Two kindred with x-linked recessive tuberculous mycobacterial disease: towards a genetic theory of infectious diseases

Abstract

The observation that only a small fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. Although many studies have provided proof-of-principle that infectious diseases may result from various types of inborn errors of immunity, the genetic determinism of most infectious diseases in most patients remains unclear. It is commonly thought that rare patients with multiple infections display Mendelian primary immunodeficiencies, whereas common infections in otherwise healthy patients reflect polygenic predisposition. However, patients cannot be ascribed to such discrete binary categories (rare v. common, multi-infected v. otherwise healthy), and we have previously documented various Mendelian traits predisposing to a single type of infection. For human genetics to establish a new paradigm, the genetic architecture of infectious diseases should be deciphered. Our laboratory tests the hypothesis that life-threatening diseases of childhood, typically in the course of primary infection, each result from a collection of highly diverse but immuno-logically related single-gene variations; whereas the corresponding infections in adults, typically caused by secondary infection or reactivation of latent infection, reflect a more complex predisposition.The genetictheory of infectiousdiseases hasimportant clinical implications, paving the way to novel treatment, aimed at restoring the patients’ immunity to specific pathogens. The immunological implications are equally important, as studies of experiments of nature define the function of host defence genes in natura, i.e., in the setting of a natural ecosystem governed by natural selection. We will illustrate our endeavors in the field of human genetics of infectious diseases by relating the clinical investigation of patients from two unrelated kindreds with X-linked recessive susceptibility to tuberculous mycobacterial diseases. The observation that only a small fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. Although many studies have provided proof-of-principle that infectious diseases may result from various types of inborn errors of immunity, the genetic determinism of most infectious diseases in most patients remains unclear. It is commonly thought that rare patients with multiple infections display Mendelian primary immunodeficiencies, whereas common infections in otherwise healthy patients reflect polygenic predisposition. However, patients cannot be ascribed to such discrete binary categories (rare v. common, multi-infected v. otherwise healthy), and we have previously documented various Mendelian traits predisposing to a single type of infection. For human genetics to establish a new paradigm, the genetic architecture of infectious diseases should be deciphered. Our laboratory tests the hypothesis that life-threatening diseases of childhood, typically in the course of primary infection, each result from a collection of highly diverse but immuno-logically related single-gene variations; whereas the corresponding infections in adults, typically caused by secondary infection or reactivation of latent infection, reflect a more complex predisposition.The genetictheory of infectiousdiseases hasimportant clinical implications, paving the way to novel treatment, aimed at restoring the patients’ immunity to specific pathogens. The immunological implications are equally important, as studies of experiments of nature define the function of host defence genes in natura, i.e., in the setting of a natural ecosystem governed by natural selection. We will illustrate our endeavors in the field of human genetics of infectious diseases by relating the clinical investigation of patients from two unrelated kindreds with X-linked recessive susceptibility to tuberculous mycobacterial diseases.