Innate Immunity: Studying Bacteria Sheds Light on Our Knowledge of Humans
What if studying ancient life forms could illuminate our understanding of human immunity? While there has been a recent large increase in knowledge of the immunity of bacteria, collaboration between two scientific teams – one led by Enzo Poirier, Inserm researcher at Institut Curie, and the other by Aude Bernhein at Institut Pasteur – has shown that bacterial defense mechanisms have been preserved in humans and can play an important role. With the support of other EvoCure project teams, the two scientists intend to decipher these inherited immune mechanisms, with the goal of identifying new therapeutic avenues for autoimmune diseases and cancer.
Innate immunity is the body’s first line of defense against pathogens. It rapidly springs into action when sentinel cells, which constantly circulate in the tissues, detect the presence of a foreign body and call on blood cells (macrophages, neutrophils, dendritic cells) and molecules produced by the body (cytokines, complement) to eliminate the danger. Its response is identical regardless of the intruder detected. This defense mechanism is referred to as “innate” as opposed to “adaptive” immunity. It occurs as a second step, after its players have recognized specific patterns of the foreign pathogen, and produce antibodies and cells (T cells) specifically directed against this pathogen, which will be kept in memory.
The scientists thought that they knew almost everything about innate immunity. “It’s a longstanding field of research and all the important pathways seem to have been described. There’s also been a slowdown in discoveries in this field since 2015, » explains Enzo Poirier, an Inserm researcher in the Immunity and Cancer Unit at Institut Curie. But together with his colleague Aude Bernheim, a microbiologist at Institut Pasteur, they made a wager that, on the contrary, there was a lot left to discover. Proof being that we do not know why viruses and cancer cells thwart this defense mechanism, or why it is deregulated in autoimmune diseases. But in order to find new innate immunity players, new approaches were needed. Which did they choose? To compare human immunity with that of organisms much older than us: bacteria.
Back to one’s roots
These microorganisms, which appeared almost two billion years before humankind, have developed a vast array of systems to defend against infections by phages, viruses that specifically infect bacteria. Since 2018, descriptions of them have been coming thick and fast. “This emerging field of research has already led to the identification of nearly 250 mechanisms, describes Bernheim, but above all, similarities with human innate immunity have been observed for some of them.” So, “we thought that if defense systems had been preserved for two billion years during evolution, there had to be a reason for this. And we made two assumptions: if a protein has been preserved, its function must have been also, and its role must be important, » continues Poirier.
By developing bioinformatics approaches to detect similarities between proteins encoded by the genome of distant species, they have provided the first proofs of concept, for example with the SIRal protein. In bacteria, part of the SIR2 protein plays a key role against infection by a phage: it causes the death of the infected bacteria to protect the rest of the population. Yet, its counterpart in humans, SIRal, is essential for activating a system involved in the surveillance of pathogens by sentinel cells and the triggering of the innate response (Toll-like receptors or TLR system).
The start of a great adventure
To go much further, the two researchers set up a consortium of five teams and launched EvoCure. Their aim was to discover new innate immunity players from this ancestral immunity. « At first, the scientific community found our research somewhat bizarre and didn’t really have faith in it. Why seek to describe the human immune system from bacteria when the two are fighting against unrelated pathogens? However, the initial evidence provided has dispelled any reluctance and attracted significant funding, in particular thanks to Inserm’s Impact Santé program which allocated us €3 million over 48 months in 2024, or via European Research Council (ERC) programs which will enable this research to be extended over several years, » concludes Poirier.
Enzo Poirier leads the Innate Immunity in Physiology and Cancer team in the Immunity and Cancer unit (Inserm/Institut Curie Unit 932) at Institut Curie in Paris. Aude Bernheim leads the Molecular Diversity of Microbes team in the Genomes and Genetics department at Institut Pasteur in Paris.
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