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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - INVADIS (Microbial invasion and dissemination within the host, mechanisms and effects)

Teaser

Summary

An infection is defined by the deleterious consequences of the interactions between a pathogen and a host. Thus, studying the biology of infection reveals critical properties of hosts and pathogens, and is a way forward to address basic biological questions and improve health. We study listeriosis, a systemic infection caused by Listeria monocytogenes (Lm). Lm is a human foodborne pathogen that crosses the intestinal barrier, disseminates systemically, replicates in liver and spleen and reaches the central nervous system (CNS) and fetoplacental unit. Given the remarkable journey Lm makes in its host, studying listeriosis offers unprecedented opportunities to understand host cell biology, physiology and immune responses, guided by Lm. The mucosal, CNS and fetal-placental tropisms of Lm are shared by other microbes which pathogenesis is far less understood. Lm therefore stands as a unique model microorganism of general biological and medical significance. The major challenge of this project is to go beyond reductionist approaches and embrace the complexity of actual infections. We will use stem cell-derived organoids, live imaging, genetically engineered mouse models, the clinical and biological data from a unique cohort of 900 patients and the corresponding causative Lm strains, to investigate the molecular mechanisms of Lm tissue invasion, dissemination and host responses. Specifically, we will (i) decipher the cell biology of microbial translocation across the intestinal epithelium; (ii) study the impact of microbial portal of entry on microbial fate, dissemination and host responses; (iii) harness Lm biodiversity to identify novel virulence factors and (iv) discover new host factors predisposing to invasive infections. Building on the unique combination of advanced experimental systems and exclusive clinical data, this integrative and innovative project will reveal novel, physiologically relevant mechanisms of infection, with scientific and biomedical implications.

Work performed

During the reporting period we have acquired following results regarding the objectives of the project:
- We have uncovered a pathway allowing the host to inhibit Listeria monocytogenes entry upon depletion of goblet cells targeted by this bacterium (Disson et al, J. Exp Med 2018).
- We have identified clonal complexes of Lm that are associated with clinical isolates and are hypervirulent (Maury et al, Nature Genetics 2016). We have shown that these hypervirulent clones are adapted to mammalian gut environment, which accounts for their association with dairy products (Maury et al, Nature Communications 2019). We have also set up a new method of core genome multi locus sequence typing (cgMLST) based on whole-genome sequencing (WGS) for surveillance of Lm as well as to determine candidate factors involved in Lm virulence (Moura et al, Nature Microbiology 2016; Emerg Infect Dis 2017). We have also studied hypovirulence: we have described a mechanism underlying loss of virulence in natural populations of Lm (Maury et al, Infection and Immunity 2017).

Final results

- We are now identifying the molecular mechanisms leading to the intestinal barrier crossing by Lm, using an ex vivo model of infection organoids that we set up.
- We are currently investigating the host response to Lm at the gut level, to understand how Lm induces a host response in parts of the gut and can cross silently in other parts.
- Based on our published results (Maury et al, Nat Genet 2016; Moura et al, Nat Microbiol 2016), we are now investigating in detail hypo- and hyper-virulent strains to determine genetic factors involved in listeriosis. By combining genomic and transcriptomic approaches, we have identified a pathway common to all virulent strains, that we will now dissect.
- Based on host genome analysis of infected patients, we have identified candidate genes that could explain host susceptibility to Lm. We are now working on confirming these hits, both genetically and functionally.

All these findings will allow understanding not only the pathology of the deadly listeriosis infection, but also how the host respond to an infection.