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Biology: a discovery that could revolutionize the treatment of many diseases?

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Interview: the intestinal microbiota, an essential ally of the immune system. The intestinal microbiota brings together all the microbes present in our intestine. It allows proper functioning as well as some protection of the colon. Gerard Eberl, chair of the Micro-environment & Immunity unit at the Institut Pasteur, tells us more in this interview.
Imagine knowing all the mechanisms (in the reductionist paradigm of biology) of a protein expression pathway involved in autoimmune and inflammatory diseases, cancer, and senescence. Since September 10, 2020, this is the case. Five studies published in the journals Science and Nature report this significant discovery in human biochemistry. To help us understand the implications of these results, we interviewed Nicolas Manel, director of research at the National Institute of Science and Medical Research (Inserm), team leader at the Institut Curie in the immunity department, and cancer. His laboratory is particularly interested in the relationships between viruses and the immune system. Currently, his team is working on a research project to understand better how our cells detect viruses, that is, how a section realizes that it is infected. This work directly concerns the mechanisms of cellular recognition of the self and the non-self.


A small retrospective of the discovery

To fully understand, it is better to start at the beginning. It has been known for a long time that genetic material found in the cytosol – the fluid in which the small components, also called organelles, of our cells, bathe – generates markers of inflammation and agents of the immune system such as interferons. (interferes with them, we talked about this at length in a previous article) and cytokines.
Since 2009, we know a little more. A protein called STING for Stimulator of Interferon Genes is essential for the production of interferons. In other words, if you block its expression, no interferon. It is in 2013 that we advance a little more in the complex understanding of the mechanism. We notice that a protein, which is in the cytosol, synthesizes a new messenger when deoxyribonucleic acid (DNA) is detected. It is called cGAMP because it is produced from Guanine triphosphate (GTP) and Adenosine triphosphate (ATP). The latter binds to the STING protein to activate a regulatory factor: IRF3 for Interferon Regulatory Factor 3. In the same year, we finally understand the ins and outs of the biological mechanism. We discover that this is the expression of an upstream enzyme, called cGAS, from which everything else derives. In order, it looks like this: the presence of DNA in the cytosol activates cGAS, which produces cGMP. cGMP binds to STING and activates the IRF3 transcription pathway from which the secretion of interferons and cytokines results and the circle is complete! Now let’s move on to discovery.

      The GCC pathway is now fully understood in the paradigm of current biology. @ natali_mis, Adobe Stock


In the nucleus, the love affair between CAS and chromatin

Futura: Can you tell us more about this discovery?

Nicolas Manel: First of all, we must remember that the detection of DNA viruses by organisms is a universal thing in living things. Restriction enzymes are present in bacteria to perform this task. The CRISPR / Cas9 pathway, now well known because it is used in genetic engineering, also has this antiviral function. In mammals, it is this pathway you referred to above that detects DNA from a virus infecting a cell. Between 2009 and 2018, everything is believed to be happening in the cytosol, as the studies, you mentioned suggest. With my laboratory, in 2018-2019, we brought new data into the equation that called into question the simplicity of the mechanism. It has been shown that half of cGAS is actually in the kernel. Therefore, a crucial question arises: how does cGAS differentiate between the DNA of the nucleus (the DNA of the self) and an external DNA that comes to infect the cell? This data was not very surprising. Many DNA viruses come to replicate in the nucleus. It is, therefore, quite logical to postulate that there are certainly means of detection directed against viral DNA in the middle.
We published a paper in the journal Cell, in 2018, which demonstrates that the human immunodeficiency virus (HIV) can be detected by cGAS in the nucleus. Indeed, there is a significant difference between viral DNA and our DNA. That of the virus is bare while ours is bound to proteins called histones, which (in part) forms what is called chromatin. Following that, it was necessary to understand the mechanism of regulation of cGAS, that is to say, by which means it is expressed or inhibited. CGAS is linked to histones 2A and 2B, and that is why it does not fire against our DNA. The work published last week provides structural confirmation; that is, we can now see the mechanism directly at work.

Futura: Does this discovery pave the way for clinical research? This biochemical pathway is involved in autoimmune diseases, cancers, and cognitive decline.

Nicolas Manel: The path to clinical research has already been open for a while. cGAS is a significant target. As you point out, its stimulation could be used for specific cancer immunotherapies, but also against infectious diseases or as a vaccine to stimulate the production of interferons. Our laboratory tests are many the people in my mind and heart of the city tory collaborate with a start-up, Stimunity, as part of our clinical research. Moreover, using the cGAS route is being studied to serve as a vaccine against SARS-CoV-2.
Conversely, its inhibition could potentially be used in certain rare childhood diseases or in inflammatory diseases, such as lupus, o reduce the production of interferons. Studies are already published concerning inhibitors of STING in the animal model. In humans, there are molecules under investigation in phase 2 clinical trials, in particular, STING activators for immunotherapies.


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