Navigation Links
Bleeding symptom leads scientists to intracellular trafficker's role in virus propagation
Date:11/14/2013

Rodent-borne pathogens like hantaviruses and arenaviruses are simple, but resourceful, and very successful at propagating. Due to a tiny genome generating a mere four proteins compared to humans' thousands, they rely on human biological machinery to do their replication dirty work, facilitating infection, plus a high mortality rate. Vermont researchers have discovered a mechanism that when targeted, may stop these deadly viruses in their tracks.

A new study published in Cell Host & Microbe by the University of Vermont's Jason Botten, Ph.D., assistant professor of medicine and microbiology and molecular genetics, and graduate student Joseph Klaus and colleagues offers a paradigm shift for scientists' understanding of the functionality of a protein that resides in the cell's secretory pathway and gets "shuttled" from one end of the cell to the other.

Antivirals or vaccines do not exist for these pathogens, so gaining a better understanding of how they replicate was at the heart of Botten and colleagues' investigation.

"The 'catch' with these viruses is that each different species has a tailor-made mouse host, like a deer mouse, white-footed mouse, etc.," explains Botten. In addition, he says, because these viruses and their rodent hosts have co-evolved for millions of years, they do not cause any apparent disease in the mice. "It's a beautiful relationship," he remarks, noting that because these viruses are not dependent on humans for their maintenance in nature, when humans do get infected, they get very sick.

The team closely examined the interaction between the virus proteins and the host proteins, a process that yielded the creation of a map the first ever of human protein partners of arenavirus and hantavirus glycoproteins (GPs). "The mapping allowed all kinds of analysis regarding which pathways of human cells the virus is tapping into," says Botten.

GPs reside on the surface of the virus and allow it to bind and enter host cells. After defining the human proteins that interact with each viral GP, the researchers examined which host proteins were common to both viruses, selecting one for further investigation ERGIC-53, one of only three known intracellular cargo receptors.

"People who don't make ERGIC-53 have combined Factor V and Factor VIII deficiency, a mild form of hemophilia," Botten says. "Despite having this condition, these individuals are in good health, provided they get synthetic clotting factors or fresh frozen plasma following a major trauma or surgery. So in essence, people don't need ERGIC-53 to survive, which makes this an attractive antiviral target."

That initial connection the fact that people with this deficiency bleed and people who get these types of hemmorhagic fever viruses bleed was what got the researchers interested in ERGIC-53; they believed this protein could be important for both the propagation of these viruses as well as their ability to make people bleed.

The team got to work, seeking to determine just how ERGIC-53 might impact virus propagation. They quickly discovered that ERGIC-53 is absolutely essential for the propagation of arenaviruses. Additionally, "we found a new means for ERGIC-53 to associate with its viral partners binding to arenavirus GPs via a previously unknown, lectin-independent mechanism," Botten says. In fact, the team discovered that ERGIC-53 also interacts with the GPs of additional pathogenic RNA viruses such as orthomyxoviruses (e.g., influenza), coronaviruses (e.g., SARS), and filoviruses (e.g., Ebola and Marburg). Importantly, they discovered that virus particles decorated with Ebola or SARS virus GPs also critically depend on ERGIC-53 to be infectious.

New information centering on viral particles, which are produced when a person gets infected, were another important finding of the study. The group determined that ERGIC-53 is a "virion component" it gets into the viral particle and while virions still form without it, they are noninfectious. According to Botten, even in cases where ERGIC-53 is absent, a person could still make virus particles in his/her blood, but these particles would essentially be duds that cannot harm the infected person. However, these same particles will presumably be seen by the immune system, allowing the person to mount an effective immune response. Therefore targeting ERGIC-53 with an antiviral could result in an immunizing form of antiviral therapy.

"Overall, our findings show that ERGIC-53, which was already an interesting and important host protein due to its normal cargo receptor functions, has a new class of pathogen-derived ligands, namely the GPs encoded by a broad range of highly pathogenic viruses," says Botten, adding that "while ERGIC-53 represents a potential broad-spectrum antiviral target for arenaviruses, coronaviruses, and filoviruses, it may also be required for additional human pathogens, such as the New World hantaviruses, orthomyxoviruses, or retroviruses (e.g., HIV), based upon its conserved interaction with their GPs."

In the future, Botten and his colleagues hope to determine exactly how these viruses harness ERGIC-53 to ensure their reproductive success.

"If we can uncover this common mechanism, it might be possible to engineer a single therapeutic treatment that could be used to treat each of these devastating pathogens," he concludes.


'/>"/>

Contact: Jennifer Nachbur
jennifer.nachbur@uvm.edu
802-656-7875
University of Vermont
Source:Eurekalert

Related biology news :

1. Stem cells enable personalised treatment for bleeding disorder
2. Resveratrol, found in red wine, worsens MS-like symptoms and neuropathology in mice
3. Penn study: Shutting off neurons helps bullied mice overcome symptoms of depression
4. Calcium plus vitamin D supplementation does not reduce joint symptoms in postmenopausal women
5. Changes to symptom structure in DSM-5 support diagnosis of toddlers with autism spectrum disorder
6. Why does a high-fat diet induce preeclampsia-like symptoms in pregnant rats?
7. Complex genetic architectures: Some common symptoms of trisomy 21
8. Symptoms of Prader-Willi syndrome associated with interference in circadian, metabolic genes
9. Pitt team finds melatonin delays ALS symptom onset and death in mice
10. In autism, age at diagnosis depends on specific symptoms
11. Folate and vitamin B12 reduce disabling schizophrenia symptoms in some patients
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:3/31/2016)... PROVIDENCE, R.I. , March 31, 2016  Genomics ... leadership of founding CEO, Barrett Bready , M.D., ... addition, members of the original technical leadership team, including ... Vice President of Product Development, Steve Nurnberg and Vice ... have returned to the company. Dr. Bready ...
(Date:3/23/2016)... , March 23, 2016 ... Interesse erhöhter Sicherheit Gesichts- und Stimmerkennung mit ... Inc. (NASDAQ: MESG ), ein ... dass das Unternehmen mit SpeechPro zusammenarbeitet, um ... der Finanzdienstleistungsbranche, wird die Möglichkeit angeboten, im ...
(Date:3/22/2016)... PROVO and SANDY, ... Screening Ontario (NSO), which operates the highest sample volume ... testing, and Tute Genomics and UNIConnect, leaders in clinical ... today announced the launch of a project to establish ... testing panel. NSO has been contracted ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... 2016 Houston Methodist Willowbrook Hospital has ... Association to serve as their official health care ... Willowbrook will provide sponsorship support, athletic training services, ... coaches, volunteers, athletes and families. "We ... Association and to bring Houston Methodist quality services ...
(Date:6/23/2016)... NEW YORK , June, 23, 2016  The ... students to envision new ways to harness living systems ... of Modern Art (MoMA) in New York ... more than 130 participating students, showcased projects at MoMA,s ... included Paola Antonelli , MoMA,s senior curator of ...
(Date:6/23/2016)... OTTAWA, ON (PRWEB) , ... June 23, 2016 , ... ... former DNA Technical Leader at the Arkansas State Crime Laboratory, has joined STACS DNA ... joining the STACS DNA team,” said Jocelyn Tremblay, President and COO of STACS DNA. ...
(Date:6/23/2016)... NEWPORT BEACH, Calif. , June 23, 2016 /PRNewswire/ ... offering new biological discoveries to the medical community, has ... and co-founder Matthew Nunez . "We ... provide us with the capital we need to meet ... funding will essentially provide us the runway to complete ...
Breaking Biology Technology: