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Innate immunity protects species from epidemics

Science and Life (nkj.ru ) based on the materials of the MSU press service.

We often hear about a cellular self—destruction program called apoptosis - it turns on when a cell has received too many mutations or when a virus or bacterium has settled in it. A sick cell causes many problems to others; apoptosis eliminates the cell along with problems: dying together with mutations, the cell does not have time to become truly malignant; dying together with infection, it stops the spread of infection from itself to other cells.

We often hear about a cellular self—destruction program called apoptosis - it turns on when a cell has received too many mutations or when a virus or bacterium has settled in it. A sick cell causes many problems to others; apoptosis eliminates the cell along with problems: dying together with mutations, the cell does not have time to become truly malignant; dying together with infection, it stops the spread of infection from itself to other cells.

The staff of the Institute of Physico-Chemical Biology (NIIFKHB) named after Belozersky write in the International Journal of Molecular Sciences (Chernyak et al., Innate Immunity as an Executor of the Programmed Death of Individual Organizations for the Benefit of the Entire Population) that the same mechanism of general safety works at the population level — its role performs innate immunity. It is the first to turn on in response to various troubles, from injuries and infections to ischemic lesions and toxin poisoning. At the same time, it is well known that innate immunity tends to overdo it, so that the disease proceeds harder than it could, with complications and frequent death in the end. (There is no need to go far for examples – deaths with COVID-19 coronavirus infection are often due to the fact that the immune system has overdone it.) It is believed that excessive activity of immune reactions is an evolutionary payback (or side effect) for the high efficiency of the immune system. That is, immunity quickly relieves us of problems, but in return we need to be prepared for some probability of complications.

However, there is convincing evidence that immune hyperactivity is not a side effect, but a special protective mechanism that prevents the spread of epidemics across populations. The immune system learns about problems with the help of special receptors. The innate immune system has a relatively small number of such receptors that recognize common features inherent in large groups of pathogens. For example, these receptors react to some properties that all viruses have whose genome is encoded in RNA, or to the properties of viruses whose genome is stored in DNA, or to some features of different types of bacteria with the same cell wall structure. These molecular properties are called damage-related patterns (or DAMPs, damage-associated molecular patterns). It was believed that they enter the blood only from damaged cells. DAMPs attract immune cells and stimulate inflammatory signals at the sites of tissue damage, promoting wound healing and organ repair.

However, data gradually began to accumulate that many DAMPs come out of intact cells during inflammation, and not just come out – the cells actively throw them out. The most striking example here is the nuclear proteins HMGB1 and CIRP. Normally, they are involved in the regulation of replication and transcription, but once outside the cell, they serve as powerful activators of the immune response. To bring these proteins out, they need to be modified in a special way – so they can exit the cell nucleus into the cytoplasm – and then they need to be enclosed in membrane vesicles-lysosomes, in which HMGB1 and CIRP will go out.

HMGB1 and CIRP proteins, as well as other DAMPs, play a huge role in the development of many pathologies. And if mice, for example, turn off the CIRP gene, they will be able to survive sepsis, which, with CIRP running, would simply kill them. With the help of antibodies intercepting some DAMPs or blocking their receptors, it is possible to prevent the development of sepsis, aseptic systemic inflammation, ischemic lesions, etc. Let's not forget that the same CIRP normal, intact cells are trying to specifically show immunity, making remarkable efforts for this. All this is difficult to explain from the point of view of the protective function of immunity, but they agree well with the hypothesis of programmed suicide: just as a cellular self-destruction program kills a cell along with an infection, so innate immunity kills a sick individual along with an infection.

By the way, a fundamentally similar strategy called "abortive infection system" works in bacteria. Usually these are just two proteins that cause the suicide of bacteria when infected with a virus (phage). It has been experimentally shown that bacteria with such a system benefit from viral infection in those who are deprived of it (we are not talking about individual bacteria, but about the community).

The hypothesis of altruistic programmed death (phenoptosis) of individual organisms for the benefit of the population was formulated by Vladimir Skulachev more than two decades ago. In addition to acute phenoptosis, which can be illustrated by what happens to patients with covid, Vladimir Skulachev suggested the existence of slow phenoptosis, which, in fact, is programmed aging. Indeed, there are quite convincing examples of how the activity of innate immunity and aging are related. So, if we select the longest-lived drosophila flies for many years, we will eventually get long-lived flies with a suppressed immune system. Something similar seems to have happened in nature with bats, whose antiviral immunity was significantly reduced due to a mutation in one gene. Bats have followed the path of peaceful coexistence with many viruses, however, in the end they have become a reservoir of many very dangerous pathogens. Perhaps it is due to the weakening of immunity that bats live much longer (10-20 years, and some species up to 40 years) than most animals of similar size.

As Boris Chernyak, head of the Laboratory of Cell Bioenergetics at the A.N. Belozersky Research Institute and one of the co-authors of the article, says, it is sad to realize that we carry a program that can kill us and at the same time serves as a driver of aging. But if we know how this program works, we can try to find means that would suppress it. After all, we also have adaptive immunity, antibiotics and antiviral drugs, so it is unlikely that the death of the sick is so necessary. One of the possible drugs against phenoptosis may be mitochondrial-directed antioxidants, such as SkQ1, developed at NIIFKHB under the leadership of V. P. Skulachev. SKQ1 suppresses many reactions of innate immunity and, apparently, this is what determines its therapeutic effect in a variety of pathologies, as well as the fact that the drug significantly increases the average life expectancy of laboratory animals. Unlike many anti-inflammatory drugs, SkQ1 has no pronounced side effects. Perhaps the development and use of such drugs can make our lives longer and safer.

The work was carried out with the support of the Russian Science Foundation.

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