quote - HOW EBOLA KILLS PRIMATES: THE MOLECULAR PATHOPHYSIOLOGY PART 2 Basically Ebola kills inadvertently. A particular strain will evolve within a pathogen-host ecology and the adapted virus will inflict a minimum amount of damage consistent with its need to survive. The virus downregulates the hosts innate and adaptive immunity; including aspects of the general antiviral system. Unfortunately, the key viral proteins that accomplish the immune system destabilisation: ZGP (in the case of the Zaire species), VP 40, VP 35, VP 24 and the viral nucleoprotein (NP) do it by critically balancing their respective Michaelis constants for their various substrates of the target host species. Its a very difficult evolutionary optimisation problem; because the proteins ALL have multiple substrates. Long-evolved viral genomes and proteomes are extremely parsimonious - they are a miracle of packaging design - they display functional compression ratios that will make most communication engineers green with envy. More on the consequences of this in a while. And in addition they have multiple functions quite apart from knocking down the hosts immune and antiviral defences. After all, a filovirus is a very busy critter. It has to infect, reproduce and disseminate itself in a population. The Ebola viruses achieve a lot of immune system havoc by: Interfering with α5 integrins Ablating/suppressing Major Histocompatibility Complex Class I (MHC I) family expression on the cell surface VP 35 and VP24 bind to and preventing very specifically, antiviral gene expression of interferons IFN-α and IFN-γ (which also further downregulate synthesis of MHC I). IFN also upregulates 2′-5′ oligoadenylate synthetase (2′-5′(A)N) a very powerful ribonuclease activator that degrades viral RNA. Unfortunately, loss of IFN ability to stimulate 2′-5′(A)N production This inhibition of IFN antiviral activity seems to ramp up production of IFNs and the very high level deranges many other systems VP 35 also specifically binds and inactivates and blocks double strand RNA a key step in viral replication VP 35 somehow stabilises the molecular complex, TPL-2–ABIN-2–NF-κB1 p105, which is able to, independently of classical means, ramp up Tumour Necrosis Factor alpha (TNF-α) to extremely high levels in macrophages etc. TNF-α at these levels is a potent apoptotic factor, causing massive death of lymphocytes - resulting in lyphocytopenia and compromisation of adaptive immunity. With the loss of CD 4 T cells the host is unable to generate Ebola antibodies. So in dying patients - despite the high levels of cytokines and Ebola antigens, there is little useful antibody production TNF-α independently turns up Nuclear Factor kappaB (NF-κB). NF-κB drastically turns up many things including Tissue factor, Macrophage Chemoattractant Protein 1 (MCP1) and inducible Nitric Oxide Synthase (iNos). Shock and Multiple Organ Failure are now in the cards Theres much much more...but this is the skeleton. The higher the viral load, the more serious the pathology. That is the evidence. Viral load, Tissue factor, TNF-α and iNOS dictate the outcome of the infection. Now to the question: How can Zaire Ebolavirus, which is comparatively innocuous in bats and mice, be so dangerous in Primates? Normally, an Ebolavirus is in an equilibrium with its host. It does damage the host... after all, it s a parasite... but not too much damage. Unfortunately, it has to carefully cripple itself so that the Michaelis constants of its protein substrate interactions are just right. This is a very constrained morphospace, the result of the enormous functional compression I spoke about earlier. Normally, i.e., statistically, a single aminoacid mutation in a protein will act to increase the Michaelis constant (i.e., decrease the affinity of the protein for substrate); this is the general case that is, in fact observed in mutant proteins... But in this highly evolved morophospace of protein-and-substrate, there is a high chance that a mutation will decrease Michaelis constant for homologous proteins in OTHER related mammals making the damn virus lethal. My next post will be on ideas of using this info to protect ourselves - should the unfortunate (very unlikely - I dearly hope!!) situation of a pandemic occur. Now for the legal disclaimer: The matter contained herein is given for purposes of general information under our Constitutional Provisions for Freedom of Speech. It is not intended to diagnose, prevent or treat any disease real or imagined.
Posted on: Tue, 14 Oct 2014 03:11:37 +0000
Trending Topics
Recently Viewed Topics
© 2015