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Life-Threatening Infectious Diseases of Childhood: Single-Gene Inborn Errors of Immunity?

Research Summary

Jean-Laurent Casanova studies the human genetic determinism of childhood infectious diseases. He has identified single-gene inborn errors of immunity underlying diseases caused by specific pathogens. His discoveries include the molecular genetic basis of mycobacterial diseases (inborn errors of IFN-γ immunity), and of other diseases (and their affected genes) such as herpes simplex encephalitis (TLR3), invasive pneumococcal disease (TIR and RPSA), chronic mucocutaneous candidiasis (IL-17), and Kaposi sarcoma (OX40). Pursuing both biological and medical goals, he attempts to establish a genetic theory of childhood infectious diseases.

Historically, childhood infections have been the greatest killers of mankind. Until the late 19th century, half the population died from infection before the age of 15 years, and life expectancy at birth was only about 20 years. With the establishment of the germ theory of disease, improvements in hygiene, and the development of vaccines, antibiotics, and surgery, the global burden of pediatric infections has since diminished. However, throughout history, severe illness from any given pathogen has occurred in only a small proportion of infected children, and this remains true today. Adult infectious diseases occurring in the course of secondary infection or reactivation from latency often result from impaired acquired immunity. However, a "somatic" immunological theory of infectious diseases cannot be applied easily to primary infections. The fundamental question in the field of pediatric infectious diseases is therefore that of interindividual clinical heterogeneity in the course of primary infection. In the 1920s, geneticists such as Archibald Garrod proposed a "germline" genetic theory of pediatric infectious diseases. However, microbiologists and immunologists did not immediately embrace the proposal that life-threatening infections of childhood might result from inborn errors of immunity.

Figure: The TLR3 connectome: an example of a gene-specific connectome.

Since the work of Ogden Bruton in the 1950s, inborn errors of immunity (primary immunodeficiencies) have been seen as rare, fully penetrant, Mendelian traits associated with multiple, recurrent, opportunistic infections in early childhood (one gene, multiple infections, and familial cases). Since the mid-1990s, we have been testing an alternative hypothesis that life-threatening infectious diseases in otherwise healthy children may result from single-gene inborn errors of immunity, not necessarily displaying complete penetrance (one gene, one infection, and sporadic cases). In doing so, we have discovered the first known genetic etiologies of a variety of chronic and acute isolated childhood infections.

Mendelian Susceptibility to Mycobacterial Diseases (MSMD)
MSMD is characterized by narrow susceptibility to weakly virulent mycobacteria. Allelic heterogeneity (i.e., the diversity of morbid mutant alleles at a locus) at nine MSMD-causing loci defines 16 different disorders, which all feature impaired interferon-γ (IFN-γ) immunity. Our most recent and surprising discovery is that of autosomal recessive (AR) interferon-induced 15 kDa protein (ISG15) deficiency, revealing a novel circuit between ISG15-secreting granulocytes and IFN-γ-producing natural killer (NK) cells. These studies have proven clinically useful in that they have led to an improvement in the care of MSMD patients, most of whom benefit from recombinant IFN-γ. The work has also provided valuable immunobiological insight, by revealing that human IFN-γ immunity is more redundant than mouse IFN-γ (Th1) immunity in host defense and by contributing to the elucidation of the basic mechanisms governing IFN-γ immunity.

Childhood Tuberculosis (TB)
We began the genetic dissection of MSMD as a first step towards understanding childhood TB. We discovered that, although AR interleukin-12 receptor β1 (IL-12Rβ1) deficiency displayed incomplete clinical penetrance for MSMD, the deficiency could underlie severe TB in a small, non-negligible fraction of otherwise healthy children without MSMD. We recently discovered autosomal dominant (AD) IL-12Rβ2 deficiency in several patients with disseminated TB. As a result of the haploinsufficiency (i.e.,  the product of a single allele is insufficient to fulfill the biological function considered) of null IL12RB2 alleles, the patients' heterozygous T cells respond poorly to IL-12. AD IL-12Rβ2 deficiency is the first known genetic etiology of childhood TB not also implicated in MSMD. We have thus provided the first evidence that childhood TB may result from single-gene inborn errors of IFN-γ immunity.

Chronic Mucocutaneous Candidiasis (CMC)
CMC is characterized by epithelial lesions caused by Candida albicans in otherwise healthy patients. We identified AD interleukin-17F (IL-17F) and AR IL-17RA deficiencies as the two first known genetic etiologies of CMC. We then found that most CMC patients were heterozygous for gain-of-function mutations in the gene encoding the signal transducer and activator of transcription 1 (STAT1, activated in particular by IFNs), which impaired the development of IL-17 T cells. We had previously shown that loss-of-function alleles of STAT1 underlie mycobacterial and/or viral disease. STAT1 is the first known human gene for which allelic heterogeneity has been shown to govern such different and specific infections. Thus, CMC can result from inborn errors of IL-17, which, unlike IL-17 and Th17 cells in mice, is essential for mucocutaneous immunity against C. albicans, but otherwise largely redundant.

Invasive Pneumococcal Disease (IPD)
In our search for genetic etiologies of acute infections of childhood, we also discovered the first known genetic etiology of X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID): hypomorphic (i.e., deleterious but not completely loss-of-function) mutations in the NEMO gene, which encodes the NF-kappa-B essential modulator, that impair NF-κB activation. Affected children display developmental anomalies and contract various infectious diseases, including IPD caused by Streptococcus pneumoniae, a common commensal organism.  We then discovered hypermorphic (i.e., gain-of-function) mutations of the IκBα gene in patients with AD EDA-ID. We also discovered AR deficiencies in the genes encoding interleukin-1 receptor-associated kinase 4 (IRAK4) and myeloid differentiation primary response 88 (MYD88) in IPD patients who exhibited no developmental defects.  Human TLR- and IL-1R-dependent immunity is thus largely redundant in host defense.  We recently discovered the first known genetic etiology of isolated congenital asplenia, which also underlies IPD: mutations in RPSA (a ribosomal protein).

Herpes Simplex Virus Encephalitis (HSE)
Some children develop HSE during primary infection with herpes simplex virus 1 (HSV-1)—an almost ubiquitous and typically innocuous virus—despite exhibiting normal resistance to other infections. We first discovered patients with HSE who had an AR UNC-93B deficiency, which abolishes Toll-like receptor 3- (TLR3-) and TLR79-dependent IFN-α/β responses (the Toll-like receptors are expressed on a range of hematopoietic and non-hematopoietic cells). Although HSE does not occur in children with MyD88 and IRAK-4 deficiencies, we found that it does in children with AD and AR TLR3 deficiencies and AD and AR deficiencies in other proteins, such as TIR-domain-containing adapter-inducing interferon-β (encoded by the TRIF gene), TNF receptor-associated factor 3 (encoded by the TRAF3 gene), and TANK-binding kinase 1 (encoded by the TBK1 gene). Using induced pluripotent stem (iPS) cells, we recently showed that these patients' central nervous system (CNS) cells fail to control HSV-1. HSE therefore results from a collection of single-gene inborn errors of CNS-specific intrinsic immunity.

Kaposi Sarcoma (KS)
Children infected with HIV (epidemic KS) or undergoing immunosuppression (iatrogenic KS) may develop KS upon reactivation of oncogenic human herpes virus 8 (HHV-8) in endothelial cells. Much more rarely, otherwise healthy children from the Mediterranean basin (classical KS) or from Sub-Saharan Africa (endemic KS) infected with HHV-8 may develop KS. We discovered the first known genetic etiologies of classical KS of childhood, with mutations in STIM1, the gene encoding the calcium sensor stromal interaction molecule 1, and OX40, the gene encoding a tumor necrosis factor receptor expressed primarily on activated CD4+ and CD8+ T cells. These studies provided proof of principle that childhood KS may result from inborn errors of immunity and revealed that OX40-dependent T cell immunity is essential to control HHV-8 in endothelial cells.

Our discovery of such novel, surprising causal relationships have solved a long-standing enigma in this field. They provided proof of principle that life-threatening infectious diseases of childhood may result from monogenic inborn errors of immunity. These studies have important clinical implications, providing a rationale for the prevention and treatment of pediatric infectious diseases with recombinant cytokines, as exemplified by IFN-γ therapy for children with mycobacterial diseases; and there is now hope that children suffering from HSE can be treated with IFN-α. Our studies also have major immunological implications. The narrow range of childhood infections associated with single-gene inborn errors of immunity reflects the considerable, but not complete, redundancy of the corresponding human genes important for survival in the course of primary infection in natural, as opposed to experimental, conditions. Our results provide compelling evidence for a genetic theory of childhood infectious diseases and further highlight the clinical and immunological impact of a genetic dissection of childhood infectious diseases. We are currently deepening our investigations, by attempting to decipher the genetic, molecular, cellular, and immunological basis of mycobacterial diseases and herpes simplex encephalitis. We are also widening our research by investigating the application of our model to other chronic and acute infections.

Grants from the National Institutes of Health and the March of Dimes provided partial support for some of these projects.

As of February 16, 2014

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The Rockefeller University
Immunology, Medicine and Translational Research