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Deciphering the host and microbial grounds that license inflammasome-mediated execution

Periodic Reporting for period 2 - INFLAME (Deciphering the host and microbial grounds that license inflammasome-mediated execution)

Período documentado: 2020-06-01 hasta 2021-11-30

Here we have adressed a critical question which is: What host factors can promote pathogen detection and elimination but also how do pathogens escape such detection by the immune system. This is closely related to the red queen hypothesis of a coevoluation of a host with its competitor/agressor
The rise of antibiotic resistance, extremely pathological infections exemplified by, but not restricted to, Sars-CoV-2 pandemic hisghlight the critical need to understand the molecular, cellular and tissue basis of the development of an efficient immune response but also the very strong tools developped by succesful pathogens to bypass/escape efficient detection and elimination.
Here, we unveiled novel inate immune strategies of the body to detect various pathogens, invluding SARS-CoV2 but also the methods developped by those pathogens to escape their efficient killing by the immune systeM. These findings exemplifiy but also provide critical informations for 1/ our understanding of host-pathogen interactions but also for our ability to specifically target proceses that favor pathogens on the detriment of their host.
Here we have unveiled novel virulence mechanisms of the opportunistic pathogen Pseudomonas aeruginosa (published in PloS pathogens/Twitter and press release)
We have also determined that infectious sepsis are exacerbated by the NLRP1 inflammasome expressed in stromal (epithelial cells) in humans. This is currently submitted (Science Immunology). This work also bring the necessity to developp novel anti inflammasome drugs targeting various other complexs, indepndetly of NLRP3
We have shown that SARS-CoV2 is detected in lung epithelial cells by the NLRP1 infalammasome, which protects people without comorbidities but confers suceptibility to people with Interferon alterations. This is under review in Cell
Finally, our human and scientific effort during the pandemic ledd to the collabortaion with the DNDi organization and the inclusion of an anti SARS-CoV2 coumpound in their phase 3 clinical studies.

Finally the paritcipation to various meetings (remote) or in presence, the support to variosu students/post docs/engineers/technicians has also been a strong priority of this period.
Beyond our findings, we have observed a strong link between gain of function mutations in NLRP1 and various infectious pathologies (SARS, Shigella, Staphylococcus). Here we also aim at evaluating the selective disadvantage/advantage of patients carrying gain or loss of function mutations in NLRP1 against various ifnectious agents
We also determined the critical ability of SARS variants to adapt to the NLRP1 detection, hence amplyfying the virulence. We currently investigate the means by which those variants intercat with the NLRP1 inflammasome response.
Beyond this, we have also made the surpising observation thta NLRP1 is also an inflammasome of stress in epithelial cells that contribute to sepsis development. Therefore, we also aim at tackling the mechanisms involved here.
Finally, beyond this, we also unveiled novel virulence mechanisms by whish various pathogens escape innate immune radars, including protease-driven Gasdermin inactivation.
Main achivements of this year regarding the SARS-CoV2-2 research