Human genetics of infectious diseases

Abstract

A lingering question in the field of infectious diseases is that of the considerable clinical variability between individuals in the course of infection, raising fundamental questions about the actual pathogenesis of infectious diseases. There is increasing epidemiological and experimental evidence to suggest that human genetics plays a major role in susceptibility/resistance to infectious diseases. There seems to be a continuous spectrum of human predisposition to infectious diseases, from monogenic to polygenic inheritance. Many monogenic primary immunodeficiencies have been clinically described and genetically deciphered, and most predispose affected individuals to multiple infections. Other monogenic traits conferring patho-gen-specific susceptibility in otherwise healthy individuals are increasingly being described. Examples of Mendelian specific resistance to infectious agents are also being discovered. At the population level, major genes are being identified in a small, but growing number of common infectious diseases. Truly polygenic predisposition to a human infectious disease remains to be definitively demonstrated experimentally, despite the unquestionable identification of individual (but not necessarily interacting) susceptibility genes. Studies of the human genetics of infectious diseases have considerable clinical implications, as improvements in our understanding of the pathogenesis of infectious disease pave the way to both genetic diagnosis and immu-nological interventions. The genetic investigation of infectious diseases, seen as 'experiments of Nature', also provides a unique approach to definition of the function of host defense genes in natura - i.e. in the setting of a natural, as opposed to experimental, ecosystem governed by natural selection.