Friday, 17 October 2014

Ebolaviruses - Ebola

This is going slightly off-topic... but still it's a process of thinking...

Now I appear to be switching from talking tech to talking virology... what are my credentials for doing this?   Well for the last 5 years in my spare time I have been studying for a second degree in Molecular Biology with the Open University.  One of these courses was Infectious Diseases and Public Health.  So I currently hold a Diploma in Health Sciences and am one module away from the degree - which I had to defer to next year due to getting an IT contract with UK Trade & Investment in London.

Ebolaviruses... so these are not the same as your normal Orthomyxiruses or retroviruses.. as they don't have a nice viral envelope... there are glycoproteins on the outer membrane wall...

Orthomyxvirus - - e.g. influenza 

Retrovirus - - e.g. HIV


Ebolavirus - - e.g. Ebola



A previous related virus to Ebola is the Marburg virus..  here's an image from Wikipedia - an impression of that central viral nucleoprotein - i.e. how the RNA is coiled tightly in the centre surrounded by packing proteins...

these proteins are produced by the RNA once inside a cell by the Polymerase molecule at the front end...  most of the infecting proteins are produced at the start of the RNA strand..  and the Polymerase can also restart... so you get a lot of the first proteins to begin with .. and then as polymerase transcribes more of the downstream proteins the balance tips and the Ebola virus switches from infecting the cell to producing new virions which then escape from the cell.

Entry

My first query was how does the polymerase start transcription?  It sits dormant in the virion until it enters the cell?   Another interesting topic I read up on was Apoptosis - the process of cell death.  Specifically Professor Guy Brown's "Regulation of apoptosis by the redox state of cytochrome c"
http://www.sciencedirect.com/science/article/pii/S0005272808000807

Cytochrome c exits the mitochondria and activates the apoptotic pathway that leads to cell death.  But Professor Brown queries here an observation that on entering the cytosol the cytochrome c molecule is automatically reduced and inactivated.  So there must be something that is keeping it in an oxidated and active state before it forms the apoptosome with the caspases...

So I wondered whether on entering the cell .. perhaps the polymerase is activated by reduction... an alteration of pH... a quick search on scholar.google.com ..  and  a paper in 2005 suggests (the title) - "Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection" by Kartik Chandran et al.  They identified that Cathepsin B (CatB, an endosomal cysteine protease) plays an important role (and Cathepsin L, CatL, a supporting role) in the breakdown of the viral matrix membrane - by removing GP1 from the GP glycoproteins.  They also suggest that CatB and CatL inhibitors can reduce the rapidity of the multiplication of the virus...  They operate in the slightly acidic endosome...  how would the polymerase be released with a trailing RNA into the cytosol.

There has been a lot of science since 2000 done on Ebola viruses... One can learn a lot with a few simple searches...

Ebola and Marburg enter cells using the Macropinocytosis and Endocytosis pathways.  These are standard pathways either initiated from within the cell to promote membrane homeostasis.. or externally by viruses or signalling molecules etc..  one of these is the cholesterol pathway - triggered by LDL attaching to receptors on the cell surface...

One paper suggests that chlorpromazine, an anti-psychotic, prevents the recycling of clathrin - the protein involved in endocytosis (it pulls the membrane inwards in the endocytosis process) - back to the membrane and so it inhibits endocytosis... and one team showed that chlathrin inhibition by chlorpromazine can inhibit further infection (and also sucrose has this effect) ..

So I was thinking about some basic cell biology .. and LDL and that got me thinking... could Ebola be using the cholesterol pathways ?  Since cells are constantly endocytosing LDL and recycling clathrin + LDL receptors back to the cell membrane...

One of the first (2002) papers is titled "Lipid Raft Microdomains A Gateway for Compartmentalized Trafficking of Ebola and Marburg Viruses" .. this team from Maryland, Sina Bavari et al identified that cell membrane lipid rafts (mostly cholesterol) as the gateway of viral attack - and exit.  Ebola has the ganglioside, GM1, in its viral envelope which is a marker for the lipid raft.   Can't lipid rafts be disrupted?  by statins?

Ok ... a quick search for "ebola statins" ... this has been thought of... NY Times in August.. good I'm catching up... :-/
http://www.nytimes.com/2014/08/16/opinion/can-statins-help-treat-ebola.html?_r=0

So .. yeah.. rather than giving statins pointlessly to a load of people in the West who really don't need it... why not donate it all to Africa... ?  if it's not going to cause a problem giving it to healthy people in the UK and US as a prophylactic treatment?  then give it to healthy people in Africa instead?

I'm not sure that's going to stop Ebola.. it's not a cure.. It might slow it down a little... but you need to stop it.  Mostly that can be done with quarantine/isolation of the infected and those suspected of infection, harsh as that can be on a society.  And also disinfecting with solution of bleach and PPE (protective clothing)... but there's not enough for everyone.

If interested to read about the measures required to protect oneself whilst dealing with Ebola..

Infection prevention and control guidance for care of patients in health-care settings, with focus on Ebola
http://www.who.int/csr/resources/publications/ebola/filovirus_infection_control/en/

Useful to know if you work with infected people..

More information on Ebola:
WHO - http://www.who.int/csr/resources/publications/ebola/en/
ViralZone - http://viralzone.expasy.org/viralzone/all_by_species/207.html

And all because someone somewhere..... "Bats for dinner, dear?"

Don't eat bats.  They're bad for you... and the rest of your country, world...

Amendment...

Getting carried away... if Ebola requires entry via a cholesterol pathway... LDL receptors or lipid rafts...  what if you have hypercholesterolaemia?  a reduction in LDL receptors etc..  could you be immune?  My guess is that there are many different types of hyperlipidemia caused by a variety of genetic mutations.

Perhaps if you could identify people with mutated receptors .. you could find ideal candidates to help treat the infected... :-)



No comments:

Post a comment