The midfield battle of the flu virus

(1) The Windy City

  We arrived at the battlefield by airborne, and before we had time to choose one of the two large black holes on the left and right, we were directly sucked in by the airflow.
  If I say, the wind is strong enough here. Although we came from the sky, the place where we landed was like the kind of wind tunnel used to test rockets. The alternating hurricanes blowing around regularly, our brothers caught up with the reverse wind and were directly hit by the wind. Sent out of the cave.
  On the inner wall of the wind tunnel, there are also long vines hanging from the upper and lower sides, and the wind will shake back and forth when the wind blows. Occasionally, a giant pollen particle would fly by me and hit the vines like a rolling stone, and the wind would become as violent as an explosion, packing all the debris out of the hole.
  It’s best not to touch these vines, so as not to be sprayed out of the wind tunnel, let alone run into reverse winds. I was lucky. When I came in, I caught up with the wind in the right direction. Instead of being sprayed out, I went all the way through the narrow wind tunnel and arrived at the open passage.
  Ahead is the Windy City! So we sneaked into the battlefield and started siege.
  Scientific knowledge
  of influenza virus
  called the Influenza virus (Influenza virus), belonging to the Orthomyxoviridae (Orthomyxoviridae), Orthomyxoviridae mucin on the surface of human or animal cells have some kind of affinity influenza virus genus and Sogod The genus Torovirus constitutes the Orthomyxoviridae family. Influenza virus is the culprit of influenza, which is a highly contagious, fast-spreading acute respiratory infectious disease that can spread through droplets and person-to-person and person-to-object contact. Influenza virus is a pleomorphic enveloped virus, usually spherical, the diameter of the virus particle is 80-120nm, the virus isolated from human or animal body for the first time is polymorphic, and the filamentous shape is common, and the filamentous length varies. Sometimes it can be as long as 2 to 4 μm.

Influenza virus structure diagram

  ① epithelial cells
  located in the skin or surface of a cell cavity, can protect the skin surface, absorption and so on; hang chamber can play secretion, absorption; organ surface can promote digestion and absorption.
  Scientific knowledge
  influenza virus characterized in
  influenza viruses can be divided into three layers, the outermost layer is a bilayer lipid envelope, the inner envelope matrix protein (MP) and an outer lipoprotein (LP) composed envelope There are 10-14nm long fibers formed by two proteins, which are hemagglutinin (HA), which can agglutinate red blood cells, and neuraminidase (NA), which can release viral particles from the surface of agglutinated red blood cells, HA and The ratio of NA on the envelope is about 5:1; the middle layer is a spherical protein shell of one or several molecules thick formed by the matrix (M1) protein of the inner layer of the envelope, and each virion has about 3000 molecules of M1 protein, It accounts for 40% of the virus protein, and has the function of protecting the inner core of the virus and maintaining the shape of the virus; the inner layer is the nucleocapsid (ie ribonucleoprotein, Ribonucleoprotein, RNP). It is composed of nucleoprotein (NP), RNA polymerase complex (three subunits of PB1, PB2 and PA) combined with viral RNA (influenza virus RNA is segmented single negative-stranded RNA).
  ②The 8-segment RNA
  influenza virus RNA of type A and B is divided into eight segments, each segment is 890-2341 nucleotides in length, and the total length is 13 600 nucleotides; influenza C virus RNA is divided into seven segments , lacks one RNA segment encoding neuraminidase (NA); influenza D virus RNA also has only seven segments. Most segments of influenza virus RNA encode only one protein, of which the nucleoprotein (NP) is encoded by segment 5, and the matrix (M1) protein is encoded by segment 7. NP and M1 proteins are relatively stable in composition and structure, with Specificity, which is an important basis for the classification of influenza A, B, and D.
  On both sides of the corridor are some people called epithelial cells①. We landed with no pain at all, but it was still a little hard to move at first. There are weeds on the corridor, which are the cilia outside the Windy City. They keep swaying in the direction we came from. We can only go against this wave. Fortunately, it was the turn of winter and spring, and the wind here became cold and dry, and it was more dry and cracked than the usual earth. This is a period of vulnerability for the enemy, and it is the best time for us to advance.
  The strong wind at the city gate continued. Looking inside, the stacked alveoli are like spherical blocks, hanging in the wind, one by one, expanding the internal area to the limit.
  The strong wind did not bring the feeling of cooling, the place was very hot, it was 38℃! Much hotter than outside. Although for us, being able to feel the temperature means we can move about and move on to the next step of invasion and proliferation, I’d rather be in the freezer for life. After all, who doesn’t want to lie down and fish? To show my strong love-hate attitude, I will complain about the heat here many times in the future.
(2) Numbers and uniforms

  The battle plan is simple: capture the enemy factory before immunity wipes us out, find a cell to replicate itself, and blast more replicas out of the wind tunnel. We first checked whether the equipment was sufficient. We are wearing a combat uniform, an envelope, the inner layer is matrix protein, and the outer layer is phospholipid molecules. If I didn’t have this dress, I wouldn’t be alive now, after all, it’s my stomach, and it doesn’t have any organs in it. Unlike enemy cells, we don’t have ribosomes, so we can’t make our own proteins; we don’t have mitochondria, so we don’t have a source of energy.
  Such a simple body contains only 8 pieces of RNA ② with some nucleoproteins and RNA polymerase. My body is like a suitcase, and it exists only to replicate these cores. I am a “tool man” fighting for these 8 pieces of RNA.
  By the way, I don’t even have the ability to produce this combat uniform out of thin air. That’s what I did by tearing a tent off the roof of my last host when I ran away from him. But this dress has a lot of background, and I have to brag about its design sense: there are several kinds of spikes that penetrate the dress and are exposed in a dense manner, called slender protrusions. These include hemagglutinin, which looks like a tentacle, and neuraminidase, which looks like a flower spike.
  Before the war, we had heard an impassioned speech about our glorious deeds that swept Europe in 1918. That was also the first time that our arch-enemy, the modern Homo sapiens among the primates, really took notice of us. At that time they were fighting the First World War, and we took the opportunity to mess up the world. When Homo sapiens were at war, they built those cramped and crowded camps, and it seemed to us a good time to spread.

  We accidentally create a lot of complications, at least 50 million people die from complications like pneumonia and myocarditis. But more people take us around the world. From camps to front lines, from vehicles and ships to ports, from country to country… We traveled by the wind, coexisted with all Homo sapiens after the pandemic, and finally infected a third of the world’s population, standing on this earth. Steady your heels.
  But I know that these honors have little to do with me.
  First of all, Homo sapiens divided our troops into three categories, A, B and C, according to our nucleoproteins and matrix proteins. It is type A that often makes a pandemic. In contrast, the war caused by Type B was more local and not vigorous enough. Type C only fights the Boy Scouts, and even the RNA has only 7 segments. My unit is Type A, which is not bad.
  Scientific knowledge
  type influenza virus
  in accordance with the influenza virus nucleoprotein (Nucleoprotein, NP) and matrix proteins (Matrix protein, M) different antigen, influenza A virus is divided into (A), B (B), propionate (C), D (D) Type IV. Among them, influenza A (A) viruses were isolated in 1931 (from pigs) and 1933 (from humans), and can be pathogenic to humans, pigs, horses, dogs, birds and marine mammals, etc. B ( Type B) influenza virus was isolated in 1940, type C (C) was isolated in 1947, and type D (D) was isolated in 2011 and was officially named in 2016, mainly infecting cattle, Pigs and other animals, so far there is no evidence of human infection.
  Influenza A virus is particularly prone to mutation and poses the greatest threat to humans. It is the main pathogen causing seasonal influenza. Currently known human influenza pandemics are caused by influenza A virus. In addition to infecting humans, it can also infect animals , causing bird flu and swine flu, etc.; influenza B virus antigenic variability is small, mainly infects people and has low virulence, usually only causing local epidemics; influenza C virus antigen is stable, virulence is weak, mainly affects infants Young children or only cause mild upper respiratory tract infection in humans, and rarely cause epidemics; Influenza D virus has only been isolated and discovered from animals in recent years, and no evidence of human infection has been found.
  The abbreviation of The last universal common ancestor, that is, the common ancestor of all life on earth.
  Influenza virus envelope
  has on the envelope of influenza virus hemagglutinin (HA) and neuraminidase (NA), HA cylindrical shape, about 500 molecules per virion HA, 25% of viral proteins , HA determines that the infection site of influenza virus is the respiratory tract; the head of NA is oblate or mushroom-shaped, and the end is embedded in the lipid membrane of the envelope. Each virion has about 100 molecules of NA, accounting for 5% of the viral protein. , NA can reduce the viscosity of the mucous layer on the surface of the respiratory mucosa, which is conducive to the adsorption of viruses and respiratory epithelial cells. The antigenicity of both HA and NA is easily variable and subtype specific.
  But there is another saying among us. It is said that different teams have different structures of the two fibrous protrusions. It’s like different numbers and different targets. For example, it was H1N1, hemagglutinin (HA) type 1, and neuraminidase (NA) type 1 in the one that made a big fuss in Europe. But the ghost knows how I am H5N1. Originally, I was in a bird’s body. The previous me copied me, and after spraying it out of the bird’s beak, I continued to attack the closest pig. But there are only a few pigs on this farm, which are too few. The birds haven’t come again recently, and we’re afraid we’re going to be trapped on this farm.
  The prospect of this battle makes us a little skeptical, but gossip does not dampen the enthusiasm for combat. Once we have selected the cells we want to invade, the laws of physics will push each molecule into action, attacking the lungs. At least in my eyes, all living beings are equal, and every Luca is worthy of being infected.

Spanish flu of 1918
(3) Copy

  We got into the thick alleys on both sides of the corridor. They say that Luca’s cells are like courtyards covering the surface of the Windy City. There is a mysterious dark room in every yard, that is the nucleus. There is a manager in each dark room, sitting in front of a large curved counter, and the red blood cells do not even have such a manager. The lights are not turned on in the house, so we can sneak in, pretend to be our own, and turn the pot over the stove to find something to eat, ignoring that every brick and tile here belongs to others.
  It was originally such a simple process, but every step of the way was difficult.
  Sneaking into these yards wouldn’t have been difficult. You say it’s a coincidence that our slender HA fits perfectly with these yard door locks…yes, let’s be honest, we have the keys. We were looking for such a yard from room to room, inserting the key and shouting: “Fellow, come out to collect the courier!” We struggled to turn the door, but on the way, a dump truck came over, and there were several pipes extending from the car. It sucked the companion next to me like a vacuum cleaner, and then sucked it into the body of the car.
  It’s a macrophage ④! Only vertebrates have this stuff, because it boils down to a bone marrow car factory. There are a few more of these cars ahead, and they all have those tentacle-like suction heads. The pig driver in the cab is very grumpy and sucks into the car body whenever they think it’s in the way.
  There are also some cold guns fired from nowhere, using protein paintballs to mark our combat uniforms with colorful marks, which is called the complement ⑤ system, which can make it easier for dump truck drivers to identify us. It seems they were not defenseless.
  Scientific knowledge
  influenza virus
  influenza virus type not named in the H and N refer to HA and NA, where, H1N1, H2N2, H3N2 subtype mainly infect humans, other major subtypes infect birds, pigs, horses, and Marine mammals, and among the avian influenza viruses, the subtypes that can infect humans are mainly H5N1, H7N1, H7N2, H7N4, H7N9, H9N2, H10N8 and so on.
  Among them, the H1N1 influenza virus is the most susceptible influenza virus to humans, because it can infect both birds, pigs, and humans. Pigs serve as the intermediate host of influenza viruses between humans and birds, and are an important source of gene recombination between viruses. . The Spanish flu epidemic of 1918 and the North American flu epidemic of 2009 were both caused by the H1N1 influenza virus. The 1957 Asian flu, which killed millions, was caused by the H2N2 influenza virus. In 1968, the Hong Kong flu centered on Hong Kong killed 750,000 people worldwide and was caused by the H3N2 influenza virus.
  According to statistics, influenza can cause 3 million to 5 million severe cases and 300,000 to 500,000 deaths every year in the world. Among them, influenza A virus is the most threatening to humans. According to the different surface antigens HA and NA, influenza A virus can be divided into different subtypes. At present, 18 HA subtypes and 11 NA subtypes have been found (two HA17, 18 and two NA10, 11 only in The gene has been found in bats, the virus has not been isolated, and there is no evidence that its gene segments can be genetically reassorted with other influenza A viruses).

  Macrophages ④
  It is involved in the detection, phagocytosis and destruction of specialized cells of bacteria and other harmful organisms. In addition, macrophages can present antigens to T cells and trigger inflammation by releasing molecules that activate other cells, called cytokines.
  ⑤ complement
  a human or vertebrate serum and tissue fluid soluble proteins involved in lysis or hemolysis.

Macrophages in Cells at Work

  Scientific knowledge
  influenza virus mutant gene reassortment
  Since the influenza virus genome consists of eight separate RNA fragments, when the host cells are simultaneously infected with two different influenza virus both influenza virus RNA segments exist in In the host cell, when the new progeny virus is assembled, it is possible to assemble the gene fragments of the two parental viruses together to form a new influenza virus with genetic reassortment. Gene reassortment can occur between different subtype strains of the same type of virus, but no gene reassortment occurs between different types of viruses.
  Influenza A is prone to gene reassortment, which is an important reason why influenza A can easily form a pandemic. In addition to gene reassortment, the RNA polymerase of influenza virus lacks the corrective function of DNA polymerase, and its RNA is more prone to point mutations during replication, which makes the replication of progeny virus genes not completely faithful to the parental virus, which will cause Increases the probability of viral antigenic mutants being formed.
  ⑥ mRNA
  single-stranded ribonucleic acid, which transmits genetic information from DNA to ribosomes. The structural feature of eukaryotic mRNA molecules is that they have a cap at the 5′ end and a tail at the 3′ end.
  ⑦ Golgi
  consisting of flat vesicular organelles, cell secretion is the main function for processing and packaging.

Golgi apparatus

  Gotta go now! I struggled to open the courtyard door with HA, and some of my companions slammed into it, or were swallowed by the courtyard. The good news is that there is no wind here, the bad news is that the yard is hotter. We rushed to the little dark room. If you enter the small dark room, you will have to lose a layer of skin. How can I say it? I had to lay my body on the door, and one foot was about to enter the door. No, I have no feet now, because my suit shell and each other’s door panels are dissolving into each other. In the end, I only had 8 genes to drag RNA polymerase into the dark room.
  There are many mRNAs of cells in the room ⑥ waiting in line, the 3′ end is the tail, the 5′ end is the head, all wearing a hat on the head. My 8-segment RNA has strong self-management ability, they rushed forward, took off the hat of one of them, and put it on their own head.
  ”Why did you come in without knocking on the door?” The one
  who spoke must be the shopkeeper Pig Pig. The 8 pieces of RNA hurried to the front of the large square-shaped counter and lined up on the counter:
  ”Just do it for me, the more the better.”
  It is not difficult to use one piece of RNA as a template to make another piece. However, our brothers took up the normal working time of others, and I am a little embarrassed. The shopkeeper has no temper. He used my RNA to quickly make mRNA, which filled the room in no time, and ran out of the small dark room one by one. Then the mRNAs ran to the kitchen of the East Cross Hospital, the ribosome, and held the kitchen hostage to make HA, NA and other proteins for us according to the information. Golgi ⑦ glanced at it and said, “Don’t go!” I was startled and thought I’d been discovered, but I didn’t expect that he just wanted to hook us up. It turns out that after the ribosome makes the protein, it has to be processed by him.
  During the whole process, no one doubted our origins at all – the most interesting part of the battle, isn’t it stealing chickens and dogs?
  Then there is the process of building the core. Since our RNAs are negative-strand RNAs, shopkeepers need to use them to make complementary positive-strand RNAs. This acts as a mold to make more of my negative-strand RNA. There is an inexhaustible supply of energy and substances in the cell, and in a short while, the required RNA and other materials are fully gathered under the courtyard wall, ready to steal the cell membrane. After tearing off a layer of wall covering and wrapping it all over, I have become many complete mes. The courtyard was quite hospitable as he pinned our HA with a keyhole and wouldn’t let us go. That’s where NA comes in handy: he can cut those keyholes and let us escape, so we can cough and sneeze out of the body through the wind tunnel.
  When they wait for the tea to cool off, they will find that the yard has been scattered, the cells are full of vacuoles, it is already decayed, and the house is about to collapse. We had to destroy the yard to induce the pig to cough on its own and send us to more yards.
  ”What’s the matter?” “My house collapsed!”
  We heard the restlessness behind us, and the courtyard was in chaos. There was also a pig-headed driver of a macrophage who took the opportunity to shout,
  ”One cloud-
  piercing arrow, thousands of troops will meet!” Then, with a “whoosh”, a signal bomb exploded in the sky. That’s a cytokine released by a macrophage. The earth became more and more hot. The war has begun.
(4) Cells

  As if destined to end, we were ambushed in the streets.
  The first is that the cytokine signaling of macrophages takes effect, calling for more dump trucks. Some cytokines fall on the moat flowing with blood, so that a large number of monocytes and neutrophils ⑧ help out on the river surface, enriching the army of dump trucks. These monsters crushed our comrades wantonly, the complement paintballs exploded everywhere, and the firepower became more and more concentrated.
  The toughest ones are neutrophils. He has only a few days to live and was born on a mission to swallow us. He has no reason to speak, and when he gets crazy, he will crash even the normal courtyard. Maybe this is the reason for their short life. They should not be welcome here.

  ⑧ neutrophils
  derived from bone marrow, phagocytic cells bactericidal action.
  ⑨ dendritic cells
  called dendritic cells, because the surface has named dendrites, the body is the most powerful antigen-presenting cells.

One of the main characters in “Cell at Work” can identify and destroy foreign objects such as virus-infected cells and cancer cells. The prototype is a real cytotoxic T cell in human blood.

  We continue to occupy the compound and engage in a tug-of-war with these dump trucks. We had a slight advantage at first, but a group of opposing tanks quickly arrived on the battlefield. It turns out that macrophages have already handed over our key fragments to “dendritic cells ⑨” – the tower of the headquarters of the opponent’s battle, then the command will send such “killer T cells” to attack us specially . No, to be precise, their purpose is not to deal with us, but to quickly turn the barrels, punch a hole in the courtyard we occupied, and then put a pack of explosives in the hole, which reads: “Take this The packager will fend for itself.” Then the shopkeepers happily lit dynamite packs and blasted the entire yard into the sky.
  What a scorched earth policy! In this way, often we have not had time to let the courtyard produce normally, and both parties die together. However, this is similar to our temper, because we only want to infect the next city in the shortest time, and have no intention of establishing a long incubation period in the city.
  Even if we act low-key and are not exposed under the noses of killer T cells, there will be another kind of tank to attack, and that is “natural killer cells”. Out of sight, another B cell is working hard to produce antibodies; and taking our numbers carefully in case we make a comeback.
  But we just tried our best this time. Companions marked by antibodies have nowhere to escape. In the eyes of those immune cells, as long as you are marked, you will immediately look delicious.
  Macrophages have been cleaning the battlefield and never stopped, because whether it is our troops or the ruins burned by the war, they are constantly producing useless debris, and they are all sucked in by them. This is literally “the fire of war”, these cells large and small mobilize all firepower against us, causing the temperature in the vicinity to rise sharply, and the whole city is feverish. Some wild animals took the opportunity to run into the city to make trouble in the fire, they did not belong to this place originally, but the bacteria that caused the secondary disease.
  In this inflammatory storm, I felt like I was about to suffocate.
  I finally found a healthy yard and continued to assemble in it. Maybe it was so hot that I had hallucinations before my eyes. A virus that I had never seen before appeared before my eyes.
  ”You which units?” I rubbed his eyes, “What is your designation is how come?”
  Did not say anything to each other, but not with my contention treasurer and cook. I fought with him, ignoring the people in the yard. I’m a little bit suspicious now that they took advantage of the mess to assemble what I wanted wrong. I did something wrong. But there’s no way, I’ve been out of the hospital wall with the wrong thing. The thick mucus wrapped around me, and a strong air current ejected me again at a very high speed. Leaving this pig’s body, I felt a great coolness.
  Failure, total failure… and then, I don’t know anything.
(5) Co-hosting

  I was woken up again.
  When I woke up I was already inside another Luca. It’s the City of Wind again, but there are clearly bursts of applause from the hollow lungs, it’s my kind. Why are you applauding for me?
  I became a hero?
  A fellow virus came over to me approvingly: “Are you awake? We are your clones, and while you were asleep, it took a few hours to expand the line. Now this person has a fever, a little hot.”
  ”Didn’t I assemble it wrong?” I looked at my body. “My RNA doesn’t seem to be right.”
  ”Never feel inferior to your body!” he said. It’s a double chain, and it’s hard to put it together if it’s wrong. We’re not applauding for that.”

  ⑩ antigenically drifted
  influenza virus antigen or completely substantial variation phenomenon.
  Scientific knowledge
  of influenza prevention and control
  in 1957, the Asian flu, is certain gene fragment avian influenza virus and human influenza virus H1N1 reassortant H2N2 influenza virus generation, which led to widespread human, resulting in millions of deaths; 1968 The Hong Kong influenza in 2009 was also caused by the reassortment between human influenza virus H2N2 and avian influenza virus H3N2; since 1997, the H5N1 highly pathogenic avian influenza epidemic in Hong Kong and many countries and regions is caused by the transmission of avian influenza virus from poultry. In humans, the influenza A virus can be transmitted between species.
  Nowadays, the influenza vaccines developed by humans include whole virus inactivated vaccines, split vaccines, subunit vaccines, live attenuated vaccines, etc. Since the high incidence season of influenza is winter and spring, influenza vaccination can be carried out when winter comes to prevent influenza Viral infection. There is no effective method for the treatment of influenza so far, and some antiviral drugs or antipyretic and analgesic drugs can be taken under the guidance of a doctor to relieve symptoms.
  ”What could go wrong? Antigen drift⑩?”
  Explain. We sometimes randomly change the keys on the surface, suddenly increasing the difficulty of the Windy City’s defense. I said that the infection time left for us is very short, and we have to fool those immune cells in a similar way.
  But…wait! He just said that this is a human body!
  This time we infected not a pig, but a Homo sapiens.
  ”None of Homo sapiens doubt us now. We are almost unobstructed in the presence of macrophages, and they can’t recognize us.”
  Logically, this is impossible. “How did you do it?”
  ”Antigen transfer!” The companions cheered like an oracle.
  I remembered. When I fought with that mysterious virus of unknown origin, something must have dropped with him. It’s all because we were too loose, both physically and emotionally. But it hit the ground running and achieved a big thing: it was an influenza virus from Homo sapiens. Originally, there was no way to re-infect a Homo sapiens with the strength of my troops alone. We mingled in that yard, exchanging genetic information, leading to my ability to infect humans. The upper airway cells of pigs have become the best springboard here, opening up the middle link of our transmission from birds to humans.
  I wandered through the new city, trying my best to get acquainted with the environment here, and smelled the victories.
  ”Human transportation and gathering behavior will bring great convenience to our spread.” They said, “The pandemic is imminent.”
  Note: The end of the story fictionalizes the idea of ​​a virus mutation. In real life, H5N1 infection of people is an accidental event, and sustained human-to-human transmission and pandemics have not occurred.

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