKV can result in high morbidity and mortality rates. CHIKV is considered endemic in countries across Asia and Africa, with Europe and America also experiencing autochthonous transmission. This review highlights recent contributions to our understanding of the interactions between CHIKV and the human host. We focus on key factors contributing to disease manifestations observed in murine and simian models of CHIKV infection. Comparisons between CHIKV and Sindbis virus, the prototypic alphavirus, as well as other well-studied alphaviruses, are raised in relation to virus replication efficiency and host cell responses to infection. Recent advances concerning the role of host innate and humoral immune responses are also discussed.
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Affiliation(s)
- Khairunnisa’ Mohamed Hussain
- Laboratory of Molecular RNA Virology & Antiviral Strategies, Department of Microbiology, Yong Loo Lin School of Medicine, National University Health System, 5 Science Drive 2, National University of Singapore, 117597, Singapore
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Cheng G, Wang LCS, Fridlender ZG, Cheng GS, Chen B, Mangalmurti NS, Saloura V, Yu Z, Kapoor V, Mozdzanowska K, Moon E, Sun J, Kreindler JL, Cohen NA, Caton AJ, Erikson J, Albelda SM. Pharmacologic activation of the innate immune system to prevent respiratory viral infections. Am J Respir Cell Mol Biol 2010; 45:480-8. [PMID: 21148741 DOI: 10.1165/rcmb.2010-0288oc] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Drugs that can rapidly inhibit respiratory infection from influenza or other respiratory pathogens are needed. One approach is to engage primary innate immune defenses against viral infection, such as activating the IFN pathway. In this study, we report that a small, cell-permeable compound called 5,6-di-methylxanthenone-4-acetic acid (DMXAA) can induce protection against vesicular stomatitis virus in vitro and H1N1 influenza A virus in vitro and in vivo through innate immune activation. Using the mouse C10 bronchial epithelial cell line and primary cultures of nasal epithelial cells, we demonstrate DMXAA activates the IFN regulatory factor-3 pathway leading to production of IFN-β and subsequent high-level induction of IFN-β-dependent proteins, such as myxovirus resistance 1 (Mx1) and 2',5'-oligoadenylate synthetase 1 (OAS1). Mice treated with DMXAA intranasally elevate mRNA/protein expression of Mx1 and OAS1 in the nasal mucosa, trachea, and lung. When challenged intranasally with a lethal dose of H1N1 influenza A virus, DMXAA reduced viral titers in the lungs and protected 80% of mice from death, even when given at 24 hours before infection. These data show that agents, like DMXAA, that can directly activate innate immune pathways, such as the IFN regulatory factor-3/IFN-β system, in respiratory epithelial cells can be used to protect from influenza pneumonia and potentially in other respiratory viral infections. Development of this approach in humans could be valuable for protecting health care professionals and "first responders" in the early stages of viral pandemics or bioterror attacks.
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Affiliation(s)
- Guanjun Cheng
- Thoracic Oncology Research Laboratory, 1015F ARC, University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, PA 19104-4318, USA
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11
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Schilte C, Couderc T, Chretien F, Sourisseau M, Gangneux N, Guivel-Benhassine F, Kraxner A, Tschopp J, Higgs S, Michault A, Arenzana-Seisdedos F, Colonna M, Peduto L, Schwartz O, Lecuit M, Albert ML. Type I IFN controls chikungunya virus via its action on nonhematopoietic cells. ACTA ACUST UNITED AC 2010; 207:429-42. [PMID: 20123960 PMCID: PMC2822618 DOI: 10.1084/jem.20090851] [Citation(s) in RCA: 236] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Chikungunya virus (CHIKV) is the causative agent of an outbreak that began in La Réunion in 2005 and remains a major public health concern in India, Southeast Asia, and southern Europe. CHIKV is transmitted to humans by mosquitoes and the associated disease is characterized by fever, myalgia, arthralgia, and rash. As viral load in infected patients declines before the appearance of neutralizing antibodies, we studied the role of type I interferon (IFN) in CHIKV pathogenesis. Based on human studies and mouse experimentation, we show that CHIKV does not directly stimulate type I IFN production in immune cells. Instead, infected nonhematopoietic cells sense viral RNA in a Cardif-dependent manner and participate in the control of infection through their production of type I IFNs. Although the Cardif signaling pathway contributes to the immune response, we also find evidence for a MyD88-dependent sensor that is critical for preventing viral dissemination. Moreover, we demonstrate that IFN-α/β receptor (IFNAR) expression is required in the periphery but not on immune cells, as IFNAR−/−→WT bone marrow chimeras are capable of clearing the infection, whereas WT→IFNAR−/− chimeras succumb. This study defines an essential role for type I IFN, produced via cooperation between multiple host sensors and acting directly on nonhematopoietic cells, in the control of CHIKV.
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Affiliation(s)
- Clémentine Schilte
- Department of Immunology, Unité Immunobiologie des Cellules Dendritiques, Institut Pasteur, 75724 Paris, Cedex 15, France
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Sourisseau M, Schilte C, Casartelli N, Trouillet C, Guivel-Benhassine F, Rudnicka D, Sol-Foulon N, Roux KL, Prevost MC, Fsihi H, Frenkiel MP, Blanchet F, Afonso PV, Ceccaldi PE, Ozden S, Gessain A, Schuffenecker I, Verhasselt B, Zamborlini A, Saïb A, Rey FA, Arenzana-Seisdedos F, Desprès P, Michault A, Albert ML, Schwartz O. Characterization of reemerging chikungunya virus. PLoS Pathog 2007; 3:e89. [PMID: 17604450 PMCID: PMC1904475 DOI: 10.1371/journal.ppat.0030089] [Citation(s) in RCA: 346] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2007] [Accepted: 05/14/2007] [Indexed: 11/18/2022] Open
Abstract
An unprecedented epidemic of chikungunya virus (CHIKV) infection recently started in countries of the Indian Ocean area, causing an acute and painful syndrome with strong fever, asthenia, skin rash, polyarthritis, and lethal cases of encephalitis. The basis for chikungunya disease and the tropism of CHIKV remain unknown. Here, we describe the replication characteristics of recent clinical CHIKV strains. Human epithelial and endothelial cells, primary fibroblasts and, to a lesser extent, monocyte-derived macrophages, were susceptible to infection and allowed viral production. In contrast, CHIKV did not replicate in lymphoid and monocytoid cell lines, primary lymphocytes and monocytes, or monocyte-derived dendritic cells. CHIKV replication was cytopathic and associated with an induction of apoptosis in infected cells. Chloroquine, bafilomycin-A1, and short hairpin RNAs against dynamin-2 inhibited viral production, indicating that viral entry occurs through pH-dependent endocytosis. CHIKV was highly sensitive to the antiviral activity of type I and II interferons. These results provide a general insight into the interaction between CHIKV and its mammalian host. Chikungunya virus (CHIKV) is a reemerging alphavirus responsible for an unprecedented epidemic in countries of the Indian Ocean region, causing an acute and painful syndrome with strong fever, asthenia, skin rash, polyarthritis, and lethal cases of encephalitis. The most recent epidemic reemergences were documented in Kinshasa, (50,000 estimated cases in 1999–2000), in Indonesia (2001–2003), the Indian Ocean islands of Mayotte, Mauritius, Réunion, and the Seychelles (270,000 cases in 2005–2006 in La Réunion island), and in India (1.4 to 6.5 million estimated cases in 2006–2007). There is a critical lack of knowledge on the biology of CHIKV. In particular, virtually nothing is known about the interaction of CHIKV (and of most alpahaviruses) with human primary cells. We have studied the replication characteristics and the tropism of clinical CHIKV strains from La Réunion. We designed various assays and reagents to follow viral replication, and we report here that adherent cells (epithelial and endothelial cells, primary fibroblasts), as well as macrophages, are sensitive to infection. In contrast, blood cells did not allow viral replication. We also characterized viral entry pathways and sensitivity to interferons. These results provide a general insight into the interaction between CHIKV and its mammalian host. This paper is the result of a collaborative effort between numerous teams from Institut Pasteur, the Groupe Hospitalier Sud Réunion, and other institutions. Our aim was to establish a task force with multiple and complementary expertise on virology, immunology, and cell biology in order to characterize this enigmatic virus.
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Affiliation(s)
- Marion Sourisseau
- Department of Virology, Unité Virus et Immunité, Institut Pasteur, Paris, France
- CNRS URA 3015, Paris, France
| | - Clémentine Schilte
- Department of Immunology, Groupe Immunobiologie des Cellules Dendritiques, Institut Pasteur, Paris, France
- INSERM U818, Paris, France
| | - Nicoletta Casartelli
- Department of Virology, Unité Virus et Immunité, Institut Pasteur, Paris, France
- CNRS URA 3015, Paris, France
| | - Céline Trouillet
- Department of Virology, Unité Virus et Immunité, Institut Pasteur, Paris, France
- CNRS URA 3015, Paris, France
| | - Florence Guivel-Benhassine
- Department of Virology, Unité Virus et Immunité, Institut Pasteur, Paris, France
- CNRS URA 3015, Paris, France
| | - Dominika Rudnicka
- Department of Virology, Unité Virus et Immunité, Institut Pasteur, Paris, France
- CNRS URA 3015, Paris, France
| | - Nathalie Sol-Foulon
- Department of Virology, Unité Virus et Immunité, Institut Pasteur, Paris, France
- CNRS URA 3015, Paris, France
| | - Karin Le Roux
- Laboratoire de Microbiologie, Groupe Hospitalier Sud Réunion, Ile de la Réunion, France
| | - Marie-Christine Prevost
- Département de Biologie Cellulaire et Infection, Plateforme de Microscopie Électronique, Institut Pasteur, Paris, France
| | - Hafida Fsihi
- Département Infection et Epidémiologie, Institut Pasteur, Paris, France
| | - Marie-Pascale Frenkiel
- Department of Virology, Unité Interactions Moléculaires Flavivirus-Hôtes, Institut Pasteur, Paris, France
| | - Fabien Blanchet
- Department of Virology, Unité Virus et Immunité, Institut Pasteur, Paris, France
- CNRS URA 3015, Paris, France
| | - Philippe V Afonso
- CNRS URA 3015, Paris, France
- Department of Virology, Unité d'Épidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Paris, France
| | - Pierre-Emmanuel Ceccaldi
- CNRS URA 3015, Paris, France
- Department of Virology, Unité d'Épidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Paris, France
| | - Simona Ozden
- CNRS URA 3015, Paris, France
- Department of Virology, Unité d'Épidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Paris, France
| | - Antoine Gessain
- CNRS URA 3015, Paris, France
- Department of Virology, Unité d'Épidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Paris, France
| | | | | | | | | | - Felix A Rey
- CNRS URA 3015, Paris, France
- Department of Virology, Unité de Virologie Structurale, Institut Pasteur, Paris, France
| | - Fernando Arenzana-Seisdedos
- CNRS URA 3015, Paris, France
- Department of Virology, Laboratoire de Pathogénie Virale Moléculaire, Institut Pasteur, Paris, France
| | - Philippe Desprès
- Department of Virology, Unité Interactions Moléculaires Flavivirus-Hôtes, Institut Pasteur, Paris, France
| | - Alain Michault
- Laboratoire de Microbiologie, Groupe Hospitalier Sud Réunion, Ile de la Réunion, France
| | - Matthew L Albert
- Department of Immunology, Groupe Immunobiologie des Cellules Dendritiques, Institut Pasteur, Paris, France
- INSERM U818, Paris, France
| | - Olivier Schwartz
- Department of Virology, Unité Virus et Immunité, Institut Pasteur, Paris, France
- CNRS URA 3015, Paris, France
- * To whom correspondence should be addressed. E-mail:
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Friedman RM. On the discovery of interferon. J Interferon Cytokine Res 2007; 27:175-9. [PMID: 17348815 DOI: 10.1089/jir.2006.9992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Affiliation(s)
- Robert M Friedman
- Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA.
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BURKE DC, BUCHAN A. INTERFERON PRODUCTION IN CHICK EMBRYO CELLS. I. PRODUCTION BY ULTRAVIOLET-INACTIVATED VIRUS. Virology 1996; 26:28-35. [PMID: 14293311 DOI: 10.1016/0042-6822(65)90022-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Wiedbrauk DL, Hadlow WJ, Ewalt LC, Lodmell DL. Interferon response in normal and Aleutian disease virus-infected mink. J Virol 1986; 59:514-7. [PMID: 2426469 PMCID: PMC253106 DOI: 10.1128/jvi.59.2.514-517.1986] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Studies were done to determine whether differences in interferon production are responsible for the resistance of pastel mink to Aleutian disease. The abilities of normal pastel and sapphire mink to produce interferon when inoculated with either Newcastle disease virus or a synthetic polyribonucleotide, poly (I):poly (C), were identical, even to the production of a novel, acid-labile interferon. The resistance of pastel mink to Aleutian disease did not correlate with interferon production, because neither sapphire nor pastel mink produced detectable amounts of interferon when infected with either the Pullman strain of Aleutian disease virus (ADV) or the highly virulent Utah I strain. Sapphire mink infected with the Pullman strain responded normally to poly (I):poly (C) early in the course of the disease, but interferon production was impaired late, when the mink were hypergammaglobulinemic and had renal, vascular, and hepatic lesions. These data suggest that ADV Pullman neither stimulates nor interferes with interferon production in infected mink and may represent a mechanism whereby ADV can more readily establish infection.
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Koivisto VA, Aro A, Cantell K, Haataja M, Huttunen J, Karonen SL, Mustajoki P, Pelkonen R, Seppälä P. Remissions in newly diagnosed type 1 (insulin-dependent) diabetes: influence of interferon as an adjunct to insulin therapy. Diabetologia 1984; 27:193-7. [PMID: 6386581 DOI: 10.1007/bf00273805] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
We studied the effect of interferon as an adjunct to conventional insulin therapy on the early course of Type 1 diabetes in 43 newly diagnosed patients. Compared with conventional therapy, interferon administration slightly delayed the improvement of glucose homeostasis and the rise of high density lipoprotein cholesterol, while C-peptide secretion was unaffected. Independent of the type of therapy, 18 patients (42%) entered partial remission. The remission began 2.0 +/- 0.6 months (mean +/- SEM) from the start of therapy and lasted for 4.1 +/- 1.1 months. Seven patients (16%) were still in remission 1 year after diagnosis. The patients who entered remission had higher initial C-peptide secretion, lower glycosylated haemoglobin levels and better initial control than patients without remission. Thus, interferon provided no benefits as an adjunct to conventional insulin therapy in unselected patients with newly diagnosed Type 1 diabetes. An important factor for the development of remission was the presence of C-peptide secretion at the time of diagnosis.
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Krueger GR. Morphology of chemical immunosuppression. ADVANCES IN PHARMACOLOGY AND CHEMOTHERAPY 1972; 10:1-90. [PMID: 4598604 DOI: 10.1016/s1054-3589(08)60520-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Friedman RM, Pastan I. Interferon and cyclic-3'5'-adenosine monophosphate: potentiation of antiviral activity. Biochem Biophys Res Commun 1969; 36:735-40. [PMID: 4309119 DOI: 10.1016/0006-291x(69)90671-8] [Citation(s) in RCA: 52] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Abstract
Friedman, Robert M. (National Cancer Institute, Bethesda, Md.). Interferon production and protein synthesis in chick cells. J. Bacteriol. 91:1224-1229. 1966.-Overnight incubation of chick embryo fibroblasts (CEF) at 4 C before infection with live Semliki Forest virus (SFV) increased virus yields but decreased interferon production. The same findings were noted when CEF were incubated for 4 hr with p-fluorophenylalanine (FPA) before infection with live SFV or inactivated Chikungunya virus. In both systems incorporation of C(14)-leucine into protein appeared to be increased after pretreatment at 4 C or with FPA. Protein synthesis could be raised in CEF incubated in 0.5% serum after trypsinization by increasing the concentration of serum. CEF in 10% serum had higher rates of C(14)-leucine incorporation than did cells in 1.5% serum, but again the cells with the apparently high rate of incorporation produced less interferon. These findings may be related to the mechanism of cellular control over interferon production.
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Reinicke V. The influence of steroid hormones and growth hormones on heterologous viral interference in tissue culture. ACTA PATHOLOGICA ET MICROBIOLOGICA SCANDINAVICA 1965; 64:543-52. [PMID: 5890404 DOI: 10.1111/apm.1965.64.4.543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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ANDERSON CD, ATHERTON JG. Effect of Actinomycin D on Measles Virus Growth and Interferon Production. Nature 1964; 203:671. [PMID: 14251002 DOI: 10.1038/203671a0] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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