scholarly journals Structural basis of Chikungunya virus inhibition by monoclonal antibodies

2020 ◽  
Vol 117 (44) ◽  
pp. 27637-27645
Author(s):  
Qun Fei Zhou ◽  
Julie M. Fox ◽  
James T. Earnest ◽  
Thiam-Seng Ng ◽  
Arthur S. Kim ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Chikungunya Virus ◽  
Neutralizing Antibody ◽  
Structural Basis ◽  
Chikv Infection ◽  
Receptor Binding Site ◽  
Viral Pathogen ◽  
Virus Attachment

Chikungunya virus (CHIKV) is an emerging viral pathogen that causes both acute and chronic debilitating arthritis. Here, we describe the functional and structural basis as to how two anti-CHIKV monoclonal antibodies, CHK-124 and CHK-263, potently inhibit CHIKV infection in vitro and in vivo. Our in vitro studies show that CHK-124 and CHK-263 block CHIKV at multiple stages of viral infection. CHK-124 aggregates virus particles and blocks attachment. Also, due to antibody-induced virus aggregation, fusion with endosomes and egress are inhibited. CHK-263 neutralizes CHIKV infection mainly by blocking virus attachment and fusion. To determine the structural basis of neutralization, we generated cryogenic electron microscopy reconstructions of Fab:CHIKV complexes at 4- to 5-Å resolution. CHK-124 binds to the E2 domain B and overlaps with the Mxra8 receptor-binding site. CHK-263 blocks fusion by binding an epitope that spans across E1 and E2 and locks the heterodimer together, likely preventing structural rearrangements required for fusion. These results provide structural insight as to how neutralizing antibody engagement of CHIKV inhibits different stages of the viral life cycle, which could inform vaccine and therapeutic design.

scholarly journals Telmisartan restricts Chikungunya virus infection in vitro and in vivo through the AT1/PPAR-γ/MAPKs pathways

2021 ◽  
Author(s):  
Saikat De ◽  
Prabhudutta Mamidi ◽  
Soumyajit Ghosh ◽  
Supriya Suman Keshry ◽  
Chandan Mahish ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
At1 Receptor ◽  
Host Factors ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Global Public Health ◽  
Chikv Infection ◽  
Ppar Γ

Chikungunya virus (CHIKV) has re-emerged as a global public health threat. The inflammatory pathways of RAS and PPAR-γ are usually involved in viral infections. Thus, Telmisartan (TM) with known capacity to block AT1 receptor and activate PPAR-γ, was investigated against CHIKV. The anti-CHIKV effect of TM was investigated in vitro (Vero, RAW 264.7 cells and hPBMCs) and in vivo (C57BL/6 mice). TM was found to abrogate CHIKV infection efficiently (IC50 of 15.34-20.89μM in the Vero and RAW 264.7 cells respectively). Viral RNA and proteins were reduced remarkably. Additionally, TM interfered in the early and late stages of CHIKV life cycle with efficacy in both pre and post-treatment assay. Moreover, the agonist of AT1 receptor and antagonist of PPAR-γ increased CHIKV infection suggesting TM’s anti-viral potential by modulating host factors. Besides, reduced activation of all major MAPKs, NF-κB (p65) and cytokines by TM through the inflammatory axis supported the fact that the anti-CHIKV efficacy of TM is partly mediated through the AT1/PPAR-γ/MAPKs pathways. Interestingly, at the human equivalent dose, TM abrogated CHIKV infection and inflammation significantly leading to reduced clinical score and complete survival of C57BL/6 mice. Additionally, TM reduced infection in hPBMC derived monocyte-macrophage populations in vitro . Hence, TM was found to reduce CHIKV infection by targeting both viral and host factors. Considering its safety and in vivo efficacy, it can be a suitable candidate in future for repurposing against CHIKV.

scholarly journals Infectious RNA vaccine protects mice against chikungunya virus infection

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Inga Szurgot ◽  
Karl Ljungberg ◽  
Beate M. Kümmerer ◽  
Peter Liljeström
Keyword(s):  
Chikungunya Virus ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
High Dose ◽  
Vaccine Platform ◽  
Encoding Gene ◽  
Rna Replicon ◽  
Nsp3 Gene

AbstractWe describe a novel vaccine platform that can generate protective immunity to chikungunya virus (CHIKV) in C57BL/6J mice after a single immunization by employing an infectious RNA (iRNA), which upon introduction into a host cell launches an infectious attenuated virus. We and others have previously reported that an engineered deletion of 183 nucleotides in the nsP3 gene attenuates chikungunya virus (CHIKV) and reduces in vivo viral replication and viremia after challenge in mice, macaques and man. Here, we demonstrated that in vitro transfection of iRNA carrying the nsP3 deletion generated infectious viruses, and after intramuscular injection, the iRNA induced robust antibody responses in mice. The iRNA was superior at eliciting binding and neutralizing antibody responses as compared to a DNA vaccine encoding the same RNA (iDNA) or a non-propagating RNA replicon (RREP) lacking the capsid encoding gene. Subsequent challenge with a high dose of CHIKV demonstrated that the antibody responses induced by this vaccine candidate protected animals from viremia. The iRNA approach constitutes a novel vaccine platform with the potential to impact the spread of CHIKV. Moreover, we believe that this approach is likely applicable also to other positive-strand viruses.

scholarly journals Emerging chikungunya virus variants at the E1-E1 inter-glycoprotein spike interface impact virus attachment and Inflammation

2021 ◽  
Author(s):  
Margarita Rangel ◽  
Nicole McAllister ◽  
Kristen Dancel-Manning ◽  
Maria G Noval ◽  
Laurie Silva ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Chikungunya Virus ◽  
Molecular Mechanisms ◽  
Cell Attachment ◽  
Host Cells ◽  
Virus Attachment ◽  
Host Membrane ◽  
Structural Impacts ◽  
Host Evolution

Chikungunya virus (CHIKV) is a re-emerging arthropod-borne alphavirus and a serious threat to human health. Therefore, efforts toward elucidating how this virus causes disease and the molecular mechanisms underlying steps of the viral replication cycle are crucial. Using an in vivo transmission system that allows intra-host evolution, we identified an emerging CHIKV variant carrying a mutation in the E1 glycoprotein (V156A) in the serum of mice and saliva of mosquitoes. E1 V156A has since emerged in humans during an outbreak in Brazil, co-occurring with a second mutation, E1 K211T, suggesting an important role for these residues in CHIKV biology. Given the emergence of these variants, we hypothesized that they function to promote CHIKV infectivity and subsequent disease. Here, we show that E1 V156A and E1 K211T modulate virus attachment and fusion and impact binding to heparin, a homolog of heparan sulfate, a key entry factor on host cells. These variants also exhibit differential neutralization by anti-glycoprotein monoclonal antibodies, suggesting structural impacts on the particle that may be responsible for altered interactions at the host membrane. Finally, E1 V156A and E1 K211T exhibit increased titers in an adult arthritic mouse model and induce increased foot-swelling at the site of injection. Taken together, this work has revealed new roles for E1 where discrete regions of the glycoprotein are able to modulate cell attachment and swelling within the host.

scholarly journals Antiviral Functions of Monoclonal Antibodies against Chikungunya Virus

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 305 ◽  
Author(s):  
Jing Jin ◽  
Graham Simmons
Keyword(s):  
Immune Response ◽  
Monoclonal Antibodies ◽  
Chikungunya Virus ◽  
Therapeutic Antibodies ◽  
Mechanistic Studies ◽  
Chikv Infection ◽  
The Past ◽  
New Generation ◽  
Human And Mouse

Chikungunya virus (CHIKV) is the most common alphavirus infecting humans worldwide. Antibodies play pivotal roles in the immune response to infection. Increasingly, therapeutic antibodies are becoming important for protection from pathogen infection for which neither vaccine nor treatment is available, such as CHIKV infection. The new generation of ultra-potent and/or broadly cross-reactive monoclonal antibodies (mAbs) provides new opportunities for intervention. In the past decade, several potent human and mouse anti-CHIKV mAbs were isolated and demonstrated to be protective in vivo. Mechanistic studies of these mAbs suggest that mAbs exert multiple modes of action cooperatively. Better understanding of these antiviral mechanisms for mAbs will help to optimize mAb therapies.

scholarly journals In vitro and in vivo efficacy of anti‐chikungunya virus monoclonal antibodies produced in wild‐type and glycoengineered Nicotiana benthamiana plants

2019 ◽  
Vol 18 (1) ◽  
pp. 266-273 ◽  
Author(s):  
Jonathan Hurtado ◽  
Dhiraj Acharya ◽  
Huafang Lai ◽  
Haiyan Sun ◽  
Somanath Kallolimath ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Nicotiana Benthamiana ◽  
Chikungunya Virus ◽  
Wild Type ◽  
In Vivo Efficacy

scholarly journals Telmisartan restricts Chikungunya virus infection in vitro and in vivo through the AT1/ PPAR-γ/MAPKs pathways

2021 ◽  
Author(s):  
Saikat De ◽  
Prabhudutta Mamidi ◽  
Soumyajit Ghosh ◽  
Supriya Suman Keshry ◽  
Chandan Mahish ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
At1 Receptor ◽  
Host Factors ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Global Public Health ◽  
Chikv Infection ◽  
Ppar Γ

Chikungunya virus (CHIKV) has re-emerged as a global public health threat. The inflammatory pathways of RAS and PPAR-γ are usually involved in viral infections. Thus, Telmisartan (TM) with known capacity to block AT1 receptor and activate PPAR-γ, was investigated against CHIKV. The anti-CHIKV effect of TM was investigated in vitro (Vero, RAW 264.7 cells and hPBMCs) and in vivo (C57BL/6 mice). TM was found to abrogate CHIKV infection efficiently (IC50 of 15.34-20.89µM in the Vero and RAW 264.7 cells respectively). Viral RNA and proteins were reduced remarkably with the TM driven modulation of host m-TOR signaling. Additionally, TM interfered in the early and late stages of CHIKV life cycle with efficacy in both pre and post-treatment assay. Moreover, the agonist of AT1 receptor and antagonist of PPAR-γ increased CHIKV infection suggesting TM’s anti-viral potential by modulating host factors. Besides, reduced activation of all major MAPKs, NF-κB (p65) and cytokines by TM through the inflammatory axis supported the fact that the anti-CHIKV efficacy of TM is partly mediated through the AT1/PPAR-γ/MAPKs pathways. Interestingly, at the human equivalent dose, TM abrogated CHIKV infection and inflammation significantly leading to reduced clinical score and complete survival of C57BL/6 mice. Additionally, TM reduced infection in hPBMC derived monocyte-macrophage populations in vitro. Hence, TM was found to reduce CHIKV infection by targeting both viral and host factors. Considering its safety and in vivo efficacy, it can be a suitable candidate in future for repurposing against CHIKV.

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

2021 ◽  
Author(s):  
Soma Chattopadhyay ◽  
Prabhudutta Mamidi ◽  
Tapas Kumar Nayak ◽  
Abhishek Kumar ◽  
Sameer Kumar ◽  
...  
Keyword(s):  
Viral Infection ◽  
Gene Silencing ◽  
Chikungunya Virus ◽  
Late Phase ◽  
Health Concern ◽  
Chikv Infection ◽  
Viral Copy Number

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, MK2 and MK3 were selected for further analysis. 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 (a) inhibitor (CMPD1) treatment demonstrated 68% inhibition of viral infection suggesting a major role of MAPKAPKs during the late phase of 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 that is responsible for releasing the virus from the infected cells.  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 this drug against CHIKV. Additionally, CMPD1 also inhibited HSV1 and SARS CoV2-19 infection in vitro. Taken together it can be proposed that MK2 and MK3 are crucial host factors for CHIKV infection and can be considered as key targets for developing effective anti-CHIKV strategies in future.

scholarly journals In vitro and in vivo studies reveal α-Mangostin, a xanthonoid from Garcinia mangostana, as a promising natural antiviral compound against chikungunya virus

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Poonam Patil ◽  
Megha Agrawal ◽  
Shahdab Almelkar ◽  
Manish Kumar Jeengar ◽  
Ashwini More ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antiviral Activity ◽  
Chikungunya Virus ◽  
In Vivo Studies ◽  
Therapeutic Effects ◽  
Garcinia Mangostana ◽  
Chikv Infection ◽  
Antiviral Compound

Abstract Background Chikungunya virus (CHIKV), a serious health problem in several tropical countries, is the causative agent of chikungunya fever. Approved antiviral therapies or vaccines for the treatment or prevention of CHIKV infections are not available. As diverse natural phenolic compounds have been shown to possess antiviral activities, we explored the antiviral activity of α-Mangostin, a xanthanoid, against CHIKV infection. Methods The in vitro prophylactic and therapeutic effects of α-Mangostin on CHIKV replication in Vero E6 cells were investigated by administering it under pre, post and cotreatment conditions. The antiviral activity was determined by foci forming unit assay, quantitative RT-PCR and cell-based immune-fluorescence assay. The molecular mechanism of inhibitory action was further proposed using in silico molecular docking studies. Results In vitro studies revealed that 8 µM α-Mangostin completely inhibited CHIKV infectivity under the cotreatment condition. CHIKV replication was also inhibited in virus-infected mice. This is the first in vivo study which clearly showed that α-Mangostin is effective in vivo by significantly reducing virus replication in serum and muscles. Molecular docking indicated that α-Mangostin can efficiently interact with the E2–E1 heterodimeric glycoprotein and the ADP-ribose binding cavity of the nsP3 macrodomain. Conclusions The findings suggest that α-Mangostin can inhibit CHIKV infection and replication through possible interaction with multiple CHIKV target proteins and might act as a prophylactic/therapeutic agent against CHIKV.

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

2021 ◽  
Vol 17 (11) ◽  
pp. e1009667
Author(s):  
Prabhudutta Mamidi ◽  
Tapas Kumar Nayak ◽  
Abhishek Kumar ◽  
Sameer Kumar ◽  
Sanchari Chatterjee ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Viral Infection ◽  
Gene Silencing ◽  
Chikungunya Virus ◽  
Health Concern ◽  
Chikv Infection ◽  
Viral Copy Number

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.

scholarly journals Overview on Chikungunya Virus Infection: From Epidemiology to State-of-the-Art Experimental Models

2021 ◽  
Vol 12 ◽  
Author(s):  
Larissa E. C. Constant ◽  
Bia F. Rajsfus ◽  
Pedro H. Carneiro ◽  
Tháyna Sisnande ◽  
Ronaldo Mohana-Borges ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
Complex Disease ◽  
State Of The Art ◽  
Cell Types ◽  
Experimental Models ◽  
Chikv Infection ◽  
Severe Manifestation ◽  
Disease Signature

Chikungunya virus (CHIKV) is currently one of the most relevant arboviruses to public health. It is a member of the Togaviridae family and alphavirus genus and causes an arthritogenic disease known as chikungunya fever (CHIKF). It is characterized by a multifaceted disease, which is distinguished from other arbovirus infections by the intense and debilitating arthralgia that can last for months or years in some individuals. Despite the great social and economic burden caused by CHIKV infection, there is no vaccine or specific antiviral drugs currently available. Recent outbreaks have shown a change in the severity profile of the disease in which atypical and severe manifestation lead to hundreds of deaths, reinforcing the necessity to understand the replication and pathogenesis processes. CHIKF is a complex disease resultant from the infection of a plethora of cell types. Although there are several in vivo models for studying CHIKV infection, none of them reproduces integrally the disease signature observed in humans, which is a challenge for vaccine and drug development. Therefore, understanding the potentials and limitations of the state-of-the-art experimental models is imperative to advance in the field. In this context, the present review outlines the present knowledge on CHIKV epidemiology, replication, pathogenesis, and immunity and also brings a critical perspective on the current in vitro and in vivo state-of-the-art experimental models of CHIKF.

Sign in / Sign up

Export Citation Format

Share Document