Skip to content

Ebola protein blocks early step in body’s counterattack on virus.

One of the human body’s first responses to a viral infection is to make and release signalling proteins called interferons, which amplify the immune system response to viruses. Over time, many viruses have evolved to undermine interferon’s immune-boosting signal, and a paper published today in the journal Cell Host & Microbe describes a mechanism unique to the Ebola virus that defeats attempts by interferon to block viral reproduction in infected cells.

The newly published study explains for the first time how the production by the virus of a protein called Ebola Viral Protein 24 (eVP24) stops the interferon-based signals from ramping up immune defenses. With the body’s first response disabled, the virus is free to mass produce itself and trigger the too-large immune response that damages organs and often becomes deadly as part of Ebola virus disease (EVD).  The study was led by scientists from Washington University in collaboration with researchers from the Icahn School of Medicine at Mount Sinai and the University of Texas Southwestern Medical Center.

The study is the first to show how Ebola viral protein 24 defeats the signal sent by interferons, the key signalling molecules in the body’s early response to Ebola virus infection.  These new details of Ebola biology are already serving as the foundation of a new drug development effort, albeit in its earliest stages.

The medical community has known for a long time that infection with Ebola virus obstructs an important arm in the human’s immune system that is activated by molecules called interferons.  By determining the structure of an eVP24 in complex with a cellular transporter, the team has learned how Ebola does this.

The study spotlights the part of the body’s defense system that fights infection called innate immunity, the mix of proteins and cells that most quickly recognizes an invasion by a virus. This part of immunity keeps a virus from quickly reproducing inside cells.

To trigger an effective, early response to viral infection, interferons must pass on their signal to other cells. This occurs through other messengers inside cells as part of interferon signalling pathways, with the last of these messengers turning on genes inside the nuclei of cells to drive the immune response.

The current study determined the structure of eVP24 when bound to its cellular targets, transport proteins called karyopherins. The study used these structures to show how, in place of interferon’s natural downstream signal carrier phosphorylated STAT1, eVP24 docks into the karyopherins meant to escort STAT1 into cell nuclei where it turns on interferon-targeted genes. By elegantly interfering at this stage, eVP24 cripples innate immunity to cause EVD.

In 2006 the team found that the Ebola virus suppresses the human immune response through eVP24, but not how. Through of combination of molecular biology techniques, cell studies and tests that reveal protein structures, the current study had defined the molecular basis for how eVP24 achieves this suppression.

Understanding exactly how the Ebola virus targets the interferon pathway could help guide drug development moving forward. The researchers describes how it may be possible to find an antibody or molecule that interferes with eVP24, or that works around its competition with STAT1, such that treatment of patients with extra interferon, long used against the hepatitis C virus for instance, might become useful against the Ebola virus.

The medical community feels the urgency of the present situation, but still must do the careful research to ensure that any early drug candidates against the Ebola virus are proven to be safe, effective and ready for use in future outbreaks.

Source:  Icahn School of Medicine at Mount Sinai

 

Ebola Virus VP24 Targets a Unique NLS Binding Site on Karyopherin Alpha 5 to Selectively Compete with Nuclear Import of Phosphorylated STAT1.  Model of KPNA (PDB ID: 1BK5) in cylinder representation. The major and minor nuclear localization signals (NLSs) span the inner surface of ARMs 2–4 and ARMs 6–8, respectively. The ncNLS used by PY-STAT1 or the KPNA binding site of eVP24 is independent of the cNLS sites. Therefore, KPNA loaded with PY-STAT1 ± cNLS cargo can translocate into the nucleus. In contrast, eVP24 binding, via a portion of the region used by PY-STAT1 via ARMs 8–10, inhibits PY-STAT1 nuclear translocation, but not the transport of cNLS containing cargo.  Amarasinghe et al 2014.
Ebola Virus VP24 Targets a Unique NLS Binding Site on Karyopherin Alpha 5 to Selectively Compete with Nuclear Import of Phosphorylated STAT1. Model of KPNA (PDB ID: 1BK5) in cylinder representation. The major and minor nuclear localization signals (NLSs) span the inner surface of ARMs 2–4 and ARMs 6–8, respectively. The ncNLS used by PY-STAT1 or the KPNA binding site of eVP24 is independent of the cNLS sites. Therefore, KPNA loaded with PY-STAT1 ± cNLS cargo can translocate into the nucleus. In contrast, eVP24 binding, via a portion of the region used by PY-STAT1 via ARMs 8–10, inhibits PY-STAT1 nuclear translocation, but not the transport of cNLS containing cargo. Amarasinghe et al 2014.

Healthinnovations View All

Michelle Petersen is the founder of Healthinnovations, having worked in the health and science industry for over 21 years, which includes tenure within the NHS and Oxford University. Healthinnovations is a publication that has reported on, influenced, and researched current and future innovations in health for the past decade.

Michelle has been picked up as an expert writer for Informa publisher’s Clinical Trials community, as well as being listed as a blog source by the world’s leading medical journals, including the acclaimed Nature-Springer journal series.

Healthinnovations is currently indexed by the trusted Altmetric and PlumX metrics systems, respectively, as a blog source for published research globally. Healthinnovations is also featured in the world-renowned BioPortfolio, BioPortfolio.com, the life science, pharmaceutical and healthcare portal.

Most recently the Texas A&M University covered The Top 10 Healthinnovations series on their site with distinguished Professor Stephen Maren calling the inclusion of himself and his team on the list a reflection of “the hard work and dedication of my students and trainees”.

Michelle Petersen’s copy was used in the highly successful marketing campaign for the mega-hit film ‘Jumanji: The Next Level, starring Jack Black, Karen Gilian, Kevin Hart and Dwayne ‘The Rock’ Johnson. Michelle Petersen’s copywriting was part of the film’s coverage by the Republic TV network. Republic TV is the most-watched English language TV channel in India since its inception in 2017.

An avid campaigner in the fight against child sex abuse and trafficking, Michelle is a passionate humanist striving for a better quality of life for all humans by helping to provide traction for new technologies and techniques within healthcare.

One thought on “Ebola protein blocks early step in body’s counterattack on virus. Leave a comment

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.