Human genetics of infectious diseases: between proof of principle and paradigm

Abstract

The observation that only a 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. As we discuss here, human predisposition to infectious diseases seems to cover a continuous spectrum from monogenic to polygenic inheritance. 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. However, in the future, studies in human genetics are likely to establish a new paradigm for infectious diseases.

Figure 1. The pedigrees of Pasteur and Darwin and the genetic theory of infectious diseases.

(A) Louis Pasteur, the founder of the microbial theory of disease, lost three young daughters to “fever” between 1859 and 1866. A few years later, in 1870, he discovered that microbes caused disease in silkworms (95), paving the way for a general microbial theory of disease. Retrospectively, it is clear that his daughters died of infectious diseases. (B) Charles Darwin, the founder of the theory of natural selection, also lost three children to infectious diseases. Charles and Emma Darwin were first cousins. These two illustrious families are representative of most families worldwide and throughout history, until recent improvements in hygiene and the advent of vaccines and antibiotics, which resulted from the microbial theory. Prior to these medical advances, it was not uncommon for at least half the siblings in a family to die of infection. The microbial theory of disease identified the microbial cause of disease but did not resolve the question of intrafamilial clinical heterogeneity in families exposed to the same microbial environment. As illustrated in the pedigrees of Pasteur and Darwin, some children survived until adulthood, despite probable exposure to at least one of the microbes that killed their other siblings. It is possible that the children who died carried a Mendelian trait predisposing them to infectious diseases, or at least had some form of genetic predisposition to such diseases.

Figure 2. Schematic representation of the continuous genetic models underlying human infectious diseases.

The spectrum of genetic susceptibilities predisposing individuals to infectious diseases is summarized. Different situations may be distinguished according to the number of genes with an additive impact on genetic susceptibility (in green) or resistance (in red), the marginal effect of each of these genes, and the number of pathogens to which the individual is susceptible. Six textbook examples are shown: SCID-associated infections (a unique gene with complete penetrance conferring predisposition to a large spectrum of infectious agents); HSE (a single gene with high penetrance conferring predisposition to a single infectious agent); malaria caused by P. vivax (a single gene with high penetrance conferring resistance to a single infectious agent); severe malaria caused by P. falciparum (a small number of genes with HbS conferring resistance to the disease); leprosy (a small number of genes with intermediate penetrance conferring predisposition to a single infectious agent); diseases in which HLA alleles have been shown to play a role (HLA-associated infections). Examples of common infectious diseases favored by multiple predisposing alleles in a given individual (truly multigenic inheritance) may be revealed by future GWA studies.