Influenza Structure PM250

so in the last video i gave you a brief recap on what viruses are and why we are looking into influenza as an example viral infection of the respiratory system in this video we are going to start looking at the influenza virus in a lot more detail now the influenza virus forms part of the ortho mixer viridae family which is a group of viruses that have negative sense single-stranded rna as its genome but what does this mean well the genetic information within the influenza virus is composed of ribose nucleic acids or rna the genetic code is split across eight individual segments of rna that are linear meaning the ends of the rna segments don't form a closed loop structure and are essentially exposed and finally each of the linear rna segments is found as a single strand not the typical double-stranded helix with base pairs that we are so used to seeing within genomes now in addition to all of this the rna strands themselves are what we call negative sense which essentially means it is unable to be translated by the host cell machinery it's just not in the right format and because it can't be translated into viral proteins that cause infection it is considered to be non-infectious genetic material now the reason why it can't be translated is because negative sense single-stranded rna is technically complementary to messenger rna so it is the opposite of what is needed therefore it needs to be converted to positive sense single-stranded rna which can then be recognized by the host translation machinery making it infectious genetic material capable of producing viral proteins okay so moving on i originally said influenza was a member of the orthomixoviridae virus family now within this virus family there are seven different genera four of which relate directly to what we call influenza therefore when we talk about the influenza virus we're not just talking about a single virus we could be referring to a group of viruses so the four genera of influenza viruses are alpha influenza virus beta influenza virus gamma influenza virus and delta influenza virus and for anyone that is good with their greek alphabet you'll notice they are essentially called influenza a b c and d viruses now in some textbooks and journal articles they will only state three genera of influenza viruses which is technically wrong but also right you see the number depends on who or what we consider to be hosts for the virus when three genera are noted they are right in that only three of the four genera that's influenza a b and c are able to cause infections in humans influenza d on the other hand is unable to cause infections in humans and is therefore sometimes forgotten instead influenza d is capable of infecting animals predominantly pigs and cattle now when i said influenza a b and c cause infections in humans that's not to say they can't cause infections in animals too in fact all of them can cause infections in animals however many sources only note the infections from influenza a specifically influenza a infections in birds and pigs to be of any importance and we'll talk more about this later on in a video as the ability to infect humans and animals is highly significant in terms of disease potential now there are minor differences between some of these viruses and major differences between others with a and b showing the most similarity between each other typically speaking most of what i have talked about and will talk about in the future is related to the influenza a virus and the reason why i'm focusing on this is again due to its disease potential as we'll find out later so moving on what is the structure of our influenza a virion remember the term virion is used to describe a single virus particle well we've already mentioned it has negative sense single stranded rna separated into eight linear segments and as you can see they are a varying lens with roughly three large segments three medium-sized segments and two small segments now this genome needs to be packaged up into something so they can be a defined variant now there are multiple different structural components that go into making an influenza virion first and foremost we have a phospholipid bilayer this is composed of the bilayer from the previous host cell and is extremely important as this is what separates and protects the viral genome essentially creating a defined boundary and making the virus a defined particle just like a cell is defined by its phospholipid bilayer separating the uncontrollable external environment from a controllable internal environment but there is also a lot more to a virion than this phospholipid bilayer which is why they are called viruses and not liposomes now the phospholipid bilayer is only a single part of what we call the viral envelope which is essentially the outermost layer of the virus so what are the other core components of the influenza a viral envelope well a key component of the viral envelope is an ion channel known as matrix protein 2 or m2 protein and this is exactly what it says on the tin a protein channel that allows ions to move between the external environment and the internals of the virion now more specifically the m2 ion channel acts as a ph active or proton selective channel whose primary goal is to change the ph within the virion during viral entry into the cells and there are various other features of the m2 protein which implicate its use in both viral assembly and release of the virion from the host cell so what you kind of could say is the m2 protein is involved in many stages of the infection process from entering the host cell to assembly of new virions within the host to the release of individual virions from the host cell now this protein is actually just one of three key proteins in the cell envelope the next one is hemoglutinin now hemoglutinin or ha or simply h protein is one of two key proteins located on the surface of the influenza virion and there are approximately 300 to 400 of these hemagglutinin proteins per virion and they are what we call a homo-trimeric glycoprotein which if we break it down means each hemoglobin is composed of three identical monomer subunits and as we can see from this structure with each subunit composed of both carbohydrates and protein hence the term glycoprotein now sticking out into the external environment is a cell binding site which allows hemoglutinin to attach to a target host cell and from the point of attachment it mediates the process of membrane fusion in a ph dependent process now the function and placement of hemoglutinin as an external facing entity means it is antigenic meaning antibodies can be raised by our bodies to neutralize its effects which if successful stops the virus from attaching to host cells and it stops an infection from being initiated now hopefully you've picked up on the fact that i have now mentioned ph twice in the context of our viral envelope proteins once for the m2 protein and again for our hemoglutanone this isn't by chance and we'll pick up on this when we explore the process of infection now going back a second i said that hemoglobin is a trimer made up of three monomers now the interesting thing is that there isn't just a single type of hemoglobin there are 18 different subtypes which have been identified to date split into two groups based on their phylogenetic similarity and that brings us to the end of hemoglutinin now there is just one final protein which forms the last piece of our virion envelope and that is neuraminidase or na or simply n-protein which is the second of our two key proteins located on the surface of the influenza virion now there are approximately 40 to 50 of these neuraminidase proteins per virion and they are what we call a homo tetrameric glycoprotein which again if we break this down means each neuraminidase is composed of four identical monomer subunits as we can see from the structure with each subunit composed of both carbohydrates and protein hence the term glycoprotein now sticking out into the external environment is an antigenic catalytic head which allows the virion to effectively escape from dying hosts without aggregating to other virions or more importantly reassociating with the dying host cell in addition to this just like hemoglobin neuraminidase proteins are antigenic but antibodies raised against it by our bodies are non-neutralizing essentially they can limit disease spread but not stop it now the head structure of our neuraminidase is attached to the phospholipid membrane through a connected stalk structure which penetrates into the virion with a cytoplasmic tail and just like hemoglobin there isn't just a single neuraminidase 11 different subtypes have been identified to date and they form the target of many of our current antiviral therapies for influenza now something that's quite interesting about neuraminidase subtitles is that they have different stalk lengths and therefore the head structure can protrude out of the virian particle at different lengths sometimes more than hemoglotonin which has the potential to alter the enzymatic activity of the virus and you might want to go away and see what this term means now our next and final protein of the virian envelope is located within the virion and it associates with all of the other envelope components and is known as the m1 matrix protein now as you might have figured this isn't a single protein there are multiple copies of this protein which form a sort of protective shell which helps to anchor our two glycoproteins in place whilst also providing structural rigidity to the virion now not only does it associate with our envelope proteins but it also forms a strategic link with various components located within the virion and i'll come back to this in a second but essentially that is the virion envelope and not to reduce it too much but effectively the phospholipid bilayer and m1 protein shell keeps things safe the hemoglutinin and m2 ion channel allow the virus to gain entry to a host cell while the neuraminidase allows newly synthesized virions to vacate a dying host cell now there is still a lot more to the virion than just the envelope there are various components located inside the virion which we'll look at now so floating around within the center of the virion we have two proteins known as non-structural protein 1 and non-structural protein 2 or ns1 and ns2 for short the complete functions of ns1 is not known however it has been proven to help the virus circumvent various aspects of the host's antiviral response mechanism ns2 on the other hand or nuclear export protein 2 as it is becoming commonly known as is involved in helping the movement of viral rna within the host cell out of the nucleus now i mentioned earlier there are eight single strands of negative sense rna and we'll talk more about these strands towards the end of this video but there are some proteins associated with these strands that are very important the first is the nucleocapsid protein nuclear protein or np protein which is present in all viruses containing negative sense single-stranded rna why well the primary function is to act as a single stranded binding protein encapsulating each strand of the viral genome to form the core component of a ribonuclear protein or rnp particle which is essential for viral transcription and viral packaging now the ribonucleoprotein is more than a strand of viral genome covered in nucleocapsid proteins it has a cap structure which is composed of three distinct polymerase proteins known as pa and pb1 and pb2 proteins which when joined together form an rna-dependent rna polymerase complex which as i said a second ago acts as a cap and so is found at the terminus of each linear single-stranded rna segment now this rna-dependent rna polymerase complex as the name suggests is extremely important in transcribing the viral genome into a readable positive sense rna so that it can be transcribed whilst also aiding in the replication of a new viral genome and essentially that is the structure of the virion for influenza there is just one final thing left to talk about in this video and that is the structure of the genome so up to this point we've spoken about 10 core proteins associated with the influenza virion but there are only eight strands of single-stranded rna within the virion so how do we get more proteins than strands of genetic material well each strand of the genome is slightly different with two strands encoding for two proteins so let's have a look at this in a bit more detail here we have the first three segments of the influenza genome which as we discussed previously are capped with three different ribonuclear proteins and completely covered in nuclear proteins to help protect the single stranded rna now these three segments are the largest segments of the influenza genome between 2 200 and 2 300 nucleotides in length and of course they are what we call negative sense now we spoke on the previous slide about the need to convert this negative sense rna into positive sense messenger rna which is able to be processed by the host cell's transcription machinery so using the virally encoded rna-dependent rna polymerase each negative sense rna segment undergoes transcription this results in our positive sense strand of messenger rna now you'll notice two things about this at one end there is a cap which one you need to know about but two i'm not going to talk about this is a self-directed learning task so go away look at the literature and see what this structure is how it forms and what its function is and if you can't do that well i will go over it in the next video so don't worry too much however what i will talk about now is what is at the other end of our transcribed messenger rna a poly adenine tail which is just to say the three prime end of this mrna strand contains many adenine residues adjacent to one another now the function of the poly a tail is thought to aid the efficient nuclear export of mrna within the host cell and is present due to the reiterative copying of uracil track at the five prime end of the negative sense viral rna template and that's just a fancy way of saying it's in the viral rna and it is just copied across so now we have our messenger rna which can leave the nucleus of the host cell and be translated by the host cell machinery in the cytoplasm giving rise to various viral proteins and as we can see here pb1 is encoded on the first segment giving rise to pb1 protein made from around 760 amino acids the pa protein is encoded on the second segment giving rise to the pa protein made of the same number of amino acids and the pb2 protein is encoded on the third segment giving rise to the pb2 protein which is slightly smaller at 720 amino acids and as we learned in the viral structure section these three proteins come together and form the rna-dependent rna polymerase which can then be used to transcribe viral genes replicate the negative sense strand of viral rna cap bind and perform various endonuclease activities now the same process occur with the next segment of the influenza genome segment 4 is around 1 800 nucleotides in length and encodes for the hemoglutinin protein which is made from approximately 560 amino acids and just like before following transcription it has this polyadenine tail to help with nuclear export segment 5 is around 1 600 nucleotides in length and encodes for the nucleocapsid protein which are approximately 500 amino acids in size and finally segment 6 is about 1 400 nucleotides in length and encodes for the neuraminidase protein which is made from approximately 450 amino acids now a key point here to remember is that the ha protein and the na proteins are the monomers so we need three or four of these to come together to form a functional viral proteins of 1680 and 1800 amino acids okay so far we've covered the three large segments of rna and the three medium segments of rna and generated six different proteins meaning our final four proteins are encoded by the two smallest rna segments now these are approximately 1 900 nucleotides in length so 1.5 to 2.5 times smaller than the other segments now as we can see here segment 7 can undergo the usual transcription translation process like the other segments to form the n1 matrix protein whereas segment 8 produces the non-structural protein one that's all good and well but as you can see following the transcription of the viral rna genome into the positive sense strand of messenger rna it can undergo a process known as splicing which is where the non-coding regions are removed from the messenger rna allowing different coding sections to be joined together which in turn allows for the production of new viral proteins the m2 ion channel in the case of segment 7 and the non-structural protein 2 or nuclear export protein 2 for segment 8. now i have glossed over this splicing process as this is something you should know from your previous genetics lectures and if you can't remember the process for this make sure you go back through your lecture notes and look it up and with that we essentially wrap up the structure of the influenza virus and the structure of the influenza genome in our next video we're going to see how all of this comes together so that the influenza virion can attach to a target cell become internalized create new variants from the enclosed genetic material and then release new viral progeny into the environment so that it can go on and infect a new cell so make sure you go over all of the information in this video before progressing you

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