Jean-Laurent Casanova

Human genetics of infectious diseases : Mendelian predisposition

Our team aims to determine the molecular basis of the monogenic determinism of rare and common infectious diseases in children. We hypothesize that a substantial fraction children with severe infectious diseases suffer from novel single-gene inborn errors of immunity, resulting in a specific susceptibility to one or a few microorganisms. During the last years, we have provided further evidence supporting this hypothesis, with the discovery of the molecular genetic basis of:

• The syndrome of Mendelian predisposition to mycobacterial disease (MSMD), severe pediatric tuberculosis, and syndromic forms of mycobacterial disease, due to mutations of IFN-g immunity. We discovered new recessive etiologies of mycobacterial disease, in patients carrying specific mutations of: 1) ISG15 in patients with mycobacterial disease and auto- immunity, 2) TYK2 in patients with mycobacterial and viral infections, and 3) RORC in patients with mycobacterial and fungal infections.
• Invasive pneumococcal disease (IPD) due to mutations in the NF-kB pathway. Following on our identification of NEMO, IRAK4, and MyD88 deficiencies, we identified the first patients with impaired linear ubiquitination, due to mutations in HOIL- 1 or HOIP, two components of the LUBAC. These patients have auto-inflammation and bacterial infections. Linear ubiquitination via LUBAC is thus essential for the modulation of inflammation and the control of bacterial infections.
• Life-threatening influenza due to IRF7 deficiency. The amplification of anti-viral IFNs is IRF7-dependent in both plasmacytoid dendritic cells (PDCs) and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells. Herpes simplex encephalitis (HSE) due to inborn errors of TLR3 immunity. The pathogenesis of HSE involves the impairment of IFN production by neurons and oligodendrocytes in the central nervous system.
• Epidermodysplasia verruciformis (EV), due to papillomaviruses, and Kaposi sarcoma (KS), due to human herpes virus 8. Both conditions can result from inborn errors of T cell immunity (mutations in RHOH and MST1 for EV, and mutations in STIM1 and OX40 for KS). Other acute viral conditions, such as fulminant viral hepatitis, are also being studied.
• Fungal diseases, such as chronic mucocutaneous candidiasis disease (CMCD) and deep dermaphytosis disease (DDD).

CMCD results from inborn errors of IL-17 immunity (loss-of- function mutations in IL17F, IL17RA and ACT1, and gain-of-function mutations in STAT1) and DDD from bi-allelic null mutations in CARD9. Invasive fungal diseases, such as cryptococcosis and aspergillosis, are also being studied.

These projects are based on a worldwide recruitment of patients, and a cutting-edge strategy combining genome- wide investigations, in particular using next-generation sequencing, with in-depth functional studies of leukocyte subsets or iPSC-derived non-hematopoietic cells. Overall, our work provides proof-of-principle that severe infectious diseases in otherwise healthy children and young adults, in the course of primary infection, may result from single-gene inborn errors of immunity that rarely display
complete penetrance. This provides a model for the genetic architecture of severe infectious diseases. Our studies also showed that certain immunological pathways play a relatively narrow role in protective immunity to infections in natural conditions, at odds with the mouse model of experimental infections.