Infectious sepsis is characterized by a runaway immune system following an infection. They are responsible for more than 6 million deaths each year worldwide. While there are several types of infectious agents (bacteria, viruses, parasites or fungi) capable of inducing sepsis, there is no generalizable treatment that is yet effective against this pathology. By studying the causes of bacterial sepsis, researchers from IPBS-Toulouse (CNRS, University Toulouse III-Paul Sabatier), in collaboration with other international teams, propose a new concept according to which mortality in infectious sepsis would be due to the explosion of a cell death essential to our organism in normal times. These results are published in the journal EMBO Reports on October 30, 2020.
Etienne Meunier's team at the IPBS-Toulouse has discovered that our cells possess proteins, called Gate-16 and Irgm2, capable of preventing our cells from dying in an anarchic manner during a bacterial infection; these proteins thus make it possible both to protect the integrity of our tissues and organs, such as the liver or the lung, and to prevent the deregulation of the immune system which is characterized by what is known as the "cytokinic storm". Thus, mice deficient in the Irgm2 protein are extremely susceptible to bacterial septic shock due to the uncontrolled occurrence of a particular cell death called "pyroptosis", responsible for the initiation of lethal septic shock. Finally, the inactivation of the protein responsible for this death, called caspase-11, protects Irgm2 deficient mice from bacterial septic shock. Remarkably, a similar discovery was made concurrently by E. Meunier's team and that of Jorn Coers in the United States1, the two studies being published in the same issue of EMBO Reports.
Highlighting the central role of deregulated cell death as the cause of bacterial sepsis is both a major change in the understanding of sepsis itself, but also a source of hope for the treatment of new infectious sepsis, such as that induced by the new coronavirus SARS-CoV-2, or many other infectious agents. This work on bacteria should be compared with a new study that suggests a protective effect of certain molecules inhibiting cell death pathways against sepsis induced by certain coronavirus strains2.
Irgm2 and Gate16 cooperate to calm the sepsis. In the absence of Irgm2 and Gate16, Caspase-11 is highly recruited to bacterial lipopolysaccharide (LPS), which promotes uncontrolled pyroptosis and the maturation and release of IL-1 cytokines, thereby contributing to sepsis. On the contrary, interferon-inducible Irgm2 and the non-canonical autophagy protein Gate16 cooperate to limit the targeting of Caspase-11 to Gram-negative bacteria.
This work was funded by the CNRS, the Fondation pour la Recherche Médicale (FRM), the ATIP-Avenir program, the European Research Council (ERC), and the European Society for Clinical Microbiology and Infectious Diseases (ESCMID).
Elif Eren*, Rémi Planès*, Salimata Bagayoko, Pierre-Jean Bordignon, Karima Chaoui, Audrey Hessel, Karin Santoni, Miriam Pinilla, Brice Lagrange, Odile Burlet-Schiltz, Jonathan C. Howard, Thomas Henry, Masahiro Yamamoto, Etienne Meunier. Irgm2 and Gate-16 cooperatively dampen Gram-negative bacteria-induced caspase-11 response. EMBO Reports. DOI: 10.15252/embr.202050829
Researcher IPBS: Etienne Meunier | Etienne.Meunier@ipbs.fr | @INFLAME_IPBS | 05 61 17 59 00
Press IPBS: Francoise Viala | firstname.lastname@example.org | 06 01 26 52 59
1 Finethy, R., Dockterman, J., Kutsch, M., Orench-Rivera, N., Wallace, G., Piro, A.., Luoma, S., Haldar, A.K., Hwang, S., Martinez, J., Kuehn, M.J., Taylor, G.A., Coers, J., 2020. Dynamin-related Irgm proteins modulate LPS-induced caspase-4 activation and septic shock. EMBO Reports. DOI: 10.15252/embr.202050830
2 Rajendra Karki, Bhesh Raj Sharma, Shraddha Tuladhar, Evan Peter Williams, Lillian Zalduondo, Parimal Samir, Min Zheng, Balamurugan Sundaram, Balaji Banoth, R. K. Subbarao Malireddi, Patrick Schreiner, Geoffrey Neale, Peter Vogel, Richard Webby, Colleen Beth Jonsson, Thirumala-Devi Kanneganti. COVID-19 cytokines and the hyperactive immune response: Synergism of TNF-α and IFN-γ in triggering inflammation, tissue damage, and death. BioRxiv DOI: https://doi.org/10.1101/2020.10.29.361048