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Wednesday, December 10, 2003 My 2.5 Cents on the Flu "Have we responded to these [infectious diseases] by better preparing for emerging disease agents, or are we continuing to act only as crises arise?" Thus a group from St. Jude asks in a recent paper in Science (a summary accessible to the public is in the Science Daily). Every year, health organizations urge people to get their flu shots. But why every year? You may ask. Why not once every couple of years like tetanus? The problem is that Clostridium tetani is fundamentally a different bug than the influenza virus. Tetanus has a double stranded DNA genome which is far more stable than the influenza RNA genome. Tetanus can immediately transcribe and translate the virulence factors (primarily the tetanus toxin) with relative ease and fidelity. On the other hand, with an RNA genome--well, to say the least, it gets a bit messy. In some ways, a bacterium is a bit simpler. Most, like the laboratory workhorse E. coli contain one loop or plasmid of DNA that contains all of their genetic information. This makes them very easy to manipulate. Viruses, however, come in a dizzying variety: DNA or RNA, double stranded or single stranded, and if single stranded, could be antisense (i.e. negative) or sense (i.e. positive). Influenza is a single-stranded antisense RNA virus. This means that before hijacking the host cellular machinery for replication, it first has to transcribe the antisense RNA to sense RNA with its own RNA polymerase. And for some reason, RNA polymerases are a lot more permissive of mistakes than DNA polymerases. To make matters worse, influenza doesn't have just one strand containing all its genetic information--it has eight. And what's even stranger, the virus leaves it entirely to chance for making new virions. In the host cell, the genetic material and capsid (the packaging for the genome) are replicated but are floating around within the cell like so many rubber duckies and sports shoes that have been accidentally dumped from a ship in the middle of the ocean. It is by sheer probabilities, then, that all eight different strands combine with the capsid to make an infectious particle. If the capsid contains the wrong combination of strands or is just plain empty, there would be no way for it to replicate. "Mixing" occurs when two different strains of influenza infect the same cell. With all the genetic material floating about, it is entirely possible that, for instance, the first three strands of RNA from virus A and the other five strands of RNA from virus B get packaged into one capsid. Reservoirs for mixing are commonly found in fowl and pigs that are kept in close quarters. Here, human and animal viruses can recombine and produce new strains that are fully capable of infecting human cells but express antigens (or surface proteins on the capsid) that have never been seen by the immune system. The Science paper mentioned earlier also described a new method for generating flu vaccines quickly. It uses the recently developed protocol for eight-plasmid reverse genetics to help engineer a vaccine seed virus. The reason why this is so new is the difficulty of the whole thing. You can't just zap the bug so it can ingest one plasmid with your genes of interest. For influenza, one also has to deal with the headache of putting eight plasmids in and this only works in a couple of cell lines, most of them in the possession of private pharmaceutical companies. A brief note on influenza nomenclature: So what's with the H's and N's and numbers associated with the different strains? One can't possibly memorize all of this. Are they just random "social security numbers" that are assigned whenever a new strain emerges? "H" stands for hemagglutinin which helps the virus infect cells and "N" stands for neuraminidase which helps the virus escape. Both of these are proteins found on the surface of the capsid. Aside from this, strains are also categorized A-E which also describe the surface of the capsid. A-E were originally differentiated by looking at the characteristics of the agglutination reaction when put into rabbits. Influenza A and B are the usual culprits during the winter time. Influenza A is the only one that has been further subtyped with HN numbers. Variants of each strain are also described by when and where they were isolated. For instance, the Asian flu pandemic was caused by Influenza A, subtype H2N2 (or more succinctly A/Singapore/1/57, i.e. type/origin/strain number/year). [posted by S. Y. Affolee on 9:01 AM : ]
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