Chikungunya virus: host pathogen interaction

Singh, Sunit K.; Unni, Salini Krishnan

doi:10.1002/rmv.681

Cited by 68 publications

(74 citation statements)

References 77 publications

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“…To this regard, it has been recently demonstrated that Hsp90 positively regulates CHIKV replication by stabilizing nsP2 levels during infection [73]. The 26S sub-genomic RNA encodes the polyprotein precursor for structural proteins, which is cleaved to yield C, pE2, 6K, and E1 that are further processed and transported to the plasma membrane [74]. After the nucleocapsid protein is produced from the polypeptide, the glycoprotein pE2 is inserted into the endoplasmatic reticulum (ER).…”

Section: Genomic Organization and Viral Replicationmentioning

confidence: 99%

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Chikungunya and Its Interaction With the Host Cell

et al. 2015

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Chikungunya virus (CHIKV) is a mosquitotransmitted alphavirus belonging to the Togaviridae family. It is a virus with a single-stranded, positive sense RNA genome, maintained in a sylvatic and urban cycle, involving humans and mosquitoes from Aedes species, mainly Aedes aegypti and Aedes albopictus. In less than 10 years, CHIKV has spread from the coast of Kenya throughout the Indian Ocean, Pacific Ocean, and Caribbean regions, causing millions of infections in over 50 countries. In other words, CHIKV has emerged as a true global pathogen. The clinical signs include nonspecific flu-like symptoms and a characteristic rash accompanied by joint pain that may last long time after the resolution of the infection. The molecular mechanism underlying the chronic polyarthralgia in patients is not well understood. In this review, we summarize the CHIKV genome organization, replication, epidemiology, clinical manifestations, and immunopathogenesis with particular emphasis on host-pathogen interactions.

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Section: Genomic Organization and Viral Replicationmentioning

confidence: 99%

“…The pE2-E1 complex moves to the cell surface through the Golgi complex. Virion assembly starts in the cytoplasm with the formation of the nucleocapsid, which has viral RNA in association with 120 dimers of C protein [74,75]. Nucleocapsids are reported to move freely through the cytoplasm.…”

Section: Genomic Organization and Viral Replicationmentioning

confidence: 99%

Chikungunya and Its Interaction With the Host Cell

et al. 2015

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“…The virus has been largely neglected due to its sporadic reemergence [3,9], but it has recently gained attention with epidemics occurring since 2006 in nearly 40 different countries [10] from Africa to Asia, Europe, US and Australia spread by infected travellers. Even though the chikungunya disease is non-fatal, its characteristic symptoms include high fever, rash, headache, arthralgia, myalgia and polyarthralgia which affects patients, and results in significant health problems worldwide [9][10][11][12][13]. Unfortunately, there are no effective drugs or specific treatments available [10].…”

Section: Introductionmentioning

confidence: 99%

“…The complete genome of CHIKV was determined in 2002 and has a length of 11,805 nucleotides [15]. It consists of two open reading frames (ORFs) [12,15] with the first ORF encoding four non-structural proteins (nsP), namely nsP1, nsP2, nsP3 and nsP4 and the second ORF encoding structural proteins including the capsid (C), envelope glycoproteins E1 and E2 and two small cleavage products (E3 and 6K). The envelope glycoproteins are involved with viral entry while the non-structural proteins are essential components and play a crucial role in viral replication and transcription [10,16].…”

Section: Introductionmentioning

confidence: 99%

Identification of chikungunya virus nsP2 protease inhibitors using structure-base approaches

Nguyen¹,

Yu²,

Keller³

2015

Journal of Molecular Graphics and Modelling

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. (2015). Identification of chikungunya virus nsP2 protease inhibitors using structure-base approaches. Journal of Molecular Graphics and Modelling, 57 1-8. Identification of chikungunya virus nsP2 protease inhibitors using structure-base approaches AbstractThe nsP2 protease of chikungunya virus (CHIKV) is one of the essential components of viral replication and it plays a crucial role in the cleavage of polyprotein precursors for the viral replication process. Therefore, it is gaining attention as a potential drug design target against CHIKV. Based on the recently determined crystal structure of the nsP2 protease of CHIKV, this study identified potential inhibitors of the virus using structurebased approaches with a combination of molecular docking, virtual screening and molecular dynamics (MD) simulations. The top hit compounds from database searching, using the NCI Diversity Set II, with targeting at five potential binding sites of the nsP2 protease, were identified by blind dockings and focused dockings. These complexes were then subjected to MD simulations to investigate the stability and flexibility of the complexes and to gain a more detailed insight into the interactions between the compounds and the enzyme. The hydrogen bonds and hydrophobic contacts were characterized for the complexes. Through structural alignment, the catalytic residues Cys1013 and His1083 were identified in the N-terminal region of the nsP2 protease. The absolute binding free energies were estimated by the linear interaction energy approach and compared with the binding affinities predicted with docking. The results provide valuable information for the development of inhibitors for CHIKV. AbstractThe nsP2 protease of chikungunya virus (CHIKV) is one of the essential components of viral replication and it plays a crucial role in the cleavage of polyprotein precursors for the viral replication process. Therefore, it is gaining attention as a potential drug design target against CHIKV. Based on the recently determined crystal structure of the nsP2 protease of CHIKV, this study identified potential inhibitors of the virus using structure-based approaches with a combination of molecular docking, virtual screening and molecular dynamics (MD) simulations.The top hit compounds from database searching, using the NCI Diversity Set II, with targeting at five potential binding sites of the nsP2 protease, were identified by blind dockings and focused dockings. These complexes were then subjected to MD simulations to investigate the stability and flexibility of the complexes and to gain a more detailed insight into the interactions between the compounds and the enzyme. The hydrogen bonds and hydrophobic contacts were characterized for the complexes. Through structural alignment, the catalytic residues Cys1013 and His1083 were identified in the N-terminal region of the nsP2 protease. The absolute binding free energies were estimated by the linear interaction energy approach and compared with the binding affinities predicted with docking. The resu...

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“…Few cases (less than 5%) are asymptomatic, and symptoms appear after a 3 -12 day incubation period (Jaffar-Bandjee, Ramful et al 2010, Singh andUnni 2011). CHIKV disease can be divided into an acute and chronic phase.…”

Section: Disease Presentationmentioning

confidence: 99%

The role of type I interferon in the immunobiology of chikungunya virus

Wilson¹

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Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that can cause explosive outbreaks of a febrile, arthritic/arthralgic disease usually lasting weeks to months, and in rare cases, more than a year. In 2004, the largest ever CHIKV outbreak began in Kenya, spreading to islands of the Indian Ocean, India, South East Asia and major outbreaks have recently occurred in the South Pacific Islands and the Caribbean.The host type I interferon (IFN) response is crucial for effective control of CHIKV infection.Herein, the dynamics, source and responses generated by the type I IFNs following CHIKV infection were investigated. RNASeq was undertaken to examine, in detail, the nature of the type I IFN responses generated in the feet and inguinal lymph nodes of mice following CHIKV infection at days 2 and 7 post-infection. High quality sequencing data was generated from III host and viral poly-adenylated RNA, permitting investigation of low level gene transcription from both sources, and the identification of novel genes/transcripts, in addition to analysis of differential gene expression.Investigation of host transcriptional activity revealed a type I IFN dominated immune response, in spite of a low induction of type I IFN mRNA transcripts at day 2 and an absence of type I IFN mRNA induction on day 7. Many type I IFN-regulated genes, including IRF7, remained up-regulated in the feet at day 7, suggesting type I IFNindependent mechanisms for maintenance of type I IFN-regulated gene expression. Six novel IRF3 isoforms and a potentially novel protein coding gene were also identified.RNA-Seq analysis of CHIKV transcriptional activity reflected the known CHIKV replication kinetics, in which virus replicates in the joints, and spreads to the draining lymph nodes, with viral titres peaking at day 2 and largely resolving at day 7. Assessment of mutations within the CHIKV genome showed an accumulation with time, with error accumulation higher in the lymph nodes than in the feet. These studies represent the first deep sequencing analysis of CHIKV genomes in tissues.The findings in this thesis substantially add to our knowledge of the role and function of the immune response after CHIKV, illustrating for the first time that type I IFNs protect against haemorrhagic shock and that expression of type I IFN inducible genes is maintained well after type I IFN induction has waned.

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Chikungunya virus: host pathogen interaction

Cited by 68 publications

References 77 publications

Chikungunya and Its Interaction With the Host Cell

Chikungunya and Its Interaction With the Host Cell

Identification of chikungunya virus nsP2 protease inhibitors using structure-base approaches

The role of type I interferon in the immunobiology of chikungunya virus

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