MK2a inhibitor CMPD1 abrogates chikungunya virus infection by modulating actin remodeling pathway.

Chikungunya virus (CHIKV) epidemics around the world have created public health concern with the unavailability of effective drugs and vaccines. This emphasizes the need for molecular understanding of host-virus interactions for developing effective targeted antivirals. Microarray analysis was carri...

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Autores principales:	Prabhudutta Mamidi, Tapas Kumar Nayak, Abhishek Kumar, Sameer Kumar, Sanchari Chatterjee, Saikat De, Ankita Datey, Soumyajit Ghosh, Supriya Suman Keshry, Sharad Singh, Eshna Laha, Amrita Ray, Subhasis Chattopadhyay, Soma Chattopadhyay
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/31689cdbcd0a4fa286d1d6e6d9146fb4
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spelling	oai:doaj.org-article:31689cdbcd0a4fa286d1d6e6d9146fb42021-12-02T19:59:52ZMK2a inhibitor CMPD1 abrogates chikungunya virus infection by modulating actin remodeling pathway.1553-73661553-737410.1371/journal.ppat.1009667https://doaj.org/article/31689cdbcd0a4fa286d1d6e6d9146fb42021-11-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009667https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Chikungunya virus (CHIKV) epidemics around the world have created public health concern with the unavailability of effective drugs and vaccines. This emphasizes the need for molecular understanding of host-virus interactions for developing effective targeted antivirals. Microarray analysis was carried out using CHIKV strain (Prototype and Indian) infected Vero cells and two host isozymes, MAPK activated protein kinase 2 (MK2) and MAPK activated protein kinase 3 (MK3) were selected for further analysis. The substrate spectrum of both enzymes is indistinguishable and covers proteins involved in cytokines production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling and transcriptional regulation. Gene silencing and drug treatment were performed in vitro and in vivo to unravel the role of MK2/MK3 in CHIKV infection. Gene silencing of MK2 and MK3 abrogated around 58% CHIKV progeny release from the host cell and a MK2 activation inhibitor (CMPD1) treatment demonstrated 68% inhibition of viral infection suggesting a major role of MAPKAPKs during late CHIKV infection in vitro. Further, it was observed that the inhibition in viral infection is primarily due to the abrogation of lamellipodium formation through modulation of factors involved in the actin cytoskeleton remodeling pathway. Moreover, CHIKV-infected C57BL/6 mice demonstrated reduction in the viral copy number, lessened disease score and better survivability after CMPD1 treatment. In addition, reduction in expression of key pro-inflammatory mediators such as CXCL13, RAGE, FGF, MMP9 and increase in HGF (a CHIKV infection recovery marker) was observed indicating the effectiveness of the drug against CHIKV. Taken together it can be proposed that MK2 and MK3 are crucial host factors for CHIKV infection and can be considered as important target for developing effective anti-CHIKV strategies.Prabhudutta MamidiTapas Kumar NayakAbhishek KumarSameer KumarSanchari ChatterjeeSaikat DeAnkita DateySoumyajit GhoshSupriya Suman KeshrySharad SinghEshna LahaAmrita RaySubhasis ChattopadhyaySoma ChattopadhyayPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 11, p e1009667 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Prabhudutta Mamidi Tapas Kumar Nayak Abhishek Kumar Sameer Kumar Sanchari Chatterjee Saikat De Ankita Datey Soumyajit Ghosh Supriya Suman Keshry Sharad Singh Eshna Laha Amrita Ray Subhasis Chattopadhyay Soma Chattopadhyay MK2a inhibitor CMPD1 abrogates chikungunya virus infection by modulating actin remodeling pathway.
description	Chikungunya virus (CHIKV) epidemics around the world have created public health concern with the unavailability of effective drugs and vaccines. This emphasizes the need for molecular understanding of host-virus interactions for developing effective targeted antivirals. Microarray analysis was carried out using CHIKV strain (Prototype and Indian) infected Vero cells and two host isozymes, MAPK activated protein kinase 2 (MK2) and MAPK activated protein kinase 3 (MK3) were selected for further analysis. The substrate spectrum of both enzymes is indistinguishable and covers proteins involved in cytokines production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling and transcriptional regulation. Gene silencing and drug treatment were performed in vitro and in vivo to unravel the role of MK2/MK3 in CHIKV infection. Gene silencing of MK2 and MK3 abrogated around 58% CHIKV progeny release from the host cell and a MK2 activation inhibitor (CMPD1) treatment demonstrated 68% inhibition of viral infection suggesting a major role of MAPKAPKs during late CHIKV infection in vitro. Further, it was observed that the inhibition in viral infection is primarily due to the abrogation of lamellipodium formation through modulation of factors involved in the actin cytoskeleton remodeling pathway. Moreover, CHIKV-infected C57BL/6 mice demonstrated reduction in the viral copy number, lessened disease score and better survivability after CMPD1 treatment. In addition, reduction in expression of key pro-inflammatory mediators such as CXCL13, RAGE, FGF, MMP9 and increase in HGF (a CHIKV infection recovery marker) was observed indicating the effectiveness of the drug against CHIKV. Taken together it can be proposed that MK2 and MK3 are crucial host factors for CHIKV infection and can be considered as important target for developing effective anti-CHIKV strategies.
format	article
author	Prabhudutta Mamidi Tapas Kumar Nayak Abhishek Kumar Sameer Kumar Sanchari Chatterjee Saikat De Ankita Datey Soumyajit Ghosh Supriya Suman Keshry Sharad Singh Eshna Laha Amrita Ray Subhasis Chattopadhyay Soma Chattopadhyay
author_facet	Prabhudutta Mamidi Tapas Kumar Nayak Abhishek Kumar Sameer Kumar Sanchari Chatterjee Saikat De Ankita Datey Soumyajit Ghosh Supriya Suman Keshry Sharad Singh Eshna Laha Amrita Ray Subhasis Chattopadhyay Soma Chattopadhyay
author_sort	Prabhudutta Mamidi
title	MK2a inhibitor CMPD1 abrogates chikungunya virus infection by modulating actin remodeling pathway.
title_short	MK2a inhibitor CMPD1 abrogates chikungunya virus infection by modulating actin remodeling pathway.
title_full	MK2a inhibitor CMPD1 abrogates chikungunya virus infection by modulating actin remodeling pathway.
title_fullStr	MK2a inhibitor CMPD1 abrogates chikungunya virus infection by modulating actin remodeling pathway.
title_full_unstemmed	MK2a inhibitor CMPD1 abrogates chikungunya virus infection by modulating actin remodeling pathway.
title_sort	mk2a inhibitor cmpd1 abrogates chikungunya virus infection by modulating actin remodeling pathway.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/31689cdbcd0a4fa286d1d6e6d9146fb4
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MK2a inhibitor CMPD1 abrogates chikungunya virus infection by modulating actin remodeling pathway.

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