For immunologists, the global pandemic has been an eye-opener. The coronavirus has surprised them in almost every way. They've learned more than they've learned from decades of research, and one of the most important discoveries will make them rewrite immunology textbooks.
This finding relates to what we know about the innate immune system.
Our two immune systems
As vertebrates, we are proud to have two immune systems: one is the innate immune system; the other is the adaptive immune system.
The innate immune system is relatively simple. It consists of a fast-reacting, universal defense system that can strike any intruder indiscriminately. One of its weapons is inflammation. Inflammation is a universal immune response to all pathogens, physical injury, and mental stress.
The adaptive immune system can be seen as an intelligent, efficient "special force" responsible for the development and deployment of highly specialized and precise weapons to deal with intruders, and has relatively strong combat capabilities. These weapons include the various antibodies, T cells and B cells that we are familiar with.
From an evolutionary point of view, the innate immune system is more ancient in evolution. It exists in all animals and plants, so animals and plants have a certain immune function against diseases. The adaptive immune system, on the other hand, evolved in vertebrates about 600 million years ago.
While our body has an adaptive immune system, it still needs the innate immune system as the first line of defense, because the adaptive immune system can take days to kick in, whereas the innate immune system kicks in almost instantly. When the pathogen has invaded and the "special force" of the adaptive immune system is still mobilizing and preparing, the innate immune system has already fought against the incoming enemy.
In addition to the differences in the speed of response and the weapons used, there is an important difference between the two sets of immune systems: people have always believed that the innate immune system lacks any memory function, so it has always been considered quite low-level and regarded as the immune system. The "little brother" in , is not very important.
The adaptive immune system, on the other hand, has "immune memory" that remembers invaders for years or even decades and can respond to them. That's why one exposure to certain viruses, such as the measles virus, can lead to lifelong immunity. And, that's how vaccines work.
Innate immunity also has memory
In the past decade, however, immunologists' views on the innate immune system have changed. First of all, when a virus invades, the adaptive immune system cannot activate spontaneously, and someone needs to sound the alarm for it. Who will raise the alarm? is the innate immune system. Therefore, apart from the innate immune system, the more advanced adaptive immune system is a useless decoration. Second, and more importantly, scientists have now discovered that the innate immune system actually has memory. After encountering a pathogen, it enters a state of high alert that lasts for months or even years, making us more resistant to future infections.
The discovery dates back decades, when immunologist Mihai Nitti of Landenburg University in the Netherlands set out to study immune responses in plants and invertebrates. These species make up more than 97% of multicellular organisms. Although they have not evolved adaptive immune systems, he suspects that these plants and invertebrates appear to have "immune memory." His suspicions were subsequently confirmed. Study after study shows that the immune systems of plants, insects and worms do remember contact with pathogens and attack them more violently the second time around.
He also found that this memory mechanism is different from the memory of the adaptive immune system. Because the memory of the adaptive immune system is highly targeted to pathogens, for example, after you have been exposed to the measles virus, the adaptive immune system only has memory for the measles virus; but this memory mechanism of the innate immune system targets pathogens Less sexual, as long as you are exposed to one virus, it has memories of all viruses. However, the results of both mechanisms were roughly the same: both enhanced defenses against viruses and bacteria; and both memories persisted for months or even years.
Tests since then have shown that the same is true for mice. Stimulating their innate immune system produces a memory immune protection. Since mice are mammals like us, this in turn suggests that the human innate immune system may also have memory.
It appears that this is the case. In 2015, Nitti conducted a clinical trial in Guinea-Bissau. The results showed that newborns who received the BCG vaccine (the vaccine against tuberculosis) also had enhanced innate immunity to other pathogens and had a far lower mortality rate than infants who had not received the BCG vaccine.
Eventually, the immunological tenet that "memory is specific to the adaptive immune system" collapsed, and the innate immune system also has a memory function. Nitti calls the process by which the innate immune system acquires broad immunity after exposure to pathogens "trained immunity".
The cunning trick of the coronavirus
In July 2019, Nitti published an article describing one of his ideas: New therapies could be developed using trained immune technology to treat stubborn diseases such as immune disorders, cancer and infectious diseases caused by viruses. Only half a year after the article was published, the new crown pneumonia epidemic broke out.
In the early stages of the epidemic, immunologists were curious to know what the new coronavirus was using to evade the body's immune defenses. Its trick, it turns out, is to evade the innate immune system response, specifically the detection of a group of proteins called "interferons."
Interferons are a key "fortification" of the innate immune system. When cells sense viral RNA, interferons are released inside the cell, interfering with viral replication. It also makes those with symptoms uncomfortable, allowing them to curl up under covers rather than go out and spread the virus. Interferons also help activate the adaptive immune system, using "heavy weapons" such as antibodies and T cells. Therefore, if the alarm bell of the innate immune system response is late, it can lead to a delay in the adaptive immune system response.
That's why the coronavirus is so dangerous. It evaded the detection of interferon, causing our body to fail to mobilize "special forces" in time. Taking advantage of this gap, the virus quickly replicated and spread in the lungs. Without the timely reinforcement of the adaptive immune system, the innate immune system may also overreact, and the firepower will be fully activated in an instant, resulting in a suicidal reaction of "killing one thousand enemies and self-destructing eight hundred". At this stage, the patient may not be dead. Due to the direct attack of the virus, they died of their own organ failure, which is what we often see in this epidemic.
Get a flu shot against the new coronavirus
The fact that SARS-CoV-2 has gained a foothold this time by disrupting the innate immune system suggests that any vaccine can enhance the innate immune system's response as a therapeutic strategy, similar to the adaptive immune system that a vaccine provokes.
This is the opportunity Niti and his colleagues have been waiting for. In the Netherlands, after the first wave of the coronavirus, they obtained the health records of more than 10,000 hospital employees. The records show whether the employees had COVID-19 and whether they had the flu shot in late 2019 or early 2020. Comparing the two sets of data, Nitti found that among those who had been vaccinated against influenza, the number of people with new coronary pneumonia decreased by 39%. This shows that the flu vaccine has a certain protective effect against new coronary pneumonia.
Niti's team also took innate immune cells from vaccinated and unvaccinated people and exposed them to the new coronavirus to test their immunity. As a result, the immune cells of people who had been vaccinated against the flu were shown to be more resistant to the virus.
Reading this, you might be saying: oops, if we had known this, we would have done mass flu vaccinations at the start of the epidemic. That's right. Of course, now that the new crown vaccine has been developed, it will be safer to get a new crown vaccine. When a new epidemic strikes in the future and the vaccine has not been developed, it may be a good idea to get a flu shot.
We can even use new knowledge now to improve the efficacy of a Covid-19 vaccine. We know that the ultimate goal of vaccination is to make the adaptive immune system have a deep memory of the virus; but the adaptive immune system relies on the innate immune response (such as the aforementioned interferon) to activate. Therefore, if the innate immune system is made more responsive by some means, the adaptive immunity will have a deeper memory of the virus and the vaccine will be more effective.
To this end, someone has developed a lung-inhalable aerosol that stimulates the innate immune system of airway cells, which can be used before vaccination. In addition, Nitti's research group is also testing whether the BCG vaccine can be used to improve the efficacy of Pfizer's vaccine, a new crown vaccine developed in the United States.
Know your immune system
Apart from the human brain, the vertebrate immune system is the most complex biological system in the universe. Broadly speaking, it is divided into two branches: innate and adaptive. Innate immunity is a general, fast-response defense system. Adaptive immunity provides slower, more targeted responses to pathogens. Here are some key components.
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