2023-06-20 15:03:34
Immune system cell infected with Brucella (green), endocytosis compartment (blue). © CIML
The proper functioning of the immune system depends on a constant supply of white blood cells from stem cells that reside in the bone marrow: blood stem cells – or hematopoietic stem cells. Researchers from Inserm, CNRS and the University of Aix-Marseille, within the Marseille-Luminy Immunology Center, have now discovered a new role played by these blood stem cells in the response immune. In their article published in the Journal of Experimental Medicinethey describe how they manage to recognize and interact directly with a bacterium called Brucella in the bone marrow, thanks to a receptor present on their surface. This is the first demonstration of the direct recognition of a living pathogen by blood stem cells, which attests to their very early contribution to the immune response.
Blood stem cells or hematopoietic stem cells are stem cells that reside in the bone marrow. They multiply and give rise to all the blood cells, that is to say the red blood cells which carry oxygen and the white blood cells which take part in the immune response.
Until now, when it comes to the immune response, blood stem cells have only been seen as the cells that give rise to white blood cells. However, a growing body of evidence indicates that they can also directly and actively contribute to the immune response: recent data have shown, for example, that they can directly detect cytokines, proteins released during infection or inflammation. .
In a new publication, a research team from Inserm, CNRS and the University of Aix-Marseille, under the direction of Michael Sieweke, as well as Jean-Pierre Gorvel[1], wished to deepen scientific knowledge on this subject. The researchers succeeded in describing the mechanisms at work during the encounter between the blood stem cell and a specific pathogen: the bacterium Brucella which is a Notifiable Microorganism (NOT)[2].
Brucella is responsible for an infectious disease called brucellosis (or Malta fever or Mediterranean fever), one of the most prevalent zoonoses that poses a significant threat to human health worldwide[3]. Brucella is an intriguing and highly interesting pathogen for scientists to study due to its ability to establish persistent and chronic infections and evade host immune responses[4].
Scientists have discovered that blood stem cells present in the bone marrow are able to detect Brucella. Their observations indicate that a specific receptor on the surface of blood stem cells, known as CD150, interacts with a protein called Omp25 present on the surface of Brucella.
Graphical summary of the discovery. Thanks to the CD150 receptor on their surface, blood stem cells in the bone marrow can detect the bacteria Brucella. After recognizing the bacteria, the blood stem cells begin to produce more white blood cells. © CIML
“Our study reveals the mechanisms by which these blood cells manage to detect bacteria via a special receiver. You can think of this as a direct handshake between the stem cell and the bacteria. No one had ever imagined that the blood stem cell might recognize a living bacterium,” explains Sandrine Sarrazin, Inserm researcher, co-last author of the study.
Scientists then showed that this “handshake” causes blood stem cells to respond quickly, which then begin to produce more white blood cells. This is the first demonstration of direct recognition of a living pathogen by blood stem cells and attests to a very early and unexpected contribution of these cells to the immune response.
Comment Brucella uses stem cells to “hack” the immune system
In line with this work, the scientists wondered if this mechanism was rather beneficial to the host or to the bacterium.
Through careful observation, researchers found that Brucella directs these stem cells to produce the white blood cells she favors for infection. The bacterium manages to invade the white blood cells produced by blood stem cells and use them to multiply and settle in the body. In this particular case, the stem cells therefore contribute to the propagation of the bacterium.
“This research provides new insight into the sophisticated mechanisms that pathogens employ to evade immune system defences. While the increased production of white blood cells would be beneficial if they might effectively fight infection, Brucella manages to exploit them to multiply,” explains Jean-Pierre Gorvel, co-last author of the study.
“This mechanism can be considered as an escape strategy exploited by the bacterium to advance the infection”, summarizes Michael Sieweke, also co-last author of the study.
The publication of this study marks an important step in understanding the complex dance between Brucella and hematopoietic stem cells. It not only provides crucial information on the pathogenesis of brucellosis, but also opens new avenues for the development of targeted therapeutic interventions.
“In addition to improving our knowledge of the functioning of the immune response, our study makes it possible to envisage in the long term the development of a targeted therapy capable of preventing interactions between Brucella and the blood stem cell, preventing the spread of the bacteria in the body, and helping patients with brucellosis disease”, concludes Jean-Pierre Gorvel.
[1] This work is the result of a collaboration between two research teams at the Marseille-Luminy Immunology Center (CIML, CNRS/Inserm/Aix-Marseille University): the stem cell and macrophage biology team of Michael Sieweke and Jean-Pierre Gorvel’s Immunology and Biology of Host-Pathogen Interactions team.
[2] The experimentation with Brucella was thus carried out at the Center for Immunophenomics (CIPHE) in level 3 containment.
[3] The World Health Organization (WHO) has identified brucellosis as one of the seven most neglected zoonoses, contributing to poverty, hindering development and causing substantial economic losses in developing countries.
[4] Previous studies carried out in the laboratory of Jean-Pierre Gorvel had led to crucial discoveries with the aim of elucidating the mechanisms underlying these phenomena.
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