What Nobody Knows about Mitochondrial Antiviral Signalling Protein

A new year, a new project!

Hi all, its Katrina here, I’ve been studying at the University of Surrey for several years now; one of my favourite things about studying here is the opportunity to undertake novel practical research into real unknowns in the world of Biochemistry.

So, what is my project? It’s ‘an investigation into the trafficking of mitochondrial antiviral signalling protein (MAVS) from its site of synthesis to the mitochondria’…no idea what I’m on about? Honestly, neither did I a few weeks ago!

Let’s start with some context…

Most of us have heard of Zika and Hepatitis C viruses in the News, these Flaviviruses are just a couple of the 73 identified with a structure resembling that illustrated in figure 1.

Figure 1- Flavivirus Structure
(Author made)
Flavivirus particles consist of genomic information in the form of single-stranded ribonucleic acid (ssRNA), enveloped in protein. The surface of this envelope protein is decorated with other smaller proteins.  

In part, their infamy is due to their capacity to cause epidemics; the first reports of Dengue-like illness are over two centuries old! However, it is also due to the frequently lethal nature of the infections they inflict via fever, bleeding and inflammation of the brain. Up to 50,000 new cases of Japanese encephalitis in children under 15 are reported per year, with a mortality rate up to 30%. With increasing global temperatures comes the spread of arthropod vectors, invertebrate animals such as mosquitos which carry disease-inducers from an infected animal or human to another, like a post man picking up and delivering bad news without reading it! Thereby, the reach of this threat is expanding beyond the millions already affected.

There is currently no specific antiviral therapy for the prevention or treatment of Flavivirus infections. This lack of therapy may, at least in part, be due to their prevalence in developing countries; with the exception of Hepatitis C, Flaviviruses have a far greater impact upon economically developing regions such as central Africa and South America, as shown in figure 2. Symptom management is the most common treatment, including administering fluids and intervening during episodes of low blood pressure.

Figure 2- Epidemic regions of 5 common Flaviviruses
(copied from Creative Diagnostics, Flavivirus)
The majority of Flaviviruses are endemic to developing regions, largely due to the prevalence of the mosquito vectors in these regions.

As with everything in Biochemistry, structure determines function! Flaviviruses contain the information required to make more virus in the form of positively charged single-stranded ribonucleic acid (+ssRNA), all we need to know about this is that it mimics the information used to make more human proteins so the virus doesn’t need any help to produce more of itself once its guided by the surface proteins into the cell. This is one of the major challenges in treating Flavivirus infection, whereas other viruses can be treated with drugs to prevent more virus being produced. Thus, establishing Flavivirus-specific therapies relies on knowing how the body’s immune system responds to the virus.

So how does the immune system respond to Flavivirus infection?

Currently, we know receptor proteins sense the Flavivirus ssRNA inside cells beginning a series of events, eventually stimulating the early immune response to reduce the production of more virus. This series of events is like a chain of falling dominos, MAVS is a key domino- if it doesn’t fall the signal stops. As with a line of dominos which must be correctly lined up to cause the ‘domino effect’, MAVS must be at the correct location in the cell, at the cells’ powerhouses termed mitochondria, to signal to downstream proteins. This is evident in Hepatitis C infection, this virus contains information to make a protein which cuts MAVS away from mitochondria resulting in a lack of antiviral immune response such that Hepatitis C induces a persistent, often life-long infection with the potential to cause serious liver diseases including cirrhosis and cancer decades later.

Despite its obviously critical role in fighting Flavivirus infection, we do not know exactly how MAVS is shuttled from its site of synthesis to the mitochondria. Such shuttling events are usually mediated by chaperone proteins which, like a parent walking their child to school, accompany the protein of interest from its site of synthesis and ensure its localisation at a specific target within the cell. No such protein has been identified in MAVS shuttling.

Figure 3- Trafficking of Mitochondrial Antiviral Signalling Protein (MAVS)
(Author made)
The virus’ positively charged single-stranded ribonucleic acid (+ssRNA) is sensed inside the cell by receptor proteins which are believed to induce movement of Mitochondrial Antiviral Signalling protein (MAVS) from its site of synthesis to its site of action via an unidentified chaperone protein.
At the site of action, MAVS activates effector proteins to induce the immune response.

Illumination of this trafficking event may open the doors to a novel anti-Flavivirus treatment increasing the localisation of MAVS to mitochondria to enhance the body’s own immune response, and to kick-start this response in Hepatitis C.

But how do we identify such a trafficking pathway?

MAVS can be exposed to a variety of chaperone proteins in the lab and any interactions assessed. We can make a protein which specifically binds to, thus removes, MAVS protein from a mixture in a co-immunoprecipitation experiment; some MAVS protein may be bound to other proteins including chaperones which can then be identified… think of it like line fishing for a crab which is holding claws with a much cooler crab. Another experiment could include surface plasmon resonance assays which sound scary but are relatively simple; MAVS is immobilised to a gold plate and a river of proteins flows over the top, any binding is detected by the change in how light is refracted at the gold plate.

Overall, Flavivirus infections are a significant global health burden for which current treatments are inadequate. I am interested in elucidating how MAVS is shuttled from its site of synthesis to its site of action because this pathway may represent a therapeutic target in the treatment of such infections. Corny as it sounds, this is why I decided to study Biology- to contribute to improving health on a potentially global scale.

Many thanks for taking the time to read my blog!

Toodles,

Katrina 😊

Bibliography:

  • Seth, R.B., Sun, L., Ea, C-K., Chen, Z.J. (2005) ‘Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-kB and IRF3’, Cell, Volume 122, Issue 5, Pg. 669-682 
  • Daep, C.A., Munoz-Jordan, J.L., Eugenin, E.A. (2014) ‘Flaviviruses, an expanding threat in public health: focus on Dengue, West Nile and Japanese encephalitis virus’, J Neurovirol, 20(6), Pg. 539-560
  • Leyssen, P., De Clercq, E., Neyts, J. (2000) ‘Perspectives for the Treatment of Infections with Flaviviridae’, Clinical Microbiology Reviews, 13(1), Pg. 67-82
  • Horner, S.M. (2014) ‘Activation and Evasion of Antiviral Innate Immunity by Hepatitis C Virus’, Journal of Medical Biology, Volume 426, Issue 6, Pg. 1198-1209
  • Creative Diagnostics. Resources/Immunology Topics/Flavivirus. [Internet]. 2014 [cited 2019 Dec 30]; Available from: https://www.creative-diagnostics.com/Flavivirus.htm