DS0404 - Innovation biomédicale

Human genetic determinism of invasive fungal diseases – HGDIFD

Submission summary

Invasive fungal diseases (IFDs) are life-threatening infections that usually occur in patients with immunodeficiencies (IDs), either iatrogenic, acquired, or primary (PIDs), often associated with other severe conditions. They represent a major public health problem with a rapidly growing at-risk population of patients, and the emergence of resistant strains of fungi. Thus, IFDs generate considerable morbidity and mortality worldwide. As they frequently develop in patients with multiple conditions, the pathogenesis of these IFDs remains poorly understood. In rare cases, however, IFDs occur in otherwise healthy patients without any known risk factors. These “idiopathic” IFDs represent a unique opportunity to gain insight into IFD pathogenesis. We hypothesized that these IFDs may be due to as yet undiscovered “pathogen-specific” inborn errors of immunity, which we aim to discover and decipher in this project. Our hypothesis is based on the observations that (i) idiopathic IFDs affect a very small minority of individuals while these fungi are ubiquitous in the environment, (ii) some well-characterized PIDs are associated with IFDs and (iii) an increasing number of infectious diseases are being shown to result from single-gene inborn errors of immunity, including some fungal diseases, as we have recently reported for chronic mucocutaneous candidiasis disease and deep dermatophytosis. We will focus our project on the three most prevalent IFDs seen in Western Europe, namely cryptococcosis, aspergillosis and candidiasis. This project capitalizes on a unique collection of patients with proven idiopathic IFDs recruited thanks to a worldwide network of long-standing field collaborators. To date, we have enrolled 73 patients and we intend to recruit, within the next three years, a total of 160 affected individuals. 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. Our preliminary data have already validated our strategy, with the identification of mutations in known genes such as CARD9 or IL12RB1, and in one new gene for which functional validation is ongoing. Our project is highly innovative, as idiopathic IFDs are not generally thought to directly result from a genetic disorder. However, it is clearly feasible, as it is built on strong preliminary data and relies on several decisive strengths: (i) the recruitment of patients with proven IFDs without any known risk factors, (ii) the extensive experience of our consortium in the field of human fungal infections in terms of molecular and medical mycology, medical and genetic epidemiology, clinical and molecular genetics, and cellular immunology, and (iii) the use of cutting-edge NGS approaches which we have successfully pioneered in the field of infectious diseases, fungal diseases in particular. The immunogenetic dissection of IFDs will shed new light on the molecular and cellular mechanisms conferring protective immunity (or lack thereof) against specific fungi, Cryptococcus neoformans and gattii, Aspergillus fumigatus and Candida albicans in particular, and provide insight into the underlying pathogenesis. The clinical implications of this project will be also considerable, as molecular genetic diagnosis and genetic counseling will be offered to the patients and their families. Moreover, these advances will pave the way for novel prophylactic or curative therapeutic interventions, in the settings of these inherited IDs but also in patients with iatrogenic or acquired IDs, based on a rational understanding of the pathogenesis. The results of this project will prove to be essential given the rapid appearance of antifungal-resistant strains and the high mortality rate associated with these IFDs, despite appropriate antifungal treatment.

Project coordination

Anne PUEL (INSERM - Laboratoire de Génétique Humaine des Maladies Infectieuses)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


INSERM U1163 (exU980) - GHMI INSERM - Laboratoire de Génétique Humaine des Maladies Infectieuses
APHP - SMIT- Necker APHP - Hopital Necker-Service des Maladies Infectieuses et Tropicales
UMM-IP Unité de Mycologie Moléculaire - Institut Pasteur

Help of the ANR 328,460 euros
Beginning and duration of the scientific project: December 2014 - 48 Months

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