The Flu Ends With...

Every year as we go into clinics or pharmacies to receive an annual flu vaccine we have a reminder of what was arguably the deadliest pandemic this world has ever seen. It wasn't from Ebola virus or yersinia perstis. It was from a much more common pathogen that that most people shrug off as never a serious threat. Maybe it's that the disease symptoms are so general that it seems mundane or maybe it's that the youth disregard influenza as something to fear, but every year when my peers are asked if they received a flu vaccine only a few people raise their hand. Admittedly I was not included in this group on more than one occasion. So what's the deal this virus? Is it sheep or is it a wolf?  Let's take a look and you can decide for yourself.

I can't imagine what the world must have felt like in 1918. No internet, no Facebook!? Such a time actually existed!? All joking aside, the world was at war. Out of this war would be the seeds that would grow into a second war. But something that is generally accepted is that out of World War I also came the flu. As soldiers marched from town to town, so to did the flu. With such a wide movement of people it's no surprise that disease followed, but what was extraordinary was that this wasn't an ordinary flu virus. This one was different and it would become known as the Spanish-Influenza. Modern virologist and epidemiologist today agree that the Spanish Influenza was a plague which remains unmatched in mortality and force.

Like nearly every other virus the origins of the flu are a mystery. I heard a very interesting theory recently wherein it was believed that the flu was caused by extraterrestrial forces in order to bolster our immune systems for some awful plague that would befall us in the future. The weak were killed, ideally leaving only those who are immune left...kind of like artificial selection on a global level. Does this have any validity? Of course not, but given the wierd-ness that is the virus it wouldn't surprise me if it were true! What we do know is that it has probably been around for as long as we have silently passing from birds into the human population without much effect. It wasn't until 1918 that the flu began to come under our radar as a serious health threat.

Influenza belongs to a class of virus called Orthomyxoviridae. Fun to say isn't it? The flu also has three subclasses A, B, and C. But we're only focusing on A because that's what caused every pandemic influenza in recorded history. Influenza A is a minus sense single-stranded RNA virus which willed be designated as         -ssRNA from here on out. It also has an envelope which it steals from the infected host cell...tricky little thief. On this envelope are two absolutely essential proteins called hemagglutinin and neuraminidase. Influenza virus particles are designated based on the differences in these proteins. Ever thought of what the "H" and the "N" meant? Well that's it! To give you an idea of how variable this virus can be (Assuming I recall my virology class correctly) Influenza A can have 29 different hemagglutinin and 16 different neuraminidase, all of which can intermix (So you can have H1N1, H1N2...H1N16 and everything else!). The point is that Influenza A can be extremely variable in its form. These two surface antigens are how the CDC decides how to immunize people for the coming flu season.

Hemagglutinin binds sialic-acid which are found on the plasma membranes of cells. This is why certain types of flu can't infect humans. Certain species of animals contain certain variants of sialic-acid residues that are recognized by specific hemagglutinin molecules. So this is why a flu that infects a horse cannot jump to humans, because the flu that is infecting the horse CAN'T infect a human to begin with! The virus particle binds to the host cell and it is taken up in a phagocytic vesicle. The vesicle is then brought to a lysosome within the host cell to be destroyed. The virus is pretty much hiding and waiting...Fusion to the lysosome releases the virus particle into the lumen of the lysosome. Right now the cell is thinking "I'm going to kill whatever this thing is." The high concentration of acid in the lysosome flows through another protein on the viral envelope called M2. The flow of hydrogen ions down M2 causes the ribonucleoproteins that are covering the genome of the virus to dissociate. BINGO! It's all the virus's game now...

An RNA polymerase that comes with the virus particle can then begin to copy the -RNA. This is necessary because without this RNA polymerase, the virus can't copy it's genome! The reason is because the cell can only recognize +RNA so it wouldn't know what to do if it saw minus sense! The genome is divided into eight seperate segments of -ssRNA. This is pretty unique to viruses which usually only have one segment of genetic material. These segments are transported to the nucleus and this is when they start a devious biochemical cycle. The -RNA is copied into +RNA. One of the segments is the RNA polymerase that the virus needs to make more of itself. The virus makes a lot of this enzymes and thus makes a load more of the +RNA.

Another segment encodes a protein which basically shuts down host cell RNA synthesis and induces apoptosis. The cell's toast at this point, so the virus moves quick. It ships the +RNA back out of the nucleus where it is translated with a high affinity by host ribosomes. Basically, instead of host RNA the ribosomes of the host cell are recognizing viral RNA more. The virus produces more proteins called nucleocapsid proteins which wrap themselves around the newly made -RNA. The RNA segments move toward the cell membrane and push the membrane outward. Neuraminidase then jumps into action. It cleaves nueraminic acid, another cell membrane protein, which releases the new virus particle and allows the virus to continue the process over again.

Now that the bio is covered let's get to what makes this virus so crazy. The RNA polymerase that it uses is prone to mistakes so the virus produces small alterations in the genome with each replicatative cycle. As I said before in a previous post the viral cycle is a game of numbers. The goal is to make as much as you can as fast as you can. In the case of influenza the inherent mutability of the genome has an evolutionary advantage especially if it alters the hemagluttinin and neuraminidase proteins in the envelope. This process is called antigenic drift and basically it's a fancy way of saying "mutations." Antigenic drift is the basis for annual flu vaccines. Even if the same strain of flu is circulating, the current variant of that strain is just slightly different than the year before. These mutations produce variants of the flu that aren't recognized by the human immune system because the antibodies that the body produces can't efficiently recognize the altered hemagluttinin and neuraminidase proteins. This is bad...

The second reason why Influenza A is such a powerful foe is because of antigenic shift. This is a higher level process that involves something called a "superinfection." What happens here is that one species of host is infected at the same time by two different types of Influenza. Take for example H1N1 and H5N1. If these two viruses infect a single cell then what we have is a situation where there are now 16 unique segments of RNA in the same cell. What can happen is that the segments can sort around and the first virus can pull other pieces of the genome from the second virus. The result can be a completely new type of virus. It's widely believed that the start of H1N1 in 1918 was the result of this process.

Hold the phone. How does it spread to humans then!? This goes back to the sialic acid that is specific to each species. What can happen with the flu is a case where a bird infects a pig. The pig contains both sialiic residues common to birds AND humans. The result is that a strain of Influenza from birds can coinfect a pig that has already been infected with a strain of flu from humans! So what happens? You guessed it, a superinfection! The bird and human Influenza can reassort their genomes and the result can be a hybrid that has the capability of infecting humans with a novel type of virus! I'm still amazed by this...Seriously, it's a biological mastermind!

The Influenza scares like "Bird Flu" and "Swine Flu" are the result of antigenic shift. The reason why the CDC places so much emphasis on these outbreaks are because these viruses had an atypical infection pattern. These strains targeted and killed young, healthy people. This is abnormal for the flu which primarily causes mortality in the very young and the very old. It's for this reason that the CDC strongly advises for a yearly flu shot. I recently saw a sign that read "The Flu Ends With U" and this is the most important reason for vaccinations. If the virus cannot replicate in a host then it is cut of from spreading anymore which dramatically reduces infections rate in the entire population. But in cases when the young and healthy who aren't supposed to be getting sick start to get sick and die a red flag is raised. 

I've always been amazed by the flu. Evolutionarily it does everything right. Antigenic drift and shift produce a wide variety of viruses that continuously permeate throughout the population. This is exactly what a good virus  should do. If the sole purpose of the virus is to replicate its genome, then influenza has achieved this end perfectly. Unlike small pox which was a strictly human virus we can never hope of ever eliminating influenza because it crosses over between animal species. This is a logistically impossible task! Antigenic shift is also a nasty weapon in the arsenal of the virus because it widens the range of host that can potentially be infected. The more hosts that can potentially be infected the more the virus can replicate its genome. It's incredible to think that such a primitive structure can be so sophisticated in evolutionary adaptation.