Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

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

More articles from Life Sciences:

nachricht Why developing nerve cells can take a wrong turn
04.06.2020 | Universität zu Köln

nachricht Innocent and highly oxidizing
04.06.2020 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Small Protein, Big Impact

In meningococci, the RNA-binding protein ProQ plays a major role. Together with RNA molecules, it regulates processes that are important for pathogenic properties of the bacteria.

Meningococci are bacteria that can cause life-threatening meningitis and sepsis. These pathogens use a small protein with a large impact: The RNA-binding...

Im Focus: K-State study reveals asymmetry in spin directions of galaxies

Research also suggests the early universe could have been spinning

An analysis of more than 200,000 spiral galaxies has revealed unexpected links between spin directions of galaxies, and the structure formed by these links...

Im Focus: New measurement exacerbates old problem

Two prominent X-ray emission lines of highly charged iron have puzzled astrophysicists for decades: their measured and calculated brightness ratios always disagree. This hinders good determinations of plasma temperatures and densities. New, careful high-precision measurements, together with top-level calculations now exclude all hitherto proposed explanations for this discrepancy, and thus deepen the problem.

Hot astrophysical plasmas fill the intergalactic space, and brightly shine in stellar coronae, active galactic nuclei, and supernova remnants. They contain...

Im Focus: Biotechnology: Triggered by light, a novel way to switch on an enzyme

In living cells, enzymes drive biochemical metabolic processes enabling reactions to take place efficiently. It is this very ability which allows them to be used as catalysts in biotechnology, for example to create chemical products such as pharmaceutics. Researchers now identified an enzyme that, when illuminated with blue light, becomes catalytically active and initiates a reaction that was previously unknown in enzymatics. The study was published in "Nature Communications".

Enzymes: they are the central drivers for biochemical metabolic processes in every living cell, enabling reactions to take place efficiently. It is this very...

Im Focus: New double-contrast technique picks up small tumors on MRI

Early detection of tumors is extremely important in treating cancer. A new technique developed by researchers at the University of California, Davis offers a significant advance in using magnetic resonance imaging to pick out even very small tumors from normal tissue. The work is published May 25 in the journal Nature Nanotechnology.

researchers at the University of California, Davis offers a significant advance in using magnetic resonance imaging to pick out even very small tumors from...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Dresden Nexus Conference 2020: Same Time, Virtual Format, Registration Opened

19.05.2020 | Event News

Aachen Machine Tool Colloquium AWK'21 will take place on June 10 and 11, 2021

07.04.2020 | Event News

International Coral Reef Symposium in Bremen Postponed by a Year

06.04.2020 | Event News

 
Latest News

Why developing nerve cells can take a wrong turn

04.06.2020 | Life Sciences

The broken mirror: Can parity violation in molecules finally be measured?

04.06.2020 | Physics and Astronomy

Innocent and highly oxidizing

04.06.2020 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>