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Harnessing the interactions between gut microbiota and immune system

Applicant Becattini Simone
Number 187018
Funding scheme Eccellenza
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Immunology, Immunopathology
Start/End 01.10.2020 - 30.09.2025
Approved amount 1'824'342.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Experimental Microbiology

Keywords (5)

transcriptomics; inflammatory bowel disease; tissue-resident memory T cells; gut microbiota; mucosal vaccines

Lay Summary (Italian)

Lead
Studio e utilizzo dell'interazione tra microbiota intestinale e sistema immunitario
Lay summary

Il microbiota e' un insieme di batteri che risiedono nell'intestino animale, e influenzano fortemente la fisiologia del loro ospite. Da un lato, questi microorganismi possono espletare funzioni fisiologiche o benefiche per l'organismo, come ad esempio orchestrare il corretto funzionamento del sistema immunitario dell'ospite e prevenirne l’eccessiva attivazione. Dall'altro, in casi di disregolazione delle sue attivita', il microbiota intestinale puo’ promuovere alcune patologie come cancro, aterosclerosi e malattie infiammatorie croniche dell'intestino. La composizione e l'attivita' del microbiota sono regolate da una constante reciproca interazione con le cellule del sistema immunitario dell’ospite, che si accumulano in grande quantita’ nel tessuto intestinale. Pertanto, comprendere quali sono i meccanismi che governano le interazioni fra microbiota e sistema immunitario consentira' di mettere a punto nuove strategie terapeutiche che agiscano sull’equilibrio fra queste due entita'.
Il presente progetto propone precisamente questo: da un lato, identificare delle strategie che ottimizzino l’efficienza strategie di immunizzazione volte alla protezione della mucosa intestinale da patogeni e tumori, tramite modulazione del microbiota intestinale; dall'altro, comprendere l’impatto delle risposte immunitarie sulle funzioni del microbiota, con particolare enfasi su quelle che promuovono danno tissutale o patologie nell’ospite, identificando fattori microbici da utilizzare come target per terapie cliniche.Lo svolgimento degli esperimenti proposti in questo progetto aumentera’ notevolmente la nostra comprensione di meccansimi di base che regolano l’interazione tra ospite e microbiota, e ci fornira’ strumenti innovative per prevenire e combattere molteplici malattie dell’uomo tramite intervento su questo asse.

Direct link to Lay Summary Last update: 27.07.2020

Responsible applicant and co-applicants

Employees

Abstract

The gut microbiota is a complex collection of microbes that inhabit the gastro-intestinal (GI) tract of virtually all metazoans. Commensals outnumber their hosts in terms of both cellular units and unique genes, and through their metabolic activity they can heavily impact host physiology promoting either health or disease. Maintenance of mutualism requires a continuous bidirectional dialogue between the microbiota and host mainly occurring accross the mucosal tissue. In particular, the intestinal immune system and commensal communities reciprocally modulate each other's composition and functions, ultimately determining the health status of the host. Dissecting the molecular mechanisms that govern such dynamic inter-kingdom interactions, and exploiting them to improve immunity and promote health, represents one of the most exciting outlooks in medicine. Advancing this field requires holistic experimental approaches to manipulate and analyze both host and microbial components of the intestinal ecosystem.Here, I propose to combine immunological, microbiological and bioinformatics tools, to dissect and modulate interactions between the host immune system and the gut microbiota, with the goal of promoting host health. In particular, by approaching host-microbe interactions bi-directionally, I will pursue three complementary aims:1) Dissect the cellular and molecular requirements underlying robust induction of tissue-resident memory T cells (Trm) in the intestine, and utilize the gained knowledge to design a mucosal immunization strategy maximizing Trm responses through combined modulation of the microbiota and delivery of a rationally optimized vaccine. To achieve this goal, I will make use of an in vivo model I recently developed (Becattini et al. I, in preparation) and adopt classical immunological techniques, as well as microbiota manipulation and sequencing approaches. The obtained results are expected to expand our understanding of T cell responses in the intestine, as well as to generate a relevant translational approach for vaccination against pathogens and tumors of the GI tract.2) Understand the functional reprogramming occurring in intestinal bacteria exposed to different types of host immune responses, and dissect the transcriptional signatures generated in selected members of the microbiota. To this end, I will utilize an ad hoc designed platform (Becattini et al. II, in preparation) that allows dissection of the transcriptional profile of single bacteria, as well as bacterial communities, following a perturbing event, in this case the immune response. I will furthermore exploit the obtained information to engineer bacteria with enhanced beneficial activity in the context of inflammation. 3) Dissect the adaptation of pathobionts, particularly Enterobacteriaceae, to intestinal immune responses, with a focus on chronic inflammation. By combining mouse models of colitis, transcriptomics (Becattini et al. II, in preparation) and mutational analyses I will unravel evolutionary events occurring in Klebsiella pneumoniae upon exposure to an inflammatory milieu. I will investigate whether similar adaptation patterns can be observed in bacteria isolated from patients with inflammatory bowel disease (IBD), in which Enterobacteriaceae commonly expand and foster pathology. Furthermore, I will address the role of such mutational and transcriptional reprogramming in modulation of the immune system and induction of disease. My research will pinpoint genes whose activity could be antagonized to reduce pathobiont expansion, favoring their clearance and dampening inflammation.Overall, by investigating at the same time the impact of the microbiota on the generation of mucosal immunity, and the functional changes promoted in intestinal bacteria by host immune responses, I will expand our overall knowledge on the host-microbe interaction, and identify novel therapeutic approaches and targets to promote host health.
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