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Research reveals how antibodies neutralize mosquito-borne virus

03.04.2013
Researchers have learned the precise structure of the mosquito-transmitted chikungunya virus pathogen while it is bound to antibodies, showing how the infection is likely neutralized.

The findings could help researchers develop effective vaccines against the infection, which causes symptoms similar to dengue fever, followed by a prolonged disease that affects the joints and causes severe arthritis. In recent outbreaks, some cases progressed to fatal encephalitis.

The researchers studied "virus-like particles," or non-infectious forms of the virus. They also obtained near atomic-scale resolution of the virus attached to four separate antibodies.

"We knew these antibodies neutralize the real virus, so we wanted to know how they do it," said Michael Rossmann, Purdue University's Hanley Distinguished Professor of Biological Sciences.

Findings are detailed in a research paper appearing Tuesday (April 2) in the journal eLife.

The scientists used a technique called cryoelectron microscopy to uncover critical structural details about the virus-like particles bound to the antibodies. The particles are made of 180 "heterodimers," molecules made of two proteins: envelope protein 1, or E1, and envelope protein 2, or E2.
The findings show the precise structure of the virus-like particle bound to a key part of the antibodies, called the antigen binding fragment, or Fab, which attaches to the heterodimers making up the virus's outer shell. The analyses showed that the antibodies stabilize the viral surface, hindering fusion to the host cell and likely neutralizing infection.

Chikungunya is an alphavirus, a family of viruses that includes eastern equine encephalitis.

"This is the first time the structure of an alphavirus has been examined in this detail," Rossmann said.

The research is aimed at learning precisely how viruses infect humans and other hosts, knowledge that may lead to better vaccines and antiviral drugs, Rossmann said.

Chikungunya in 2005 caused an epidemic on Réunion Island. A mutation in the E1 protein has allowed the virus to replicate more efficiently, which is considered the primary reason for its recent extensive spread, infecting millions of people in Africa and Asia.
The paper was co-authored by Purdue researchers Siyang Sun and Ye Xiang, Akahata Wataru of the National Institutes of Health, Heather Holdaway of Purdue, Pankaj Pal of the Washington University School of Medicine, Xinzheng Zhang of Purdue, Michael S. Diamond of the Washington University School of Medicine, Gary J. Nabel of the NIH, and Rossmann.

The research team conducted experiments to record the structure of the virus in different orientations and obtained a three-dimensional structure with a resolution of 5.3 Ångstroms, or 5.3 ten-billionths of a meter.
The research, funded by the NIH, is ongoing and involves one graduate student and five postdoctoral students. One goal is to learn how the virus is modified when the antibodies bind to the virus and to obtain higher-resolution images.

Writer: Emil Venere, 765-494-4709, venere@purdue.edu

Source: Michael Rossmann, 765-494-4911, mgr@indiana.bio.purdue.edu
Note to Journalists: Journalists may obtain a copy of the research paper by contacting Emil Venere, 765-494-4709, venere@purdue.edu

ABSTRACT

Structural Analyses at Pseudo Atomic Resolution of Chikungunya Virus and Antibodies Show Mechanisms of Neutralization
Siyang Sun1,4, Ye Xiang1,4, Akahata Wataru2, Heather Holdaway1,5, Pankaj Pal3, Xinzheng Zhang1, Michael S. Diamond3, Gary J. Nabel2, Michael G Rossmann1,* (1 Dept of Biological Sciences, Purdue University; 2 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health; 3 Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine; 4 These authors contributed equally to this work)

* Corresponding author. Department of Biological Sciences, 240 S. Martin Jischke Drive, Purdue University, West Lafayette, IN 47907-2032, USA. Tel.: +1 765-494-4911; Fax: +1 765-496-1189; E-mail: mr@purdue.edu

A 5.3 Å resolution, cryo-electron microscopy (cryoEM) map of Chikungunya virus-like particles (VLPs) has been interpreted using the previously published crystal structure of the Chikungunya E1-E2 glycoprotein heterodimer. The heterodimer structure was divided into domains to obtain a good fit to the cryoEM density. Differences in the T=4 quasi equivalent heterodimer components show their adaptation to different environments. The spikes on the icosahedral 3-fold axes and those in general positions are significantly different to each other, possibly representing different phases during initial generation of fusogenic E1 trimers.

CryoEM maps of neutralizing Fab fragments complexed with VLPs have been interpreted using the crystal structures of the Fab fragments and the VLP structure. Based on these analyses the CHK-152 antibody was shown to stabilize the viral surface, hindering the exposure of the fusion-loop, likely neutralizing infection by blocking fusion. The CHK-9, m10 and m242 antibodies surround the receptor-attachment site, probably inhibiting infection by blocking cell attachment.

Emil Venere | EurekAlert!
Further information:
http://www.purdue.edu

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