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Scientists discover the mechanism behind the innate immunological memory

Posted September 1, 2015

There can be no argument – it is extremely important to understand how immunity works. Better knowledge about immunity would help scientists to come up with new, more effective ways to prevent outbreaks of diseases. However, at this moment science is lacking needed knowledge about human immunity.

Some discoveries are hard to explain. In short - innate immunological memory is based on epigenomic changes induced by pathogens and in the future it may help to create better, more effective vaccines. Image credit:

Some discoveries are hard to explain. In short – innate immunological memory is based on epigenomic changes induced by pathogens and in the future it may help to create better, more effective vaccines. Image credit:

For example, for a long time it was believed that acquired immunity—a type of immunity mediated by T- and B-cells—had memory, whereas innate immunity—which is mediated by macrophages and other types of cells that react to certain molecules typically associated with pathogens—did not. But now scientists know things are not so simple.

This was not hard to figure out, as plants and insects have innate immunity only, but seem to have immunological memory. Furthermore, scientists observed that herpes virus infection increases the resistance against bacteria in vertebrates, which suggests that innate immunity also has memory, even though researchers have struggled to understand the mechanism behind it.

However, now scientists from the RIKEN Molecular Genetics Laboratory have revealed the mechanism underlying the memory of innate immunity. It turns out there are epigenomic changes induced by pathogen infections mediated by a transcription factor called ATF7. Although it seems to be extremely complicated phenomenon, in the future this discovery may help everyone, including those, who struggle to understand the mechanisms behind the memory of innate immunity.

At first, research team discovered that in ATF7 knockout mice, macrophages appear similar to wild-type macrophages that have been activated by exposure to molecules that occur commonly in infections. Even before that scientists knew heat shock or psychological stress induced epigenomic changes were mediated by ATF7-related transcription factors. After exposure to that stress, changes remained for a long duration of time. This made researchers think that pathogen infections could induce epigenomic changes in macrophages via ATF7.

Scientists found that ATF7 transcription factor simply binds itself to a group of innate immune genes and silences their expression, which makes cells less responsive to infections. Scientists managed to make ATF7 inactive, by using a molecule found in the outer membrane of Gram-negative bacteria, called a lipopolysaccharidel. It made ATF7 phosphorylated and immune-related genes in mice models were no longer silenced. Shunsuke Ishii, leader of the research team, said: “we were intrigued to find that even three weeks after the administration, the genes still showed increased activation. In mice, this status was shown to lead to increased resistance to Staphylococcus aureus, Gram-positive bacteria.”

There are some very important implications of these discoveries. First of all, it may increase our understanding of the “hygiene hypothesis”. It is the concept saying that pathogen infection and unhygienic environment during infancy reduces the risk of allergy later in life. “Hygiene hypothesis” is used to explain why in more developed countries with better hygiene habits the incidence of allergies and asthma is increasing. Now scientists say that since they can explain that the pathogen-induced epigenomic changes mediated by ATF7 maintain for a long period of time, they have a better explanation about how the changes are induced.

Secondly, these new findings may be very helpful developing vaccines with more effective adjuvants. Adjuvants are compounds used in vaccines that activate innate immunity – they are necessary ingredient of efficient vaccines. For a long time scientists thought that the effect of adjuvant can be maintained a several days only. But this new research shows that it is not necessarily true. New findings show that there is possibility to maintain effectiveness of adjuvants for longer periods of time, which would make for much more effective vaccines.

As much as human immune system still remains not completely clear for science, this new research provides better understanding about how our immune system remembers appropriate reactions to stress. Knowing how to form these memories may hide the key to creating better, more effective and long-lasting vaccines.


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