SFI 2025

Jean-Laurent Casanova is a pediatrician and immunologist by training and have in practice become a human geneticist studying the pathogenesis of infectious diseases. A fundamental question in medicine is that of interindividual clinical heterogeneity in the course of infection: why do only a small minority of infected individuals develop severe clinical diseases upon infection by almost any given microbe? This ‘infection enigma’ was first posed around 1900 and has yet to be answered for most infections and patients. The microbe is necessary, but not sufficient for disease development. What are the other determinants? The genetic theory of infectious diseases, proposed in the 1910s, suggests that human germline genetic variability underlies clinical variability; under this hypothesis, severe infectious diseases are thus also genetic traits.
From the 1950s until we began our research in the early 1990s, it was thought that mutations in a single gene were rare and conferred susceptibility to multiple infectious diseases. We showed that severe infectious diseases in otherwise healthy individuals can result from collections of rare single-gene inborn errors of immunity, which are rarely fully penetrant. We have characterized a new, expanding group of genetic defects that predispose otherwise healthy children, adolescents, adults, and even the elderly to a single type of infection, a new causal relationship modifying a paradigm that had prevailed in this field for five decades. We have deciphered the molecular, cellular, and immunological basis of various rare and common infectious diseases, encompassing mycobacterial diseases including tuberculosis (type II interferon-dependent immune response (mutations in 19 genes and in TNF), pneumococcal disease (NEMO, IKBA, IRAK4, MYD88, HOIL1, HOIP, RLTPR), isolated congenital asplenia (RPSA), staphylococcal disease (TIRAP, ZNF341, IL6ST, OTULIN), Whipple’s disease (IRF4), mucocutaneous candidiasis (IL17-dependent immune response (mutations in 8 genes), dermatophytic disease (CARD9), Kaposi sarcoma (OX40), influenza pneumonitis (IRF7, IRF9, TLR3), herpes simplex encephalitis (type I IFN-dependent immune response (mutations in 6 genes and in SNORA31, RIPK3, TMEFF1), viral infections of the brainstem (DBR1), epidermodysplasia verruciformis (RHOH, CIB1), NK cell deficiency (MCM4, GINS1), fulminant viral hepatitis (IL18BP), yellow fever vaccine-associated disease (IFNAR1, IFNAR2), HPV laryngeal papillomatosis (NLRP1), disseminated warts (CD28), infection and autoimmunity (PTCRA), cytomegalovirus disease (NOS2), West Nile and tick-borne virus encephalitis (auto-antibodies to type I IFNs), severe COVID-19 (8 genes and their auto-immune phenocopy, disrupting type I IFN immunity), and the SARS-CoV-2 complication multisystem inflammatory syndrome in children (MIS-C) (OAS1, OAS2, RNASEL).
These studies are not merely a reductionist catalog of genes; they have defined, in a mechanistic and holistic manner, the molecular, cellular, and immunological pathways controlling these microorganisms. In a long argument, they all support the idea that severe infections striking otherwise healthy individuals can be genetic, and even monogenic, albeit only rarely fully penetrant. Remarkably, they also provide proof-of-principle that the discovery of the genetic basis of rare infections can lead to the elucidation of the mechanism of disease in a significant proportion of patients with common infections. Inborn errors of type II IFN immunity in patients with weakly virulent mycobacterial disease led to the identification of a genetic etiology of tuberculosis in 1% of European cases, while the discovery of inborn errors of type I IFN immunity in patients with severe influenza led to the identification of auto-antibodies to type I IFNs in 15% of patients with severe COVID-19 and 40% of patients with West Nile encephalitis. These studies have clinical implications, as they provide a basis for genetic counseling and a rationale for developing new therapeutic approaches based on an understanding of the host component of infectious diseases.
These studies also have biological implications, as they reveal the largely redundant function of host defense genes in an ecosystem governed by natural selection.

Other Experience and Professional Memberships:

• 2025 - Founding Editor-in-Chief, Journal of Human Immunity (New York, USA)
• 2006 - Editor, Journal of Experimental Medicine (New York, USA)

Honors:

• 2021 - Doctor Juan Abarca International Award of Medical Sciences, Spain, EU
• 2019 - ‘Grand Prix Claude Bernard’, Paris, France, EU
• 2016 - ‘Grand Prix, Institut National de la Santé et de le Recherche Médicale’, France, EU
• 2016 - Stanley J. Korsmeyer Award, American Society for Clinical Investigation
  
• 2015 - International Member, National Academy of Medicine, USA
• 2015 - Foreign Associate, National Academy of Sciences, USA
• 2014 - ‘Robert Koch Prize’, Germany, EU
• 2014 - Sanofi-Institut Pasteur International Mid-Career Award, France, EU
• 2011 - ‘InBev-Baillet Latour Health Prize’, Immunology and Infectious Diseases, Belgium, EU
• 2008 - ‘Richard Lounsbery Award’, French Academy of Sciences, National Academy of Sciences USA

Professor Dame Fiona Powrie research interests include characterization of the interaction between the intestinal microbiota and the host immune system and how this mutualistic relationship breaks down in inflammatory bowel disease. Fiona's work has identified the functional role of regulatory T cells in intestinal homeostasis and shed light on their development and mechanism of action. She has also shown that both adaptive and innate immune mechanisms contribute to intestinal inflammation and identified the IL-23 pathway as a pivotal player in the pathogenesis of chronic intestinal inflammation. Her current work seeks to translate findings from model systems into the clinic in inflammatory bowel disease patients.

Honors:

• Fiona received the ‘Ita Askonas Award’ from the European Federation of Immunological Societies for her contribution to immunology in Europe, the Louis-Jeantet Prize for Medicine 2012 and an Honorary Lifetime Membership of the British Society of Immunology in 2021.
• She was elected a Fellow of the Royal Society in 2011, EMBO in 2013, the Academy of Medical Sciences in 2014 and an International Fellow of the National Academy of Sciences in 2020.
• Fiona joined the Wellcome Trust Board of Governors in 2018 and was appointed Deputy Chair in 2022.