how does ebola kill primates ---------- Forwarded message ---------- From: VVVVVVVVVVVVVVVVVVVVVVVVV> Date: 12 October 2014 17:43 Subject: Re: EBOV GUINEA 2014 - dont laugh! To: HOW EBOLA KILLS PRIMATES: THE MOLECULAR PATHOPHYSIOLOGY PART 1 This write-up is intended for ANYONE who wants to do her/his own research into the whys and wherefores of Ebola. Since all we can do at this point is to embark on a course of watchful waiting; while the brave troops on the ground in West Africa learn from their mistakes - at the risk of their lives - and try (I hope very successfully) to contain the epidemic there; it might help if those of us who were technically inclined back here on T&T, should peruse the literature. Who knows? Anyway, this is my start in a THREE PART POST. If anyone needs to see individual pdfs you can email me. I am going through scads of research papers - which is a lot like rummaging through a dustbin. You have to clear away a LOT OF RUBBISH before you find anything good to eat. If anyone wants to help...feel free. the basics: EBOV Guinea 2014 seems to be an evolving humanised mutant of Zaire Ebolavirus, Viral Family filoviridae. There are 5 species of Ebolavirus, four seem to cause human disease. The virus species are: Bundibugyo Ebolavirus; Reston Ebolavirus; Sudan Ebolavirus; Tai Forest Ebolavirus; and Zaire Ebolavirus. Reston Ebolavirus does not seem to cause human disease. Zaire Ebolavirus is highly pathogenic in primates. Like many viruses, EBOV uses important cell membrane proteins of the integrin family to dock with and enter target cells. A multi-use viral glycoprotein, which Ill call ZGP, in Zaire Ebolavirus, is produced in two flavours- a soluble secreted glycoprotein; and a structural glycoprotein which is incorporated into the viral coat. The structural glycoprotein is smaller; one account seem to say it is obtained by RNA editing; other accounts say that a precursor is cleaved to produce two subunits that heterodimerise. Trimers of these heterodimers come together to form the viral coat. At any rate, the soluble glycoprotein resembles a Type 1 Transmembrane protein. It plays an important role in viral docking and incorporation into the cell. Because it is functionally a Type I Transmembrane protein; we should expect that it has the propensity to cause a lot of mischief. It does. EBOV uses at least α5β1 and α5β3 integrins to do some of its dirty work. Expression of just the viral ZGP - without the virus - in vitro causes profound changes in mammalian target cells: cells lose critically important molecules on their surface that help them coordinate their activities; hold on to the extracellular matrix - and to each other - and turn on and integrate their innate immunity. So just the ZGP is pathogenic. And when we do independently express different Ebola virus GPs in a virus-free experiment, their effects on target cells partially correlate with pathogenicity of the various Ebolavirus species. However chimeric virus constructs - one viral species expressing another speciess GP - show that ZGP alone is not the only contributor to virulence. In fact by selective passaging, a strain of extremely human-virulent Zaire Ebolavirus, which is relatively non-pathogenic in mice, can be developed into one that produces lethal human-like disease in mice. gene screening for mutant DNA on such mouse-lethal viruses showed amino acid changes in the ZGP (3 mutations); one amino acid change each to viral proteins VP 35, VP 24 and viral nucleoprotein; and two amino acid changes to the viral polymerase L. Changes were also found in noncoding regions The number of passages needed to effect this new-found pathogenicity was surprisingly small - which generally agrees with the viral genome study on EBOV Guinea 2014 which I attached at the opening post of this thread on Sept 1st 2014. So we see that EBOV makes a good living by docking with cells by binding to integrins; which conveniently disrupts the adhesion of cells; and cripples immune response early in the game. This so that the inoculating viruses have time to build up their strength without being in the surveillance of the innate immune system. Nothing special in this. Lots of viruses use this trick. But how does Ebola kill? Before we get down to the molecules - whats the gross pathophysiology like?? It turns out that Ebola is not your average haemorrhagic fever. Ebola victims are massively lymphopenic; are very hypotensive; show extremely poor tissue perfusion; are in tissue fluid distribution disarray; display disseminated intravascular coagulation with other coagulopathies; and exhibit massive leakage from the vascular compartment. Death from multiple organ failure is in the cards. Its remarkably like septic shock. And you can imagine the impossibility of simultaneously managing a few score thousand critically ill people - all in dire need of an ICU and very skillful intensivists - somewhere in a very poor West African nation. Or on T&T for that matter. So, umm, how does a virus that couldnt harm a mouse, kill a human? What are the root molecular mechanisms? THATS PART TWO... VVVVVVVVVV ===== On 10 October 2014 06:29, VVVVVVVVVVVVVVVV> wrote: Someone on this microblog list said: even if it proves to be manageable, by draconian measures, then the draconian measures themselves may lead to lethal consequences for a whole lot of us, trade, food distribution .... the long long list... alain says: This is a World Bank Paper, dated Oct 7th 2014. I would have failed it and ordered a redo from scratch. Maybe it was a rush job. Who knows? ========================== On 10 October 2014 06:08, thierry-alain huitdeniers wrote: In case some of us dont know, we can download current Ebola protocols as pdfs from the comprehensive and frequently updated CDC page: cdc.gov/vhf/ebola/hcp/index.html In future posts Ill also try to look at the molecular pathophysiology of this disease which is extremely lethal in Primates; and not quite so badly behaved in many other mammals. That should lead to the next question: What are the possible drug fixes - preventative & curative? Because, after all, ISNT THIS THE NITTY GRITTY?
Posted on: Mon, 13 Oct 2014 10:30:07 +0000