Severe infectious diseases of childhood as monogenic PNAS PLUS inborn errors of immunity Jean-Laurent Casanovaa,b,c,d,e,1 aSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; bHoward Hughes Medical Institute, New York, NY 10065; cLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Necker Hospital for Sick Children, 75015 Paris, France; dImagine Institute, Paris Descartes University, 75015 Paris, France; and ePediatric Hematology and Immunology Unit, Assistance Publique–Hôpitaux de Paris, Necker Hospital for Sick Children, 75015 Paris, France Contributed by Jean-Laurent Casanova, November 3, 2015 (sent for review September 15, 2015; reviewed by Max D. Cooper and Richard A. Gatti) This paper reviews the developments that have occurred in the normally in other cells. P. vivax infections are rarely lethal today, field of human genetics of infectious diseases from the second half but the selective pressure exerted by this parasite may have fa- of the 20th century onward. In particular, it stresses and explains vored the spread of this allele, which is more common in infested the importance of the recently described monogenic inborn errors areas and is fixed in some African populations. These findings do of immunity underlying resistance or susceptibility to specific infec- not explain the pathogenesis of P. vivax malaria, but they do tions. The monogenic component of the genetic theory provides a explain why some individuals are not infected despite repeated plausible explanation for the occurrence of severe infectious diseases exposure to the parasite. They also show that a pathogen can during primary infection. Over the last 20 y, increasing numbers of favor the spread of a human allele conferring Mendelian pro- life-threatening infectious diseases striking otherwise healthy chil- tection against the pathogen concerned. dren, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired Other Forms of Mendelian Resistance to Infection by seminal but neglected findings in plant and animal infections. Another set of similar studies in 1996 explained why the HIV did Infectious diseases typically manifest as sporadic traits because not infect rare individuals in vivo, despite repeated exposure human genotypes often display incomplete penetrance (most genet- + through sexual contact. The CD4 T cells of these individuals GENETICS ically predisposed individuals remain healthy) and variable expressiv- were shown to be resistant to infection in vitro. An autosomal ity (different infections can be allelic at the same locus). Infectious recessive chemokine (C-C motif) receptor 5 (CCR5) deficiency diseases of childhood, once thought to be archetypal environmental was rapidly identified in these subjects (5–7). The most com- diseases, actually may be among the most genetically determined mon mutation underlying this phenotype probably originated in conditions of mankind. This nascent and testable notion has in- Scandinavia, and the evolutionary forces driving its spread to- teresting medical and biological implications. ward Southern Europe have remained elusive. The third and last case we will consider here is autosomal recessive fucosyl- human genetics | immunology | infectious diseases | pediatrics | transferase 2 (FUT2) deficiency, which was discovered in 2003. primary immunodeficiency Individuals with this deficiency are naturally resistant to diarrhea caused by noroviruses (8, 9). This condition is typically benign in his paper reviews the monogenic inborn errors of immunity the developed world today but would have been potentially life- Tthat have been shown to underlie resistance or vulnerability threatening in ancient times, as it still is in developing countries. to human infectious diseases. These studies, first conducted in With these three examples, we have true genetic determinism the 1970s, gained momentum from the mid-1990s onward. The that is autosomal recessive with complete or almost complete analysis of Mendelian traits was followed by that of non- penetrance. The monogenic lesions prevent infection through a Mendelian monogenic traits, characterized by incomplete clini- cal penetrance and variable expressivity. causal mechanism (i.e., lack of cell infection by a specific microbe). Significance Mendelian Resistance to Malaria An example of infection shaping the human genome was pro- The key problem concerning pediatric infectious diseases, and vided by the discovery of Mendelian resistance to Plasmodium vivax more generally clinical diseases during primary infection, is (1, 2). It is important to stress here that these studies their pathogenesis. A plausible and testable human genetic concerned infection per se and not its manifestations (Table 1). theory of primary infectious diseases has recently emerged, As discussed in the companion paper (3), only a minority of building on elegant studies in plants and animals. Three ex- infected individuals develop clinical disease, and an even smaller amples of monogenic resistance to common infections have minority develop life-threatening disease in the course of pri- been discovered. Moreover, a growing range of monogenic mary infection. Moreover, not all exposed individuals become single-gene inborn errors of immunity, rarely Mendelian (with infected. In at least three cases, this phenomenon has been complete clinical penetrance) but more commonly non- shown to be a Mendelian phenotype because of a well-defined Mendelian (with incomplete penetrance), have been found to monogenic genotype for a microbial receptor or coreceptor. underlie severe infectious diseases striking otherwise healthy Louis Miller carried out pioneering studies in this area. In 1976, children during primary infection. These findings provide a he discovered that an autosomal recessive deficiency of the Duffy synthetic framework for inherited and infectious diseases and, antigen and receptor for chemokines (DARC) in erythrocytes more generally, for inborn and environmental conditions. prevented the infection of these cells with Plasmodium vivax in vitro and the infection of individuals in vivo (1). An elegant set of Author contributions: J.-L.C. designed research, performed research, analyzed data, and follow-up studies demonstrated that this resistance could be at- wrote the paper. tributed to a single nucleotide mutation in the DARC promoter, Reviewers: M.D.C., Emory University; and R.A.G., University of California, Los Angeles. preventing the binding of the transcription factor GATA-binding The authors declare no conflict of interest. protein 1 (GATA1), which is required for DARC expression in Freely available online through the PNAS open access option. the erythrocyte lineage (4). Affected individuals express DARC 1Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1521651112 PNAS Early Edition | 1of10 Downloaded by guest on September 26, 2021 Table 1. Mendelian resistance to human infection errors of IFN-γ immunity involving nine genes (19–23). Some γ Infection Gene Inheritance Year MSMD-causing genes control the production of IFN- ; others govern its action. These nine MSMD-causing genes display high P. vivax DARC Autosomal recessive 1975 levels of allelic heterogeneity. However, these deficiencies dis- HIV CCR5 Autosomal recessive 1996 play physiological homogeneity, because all defects impair IFN-γ Norovirus FUT2 Autosomal recessive 2003 immunity. Moreover, human IFN-γ immunity, as a quantitative trait, controls host defense against mycobacteria. The clinical The three phenotypes are autosomal recessive. Biallelic mutations underlie γ complete deficiency of any of these three microbial receptors or coreceptors. features of MSMD depend strongly on the levels of IFN- im- These deficiencies can be common, especially in areas where the correspond- munity, being most severe in patients with complete IFN-γ de- ing infection can select the resistance genotype. Clinical penetrance (resistance ficiency (24). The clinical implications of this work are obvious. to infection per se) is complete or almost complete. The infections and re- These studies identified the genetic defects underlying these sistance genes are described in the text, as are the references. Mendelian infections, providing molecular genetic proof that mycobacterial disease could be Mendelian. The patients are treated with IFN-γ and antibiotics or by hematopoietic stem cell These findings concern very large numbers of individuals and neatly transplantation when the receptor is completely nonfunctional. illustrate the potential impact of Mendelian genetics at the pop- The immunological implications are not negligible: These studies ulation level. These findings have important biological implications, confirmed Carl Nathan’s suggestion that IFN-γ is much more a because these three sets of studies demonstrate the essential nature macrophage-activating factor than an antiviral agent (25). They of a single specific gene for each infection. The clinical implications + also showed that the Th1 arm of CD4 T cells (IL-12 being the are equally important, because blocking these molecules in other γ individuals is a rational approach to prevention or therapy. It is Th1-inducing signature cytokine and IFN- the Th1 effector sig- surprising that this field has not blossomed. For almost all common nature cytokine), which in inbred mice had been reported