简介
I am 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, interfamilial, and interpopulation clinical heterogeneity in the course of primary infection: why do only a small minority of infected children, adolescents, or adults develop severe clinical diseases upon infection by almost any given microbe? This ‘infection enigma’ was first posed around 1910 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 factors involved? The genetic theory of infectious diseases, proposed in the 1920s, 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 hypothesized that severe infectious diseases can result from collections of rare single-gene inborn errors of immunity, which are rarely fully penetrant. We have identified and characterized a new, expanding group of genetic defects that predispose otherwise healthy children, adolescents, and even adults 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 infectious diseases and related conditions, encompassing mycobacterial diseases including tuberculosis (mutations in IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, NEMO, IRF8, CYBB, ISG15, TYK2, SPPL2A, IL12RB2, IL23R, RORC, IFNG, TBX21, PD1), 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 (IL17F, IL17RA, IL17RC, STAT1, ACT1, RORC, ZNF341, JNK1), dermatophytic disease (CARD9), Kaposi sarcoma (OX40), flu pneumonitis (IRF7, IRF9, TLR3), herpes simplex encephalitis (UNC93B1, TLR3, TRAF3, TRIF, TBK1, SNORA31), 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), cytomegalovirus disease (NOS2) and severe COVID-19 (8 genes and their auto-immune phenocopy, disrupting type I IFN immunity). In collaboration with other groups, we also discovered mutations in other genes and disruptions in other immunological pathways. 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 one single idea, namely that severe infections striking otherwise healthy individuals can be genetic, and even monogenic, albeit only rarely fully penetrant. These studies have important 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. Moreover, they provide a mechanism that applies to the pathogenesis of the same infections in other patients. For example, the discovery of inborn errors of type I IFN immunity in patients of all ages with severe COVID-19 pneumonia led to that of autoantibodies to type I IFNs in the elderly population, accounting for their much higher risk of severe disease. These studies also have major biological implications, as they reveal the largely redundant function of host defense genes in natura, in the setting of a natural ecosystem governed by natural selection. This is a major added value of human genetics, when compared with animal models, which have their own added value of being perfectly controlled experimentally.
