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ANR funded project

Innovation biomédicale (DS0404) 2014
Projet PNEUMOPID

Childhood invasive pneumococcal disease: toward the identification of novel primary immunodeficiencies

Streptococcus pneumoniae infects most children, but is typically innocuous. In contrast, invasive pneumococcal disease (IPD) is rare, life-threatening, and principally affects children under 2 years of age. Its incidence is estimated at 10/100,000 cases/year. Pneumococcal vaccines have reduced the burden of IPD, but new serotypes are emerging. IPD recurs in about 4 % of patients, and previous IPD is the greatest risk factor for IPD. Other known risk factors include HIV infection, sickle-cell disease and some primary immunodeficiencies (PIDs). However, IPD pathogenesis is unclear in most children. We began the genetic dissection of childhood IPD 15 years ago, with the identification of mutations in NEMO and IKBA in patients with IPD and other infections. We then identified 2 new genetic disorders more specific of IPD and selectively impairing TLR/IL1R responses: IRAK4 and MyD88 deficiencies. More recently, we discovered HOIL1 mutations in 3 patients with bacterial infections, including IPD. These mutations impaired NF-kB activation by IL-1beta. We also identified heterozygous RPSA mutations in patients with isolated congenital asplenia, mostly revealed by IPD. All these deficiencies account for fewer than 10% of the IPD cases studied. We hypothesize that IPD may result as a rule from other single-gene inborn errors of immunity. Our long-term goal is to understand the pathogenesis of childhood IPD by deciphering its human genetic and immunological basis in children. Since 2005, we have enrolled 200 children from French pediatric units and 130 from abroad, and we have identified 30 children with known PIDs. The present project is based on the investigation of 200 IPD patients by a genome-wide (GW) strategy to identify the most promising candidate IPD-causing mutations and validate them with appropriate functional methods. More specifically, we will pursue 3 specific aims: 1) to expand our cohort of IPD patients up to 430 patients, and to select 200 patients (in particular the familial cases and the most severe forms) without known PIDs for further investigations, 2) to search for IPD-predisposing genes by a GW strategy combining whole-exome sequencing and high-density genotyping, and 3) to study the B cell-mediated anti-pneumococcal immunity in IPD patients, but also in healthy immunized individuals, in order to formally identify the B cell subsets responsible for the production of Immunoglobulins (Ig) M, IgG2 and IgA against pneumococcal capsular glycans. Anti-pneumococcal capsular glycans antibodies can prevent IPD and can protect of asymptomatic pneumococcus carriage. Our preliminary data based on the investigation of 100 of these patients have already validated our strategy, with the identification of one new genetic etiology. We identified 2 brothers with IPD who are a homozygous for a rare TIFA mutation, and also heterozygous for a more common TACI polymorphism. TIFA is involved in the activation of both NF-kB and MAPK, and TACI is involved in B-cell activation. The in-depth study of B cells populations in IPD patients could shed new light on the genetic control of their development and maintenance and, on their function in controlling antibody responses to glycans and anti-pneumococcal immunity. Overall, this project will provide fundamental new insights into the cellular and molecular mechanisms of immunity to pneumococcus. At the medical level, the information gained from this project will allow physicians to offer patients the possibility of molecular diagnosis and to provide families with genetic counseling. It will also provide the basis for new avenues of treatment, based on a rational understanding of pathogenesis that is essential given the rapid selection of both antibiotic-resistant pneumococci and strains not covered by current vaccines.

Partners

APHP - UIHP-Necker Unité d'Immunologie et Hématologie Pédiatrique, Hôpital Necker - APHP

GHMI - INSERM U1163(exU980) Laboratoire de Génétique Humaine des Maladies Infectieuses - INSERM U1163 (exU980)

INSERM Institut National de la Santé et de la Recherche Médicale

ANR grant: 321 100 euros
Beginning and duration: janvier 2015 - 36 mois

 

ANR Programme: Innovation biomédicale (DS0404) 2014

Project ID: ANR-14-CE15-0009

Project coordinator:
Madame Capucine Picard (Laboratoire de Génétique Humaine des Maladies Infectieuses - INSERM U1163 (exU980))

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.