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Phd contract: Genetic dissection of invasive pneumococcal disease, Institut Imagine, Paris

Détails de l'offre

  • Type de poste: PhD/Doctorat
  • Secteur : Public
  • Localité : France 
  • Limite de candidature : 02/11/2021
  • Profil de poste:
    Recherche et innovation
  • Domaine(s) :
    Microbiologie et Immunologie


Job offer available on this link.

Paris – Ile-de-France – France

Phd Decription: Project 06- GEN-IPD|Human genetic of infectious disease
severe bacterial infection, Streptococcus pneumoniae, vaccine, monogenic, susceptibility, NF-kB

PhD Proposal abstract

Invasive pneumococcal diseases (IPD) is one of major risk of death for children with primary immunodeficiencies (ID) associated with antibody or complement deficiency. However, the majority of IPD occurs in children without known deficiency and despite anti-pneumococcal vaccination. We hypothesize that these “idiopathic” IPD may be caused by single-gene inborn errors of immunity. We intend to investigate patients with proven idiopathic IPD. We will identify and characterize the underlying genetic defects by a strategy combining powerful genome-wide explorations and in-depth functional experiments.

PhD Proposal
Streptococcus pneumoniae is a Gram-positive encapsulated bacterium, which is almost ubiquitous, with the prevalence of asymptomatic carriage in the rhinopharynx approaching 90% in healthy children. However, in rare cases, pneumococcus may cause invasive diseases, such as arthritis, septicemia, and meningitis (designated as IPD). IPD is life-threatening, not only because of its rapid clinical course, but also because of the spread of antibiotic-resistant bacterial strains. Most children with IPD are between the ages of 3 months and 3 years. Non-conjugated pneumococcal vaccines are poorly protective in children under 18 months of age, and the conjugated vaccines protect against even fewer serotypes. Thus, childhood IPD poses a major public health problem.
Environmental factors, such as socioeconomic conditions, probably account for the higher incidence of IPD in developing countries. However, the occurrence and rarity of IPD in Western countries suggest that host factors also play a prominent role in its pathogenesis. Some acquired (HIV, splecnectomy, cancers, …) and inherited host factors including drepanocytosis and certain IEIs (1) have been identified. Among the inherited host factors, children with ICA or impaired complement- or Ab- mediated opsonization are specifically susceptible to encapsulated bacteria, pneumococcus in particular. Remarkably, the greatest risk factor for IPD is IPD itself, with a 2-4% recurrence rate.

Within this context and accelerated by recent advances in Next Generation Sequencing (NGS) technologies, a search for IPD-predisposing single gene lesions was initiated about 15 years ago in our laboratory, with the aim of identifying new PIDs conferring a selective predisposition to IPD. Our first breakthrough came in 2001, with the discovery of hemizygous mutations in the X-linked NEMO gene, in male patients with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (2). In these patients, impaired NF-B signaling results in susceptibility to multiple pathogens, including pneumococcus in particular. Children with EDA-ID fail to mount an Ab response to capsular glycans.Later on, we and others identified other inborn errors of NF-B pathways (3-9), all leading to high susceptibility to IPD.
Altogether, we recently found that up to 10% of French children with IPD, recurrent or not, had a known PID, based on a candidate gene approach (10). The genetic epidemiological features of childhood IPD had also not been subject to in-depth study until our own French survey. We hypothesize IPD may result from inborn errors of immunity in a sizeable proportion of patients, which we aim to discover and decipher.
We propose to tackle this hypothesis using on a unique collection of patients (n=300) with proven idiopathic IPDs enrolled thanks to a worldwide network. We will search for and characterize the underlying genetic defects using 1) cutting-edge genome-wide strategies, including next-generation sequencing (NGS) technologies, and 2) in-depth functional studies to validate the genetic variants identified. The immunogenetic dissection of IPDs will shed new light on the molecular and cellular mechanisms conferring protective immunity against specific bacteria, Streptococcus pneumoniae in particular, and provide insight into the underlying pathogenesis.
1. Picard et al. Curr Opin Allergy Clin Immunol, 2003. 3(6): p. 451-9.
2. Doffinger et al. Nat Genet, 2001. 27(3): p. 277-85
3. Boisson. Human Genetics, 2020. 139(1) p. 981–991 4.
4. Boisson et al.. Nat Immunol, 2012. 13(12): p. 1178-86. 5.
5. Boisson et al. J Exp Med, 2015. 212(6): p. 939-51.
6. Boisson et al. J Clin Invest, 2018.
7. Li, J, … …, Boisson, B. J Exp Med, 2021. 218(11). 8.
8. Picard et al.Science, 2003. 299(5615): p. 2076-9.
9. von Bernuth, et al.. Science, 2008. 321(5889): p. 691-6.
10. Gaschignard et al. C. Clin Infect Dis, 2014. 59(2) p. 244-251
Prise de fonction : 03/10/2022

Nature du financement : Financement public/privé

About the Imagine Intitute


First European centers of research, care and education on genetic diseases, the Imagine Institute aims to understand them and cure them. The Institute brings together 1000 of the best doctors, researchers and healthcare personnel in a creative architecture of synergies. Today Imagine is focused on its ambition to change the lives of families affected by genetic diseases.

Intitulé du doctorat : Doctorat de Biologie

Pays d’obtention du doctorat : France

Ecole doctorale : Profil du candidat

The program is intended for students who hold a Master’s degree (or equivalent) from a university outside France and who have not worked or resided in France for more than 12 months in the 3 years preceding their recruitment.

The selection of the PPU-IMAGINE program is organized by Institut Imagine and selected students carry out their research in one of Institut Imagine lab.

Expected profile / where to apply

Genetic and molecular biology training course

Exome/Genome or RNAseq and computational skills

Six-month lab experience


Apply to this job on the Association Bernard Gregory website.