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  • How hemaglutinin work

    Hello to all science lover,

    Many discussion have occured about change that could spark an pandemic with H5N1. Many of them point out the need for H5 to acquire specificity for a2,6 proteoglycan receptor c will give the virus the ability to infect the upper respiratory tract.

    http://www.flutrackers.com/forum/sho...=6576#post6576

    Some other point toward the the cleavage site an its ability to be fonctionnaly cleaved by exogenous protease in the right kind of cells.

    http://www.flutrackers.com/forum/sho...2&postcount=22

    http://www.pubmedcentral.gov/article...z&artid=249560


    So various discussion there and there have turn around two important features of the protean hemaglutinin which is the major protean determining the influenza's infectivity.

    These two feature work together and will determine which kind of cells, which host and witch level of infectivity.

    With these two picture already post elsewhere check the shematic drawing I'll post down there.
    .

    (Mellie edited to fix the broken url only.)
    Last edited by Mellie; April 6, 2006, 10:07 PM.

  • #2
    Re: How hemaglutinin work

    Sorry,

    I'll come back tomorrow I have some problem with my computer and I cannot put my pictures...

    Comment


    • #3
      Re: How hemaglutinin work

      Maybe these can add to your work Mingus.

      Here are some diagrams of how the HA works:
      Attached Files
      Last edited by AlaskaDenise; July 27, 2007, 05:19 PM.
      "The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation

      Comment


      • #4
        Re: How hemaglutinin work

        Your 4th is a nice one.

        Denise your a quick autodidact !

        Ok i'll try here ( at work )

        I'll come back later and hope to start a good discussion about what affect each step and how the virus must addapt to his host if the step is host dependent.
        Attached Files

        Comment


        • #5
          Re: How hemaglutinin work

          My little drawing is an attempt to summarise various information from scientific litterature and from the basic microbiology concepts into a easy picture.

          1-
          To become a human strain, a good Receptor Binding Site adapted to the right proteoglycan must stick with a a2,6-proteoglycan which is on the surface of a human cell in the upper respiratory track.

          2-
          Thereafter the good cleavage site must be cleaved in the medium where this a2,6 cell is.
          This cleavage drive a drastic conformational change. I tried to represent it like a spring that suddently broke and flip making the virus envelope and the cell's own to merge so the genetic material of the virus can enter the cell and start his evil pirate work.

          This step is dependent upon other protean in the medium, theses are the exogenous proteases who are naturally made by the host (human in this case).)

          Low pathogenic strain are not easy to cleave and are very dependend upon the exogenous proteases.

          High pathogenic strain are easy to cleaves and can be so in a wide variety of cell and a wide variety of exogenous proteases and sometime be autocatalytic and be cleaved by only a low PH.
          So we can easily understand how nasty can be a high pathogenic strain like H5 and H7 can be.

          Many mechanism can explain the pathogenicity of H5N1 but the extreme cleavability of his CS is one major.
          It can explain why this virus can yeild such high viral load as many study have claimed it do.

          So with this high cleavability less virus enter in more cells so the whole replication exponential curve is driven up !

          Remember the study (Osterholm made reference to it) that compare the infectivity of the 1918 virus and the H5N1 and find that ten fold less H5N1 virus was able to drive the same answer that the 1918 virus ...

          If someone find it please post it !

          3- The virus's genetic material is inside the cell and start to replicate himself, so from one cell will emerge ( drive out by neuraminidase this time ) thousand of new virus ready to infect surrounding area.
          Last edited by Mingus; April 7, 2006, 07:23 AM.

          Comment


          • #6
            Re: How hemaglutinin work

            Here is the image, open on the spot...
            Nice image. Thank you Mingus.

            Click image for larger version

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            Comment


            • #7
              Re: How hemaglutinin work

              If you read this article( AlaskaDenise find it ) you will find interresting idea link with this processus.

              http://www.pubmedcentral.gov/article...z&artid=249560

              This is particularly interesting because we realised that a highly pathogenic strain of Influenza haved already pass from a bird species to a mammals.

              It happend in 1979 in new england !

              Influenza virus A/seal/Mass/1/80 (seal virus, H7N7) was first isolated when approximatively 20% of the harbor seal polulation on the New England coast of the United States died in 1979-1980 because of acute hemprrhagic pneumonia. The virus was antigenically characterized as H7N7 serotype, similar to some naturally occuring avian influenza viruses.
              So it did Happen in the past in another species and this drive a total population fatality rate of 20%


              Think of it, read it, and I'll come back tomorrow to told about the type cell adaptation experiment dissuss in the paper.
              Last edited by Mingus; April 6, 2006, 10:10 PM.

              Comment


              • #8
                Re: How hemaglutinin work

                Above I edited to fix the broken url only.

                Comment


                • #9
                  Re: How hemaglutinin work

                  Also, at the end of the cited article's abstract.......

                  The lethal outcome of the infection in chickens demonstrated for the first time that an influenza virus derived from a mammalian species can be modified during adaptation to a new cell type to such an extent that the resulting virus variant becomes pathogenic for an avian species
                  .

                  .
                  "The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation

                  Comment


                  • #10
                    Re: How hemaglutinin work

                    in www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&li st_uids=3576972&query_hl=2&itool=pubmed_docsum

                    ?..virulent H5 influenza viruses contain a series of basic amino acids at the cleavage site of the HA, whereas avirulent strains contain only a single arginine ?... Thus, a series of basic amino acids at the cleavage site probably forms a recognition site for the enzyme(s) responsible for cleavage.


                    This looks as if you have a doors with variable number of locks. In LPAI, your door has one lock, so only the correct single key protease) will activate the door. In HPAI, your door has multiple different locks, so that a variety of keys (proteases/low Ph) are available to unlock the door.

                    <O =""></O>
                    The perfect solution for those who cannot remember which key opens which door.

                    <O =""></O>
                    Are there other factors that influence cleavability?

                    <O =""></O>
                    I think I read about a HA cleavage mutation that was activated by protease in the circulating blood. When that happened, it could impact any organ the blood traveled through. Isn't this a different drama than that of the respiratory system?

                    .
                    Last edited by AlaskaDenise; April 7, 2006, 03:57 PM.
                    "The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation

                    Comment


                    • #11
                      Re: How hemaglutinin work

                      one cell produces 500000-1mio copies of the virus, but the mutation
                      rate is so high, that only about thousand survive, the others
                      are nonfunctional.
                      I'm interested in expert panflu damage estimates
                      my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

                      Comment


                      • #12
                        Mammalian to Avian and reverse

                        So the main issue of that article was something like to demonstrate that an virus recently passed from a species to another have still the ability to reverse-mutate into the species specificity of his origin.

                        What I found especially interesting is the way they did recreate a kind of avian virus.

                        Like Dr.Niman has often reffered about when he was talking about the lost S227N in the turkish outbreak, there is two major way to make a virus culture in a virology lab.

                        1. Chicken Embryo Cells ( CEC ) which is the classic way to culture a influenza virus.
                        In practice, it's a little disgusting because we infect an chicken's foetus. and the manipulation is more "toutchy" for a lab technician.

                        2. A more recent method (not so recent but ...) the Madin Darby Canine Kidney ( MDCK ) cells which is believe it or not a dog's cancer cells.
                        Cancer is a desease that originate when normals cells in a body lose the control of its replication and start to replicate endlessly like do a pathogenic bacteria.
                        This was a problem for the dog where they originate but is very practical for a lab technician because theses cells can grow in a little petri dish with some growt factor. So the virus simply replicate in theses little petri full of dog's cancer...

                        Check this for more, "History of MDCK cells" http://72.14.203.104/search?q=cache:...a&ct=clnk&cd=1


                        So basicaly, due to theyre origin MDCK cells are mammalians cells.
                        Ok some strains replicate endlessly since the sixties and they are very modified since the original dog cell.
                        But they we can assume that a virus that replicate well in theses cells are more mammalian and that virus that replicate best in CEC are more avian.

                        But it is not so simplist because they have been kept like a virus' culture method just because they can replicate almost all kind of virus if we add some exogenous proteases .
                        The key to activate the cleavage site, Trypsin is the most used one. For reference : http://en.wikipedia.org/wiki/Trypsin

                        In the article they cultivate the A/seal/Mass/1/80 H7N7 in theses two kind of cells without the use of this exogenous protease called Tripsin.

                        They did this to let the high pathogenic feature of the H7 to work alone.

                        Doing so they did let the virus replicate himself trought several passage.
                        A passage can be understood like a single petri dish being infected.
                        Several passage is one petri infecting one another and so on...

                        One of theyre finding is...

                        This virus need 7 to 10 passage in MDCK cells to become a tipical mammalian virus.
                        But it need between 32, 35 to 102 passage in CEC cells to become a tipical avian virus and regain the avian multicleavage site.


                        What does it mean ?
                        This virus who where took from seal where more mammalian that avian.
                        Virus can mutate whitout the need of other strain to reassort or recombine, expect maybe self-recombination (between two gene of the same virus ?).

                        This particular virus has aproximatively 102 passage distance between his mammalian form and his avian form...
                        How does this experimental data link with the number of H2H needed for an avian HPAI to become fully mammalian addapted we still dont know but the question is open

                        They also postulate this
                        Based on the data available, we propose that, because the mammalian cells that are the primary target sites of infection may contain proteases with a broader substrate specificity than those found in avian cells, there is never a need for mutans of mammalian viruses to arise with a multibasic peptide at the HA cleavage site. This hypothesis could explain why pantropic mammalian influenza viruses have not been found.
                        It is just an hypothesis but it can explain why avian virus need to be more "NASTY" to affect theyre host and why bird are more resistent and sometime asymptomatic to virus that kill mammals.

                        Other interesting point of theyres data is that they analyse the kind of changes found in theses variant they obtain.

                        Most of the changes they found expept changes in the cleavage site where around the important features of the virus like the cleavage sites and the RBS but not direcly in.

                        What kind of changes do we see theses time in all the new H5N1 human and mammalian sequences ? alway around but not directly in.

                        All of this tell us manything

                        Every change can be significative, most of them is simple adjustment of the 3D shape, some other are major features.
                        Many way is possible for a stain to pass from a avian to an mammalian form.
                        This processus is reversible under some condition.
                        The high pathogenic feature may disapear after some year in the human population ( oof ! )

                        20% die-off in a mammalian population is possible !

                        and one unanswered question :
                        Are we 100 passage away from a pandemic ?

                        Comment


                        • #13
                          Re: How hemaglutinin work

                          Are the 100 passages within ONE person or 100 people? If one person, doesn't that happen within one normal clinical presentation? Or perhaps that accounts for the outcome change in the heavily tested vietnam woman, whom they thought developed Tamiflu resistance.

                          One replication cycle takes how long?

                          .
                          "The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation

                          Comment


                          • #14
                            Re: How hemaglutinin work

                            Originally posted by AlaskaDenise
                            Are the 100 passages within ONE person or 100 people? If one person, doesn't that happen within one normal clinical presentation? Or perhaps that accounts for the outcome change in the heavily tested vietnam woman, whom they thought developed Tamiflu resistance.

                            One replication cycle takes how long?

                            .
                            A petri is very different from a human.
                            It's just an experimental example, and no scientist now exacly how this model match the reality.

                            That's the problem with science. Everything is based upon model that doesn't exacly match reality.

                            So I don't know

                            Comment


                            • #15
                              Invitation

                              Hello to all,

                              I hope interested readers have been glad to read little explanation that i did in this tread.
                              It give me the idea to start a archive of explanation, pedagogic work and links related to Molecular Biology, Biochemistry and Virology.

                              The FluTracker administation have been kind with me and give me the possibility to built so over the time in the Workshop area.

                              I do not consider myself as an expert but I have a solid formation in theses fields and some year experience in research and diagnostic Lab link to the veterinary industry.

                              What I'll try to do is to explain the science how I personnaly understand it in a way I hope most people will understand and my goal is to help more and more people understand the science behind the issue.

                              I'll be happy to hear your commentary, question or to be contradict by information you bring me that I was not aware to.
                              As I do no consider myself as an expert I hope everyones to always stay alert and notify me if I made mistake or if you not agreed.
                              English is not my usual language so I hope readers to be conprenhensive and ask if I'm not clear.

                              But be careful, since my name is not Niman, I dont expect personnal attack.

                              So I invite you all to continue the disscussion there:

                              http://www.flutrackers.com/forum/showthread.php?t=3901

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