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Lymphocyte T helper (Th) cell differentiation in patients with inborn errors of immunity to Mycobacterium and/or Candida species

English title Lymphocyte T helper (Th) cell differentiation in patients with inborn errors of immunity to Mycobacterium and/or Candida species
Applicant Sallusto Federica
Number 182728
Funding scheme Project funding
Research institution Istituto di ricerca in biomedicina (IRB) Facoltà di scienze biomedice
Institution of higher education Università della Svizzera italiana - USI
Main discipline Immunology, Immunopathology
Start/End 01.01.2019 - 31.12.2022
Approved amount 862'778.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Clinical Immunology and Immunopathology

Keywords (8)

Mycobacterial diseases; IL-17; IFN-gamma; Human inborn errors of immunity; Th1*; Fungal diseases; Th1; Th17

Lay Summary (Italian)

Lead
In questo progetto ci proponiamo di studiare casi sporadici di infezioni gravi dovuti ad immunodeficienze primitive, in particolare infezioni causate da micobatteri (come ad esempio il batterio della tubercolosi) o funghi (come ad esempio Candida albicans). Alcune mutazioni che causano queste infezioni sono già state identificate in geni coinvolti nella differenziazione e funzione di linfociti T (come ad esempio nei geni che codificano le citochina IFN-gamma o IL-17 e i recettori per le citochine IL-12 o IL-23). L'eziologia genetica rimane sconosciuta in circa la metà dei pazienti con infezioni da micobatterio o Candida albicans. Ci proponiamo quindi di identificare nuovi difetti genetici coinvolti nell’immunità contro questi patogeni e di caratterizzare il loro impatto nello sviluppo e nella differenziazione dei linfociti T.
Lay summary

Gli obiettivi specifici sono:

1) scoprire nuovi geni che causano malattie micobatteriche e micosi croniche in una coorte di 800 pazienti;

2) una volta definito il difetto genetico, studiare le cellule T della memoria utilizzando diverse metodiche;

3) studiare l'impatto dei geni identificati nella differenziazione delle cellule Th umane indotte da agenti patogeni.

Questo progetto innovativo è proposto da due gruppi di ricerca con sede in Svizzera e Francia con competenze complementari nei campi della medicina, della genetica umana, dell'immunologia e delle malattie infettive. I risultati di questa collaborazione accresceranno le nostre conoscenze sui meccanismi alla base della risposta immunitaria protettiva contro agenti patogeni e avranno implicazioni in campo medico per la diagnosi e il trattamento di malattie come la tubercolosi o le micosi croniche.  
Direct link to Lay Summary Last update: 30.01.2019

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
189331 New approaches to study T cell activation, differentiation and plasticity in humans 01.01.2020 Project funding

Abstract

Most known primary immunodeficiencies (PIDs) are associated with infections caused by multiple microbes. Severe infections striking otherwise healthy individuals, even sporadic cases, can also result from single-gene inborn errors of immunity. In that context, the investigation of patients with inherited defects causing selective susceptibility to Mycobacteria and/or Candida spp should help to decipher the immunological mechanisms crucial in fighting against those microbes in natural conditions of infections. Mendelian Susceptibility to Mycobacterial Diseases (MSMD) is a PID characterized by severe infections due to weakly virulent mycobacteria, in particular the BCG vaccine. These patients are also vulnerable to tuberculosis. MSMD-causing mutations have been identified in ten genes involved in the IL-12/IL-23-IFN-? immune axis. Chronic mucocutaneous candidiasis (CMC) is characterized by severe, chronic, mucocutaneous infections caused by C. albicans, affecting nails, skin, and mucosae. CMC is common and syndromic (i.e. associated to other infectious or non-infectious features) in patients with inherited and acquired T cell deficits. Isolated inherited CMC-disease (CMCD) is rare, and mutations in four genes involved in the IL-17 immunity were shown to be responsible for CMCD so far. The genetic etiology remains unknown in about half the MSMD or CMCD patients and the cellular mechanisms critical to human anti-mycobacterial and/or anti-Candida immunity are poorly understood. This joint research project, proposed by two leading laboratories in Switzerland and France with complementary expertise, aims at identifying new genetic defects involved in IFN-? or IL-17 immunity, and at characterizing their impact in the development and in the differentiation of T helper (Th) cell subsets, and in the function of naïve and memory CD4+ T cells reactive against Mycobacteria or Candida. The specific aims are: Specific aim 1: To discover new MSMD- and CMCD-causing genes. In a unique cohort of 800 MSMD and CMCD patients, we will search for and characterize the underlying genetic defects using i) cutting-edge genome-wide strategies and ii) in depth-functional studies to validate the mutations identified. Our current research and preliminary data show very promising mutations in novel MSMD- (IFNG, IL23R, IL12RB2, TYK2, SPPLA2, TBX1, and IRF1), and CMCD- (JNK1, REL, and ZNF341) causing genes. Specific aim 2: To study ex vivo memory Th (e.g. Th1, Th2, Th1*, Th17) subsets in novel inborn errors of anti-mycobacterial and anti-fungal immunity. We will evaluate by flow cytometry the frequency and distribution of various T helper cell subsets, especially, Th1, Th1* and Th17 ex vivo in patients with mutations in the recently identified genes, as well as in the new genetic etiologies to be discovered. We will also use high throughput cell-based screening assays to identify, quantify and functionally characterize memory CD4+ T cells (Th1, Th2, Th1* and Th17) induced in vivo by Mycobacteria and Candida in patients with novel mutations. Specific aim 3: To study the impact of the identified MSMD- and CMCD-causing genes in pathogen-induced human Th cell differentiation. We will use established in vitro priming systems to study naïve T cell differentiation induced by M. tuberculosis or Candida albicans staring from naïve T cells isolated from patients with the novel mutations. The project is innovative, achievable, supported by strong preliminary data, and builds on the longstanding collaboration between the two participating laboratories. This endeavor is unique in the fields of medicine, human genetics, immunology, and infectious disease. The outcomes of this project should have considerable consequences in immunology, in terms of understanding anti-Mycobacteria and anti-Candida cellular immunity, as well as profound and broad medical implications, in terms of diagnosis and treatment of human mycobacterial and fungal diseases.
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