Human genetic basis of interindividual variability in the course of infection

Abstract

The key problem in human infectious diseases was posed at the turn of the 20th century: their pathogenesis. For almost any given virus, bacterium, fungus, or parasite, life-threatening clinical disease develops in only a small minority of infected individuals. Solving this infection enigma is important clinically, for diagnosis, prognosis, prevention, and treatment. Some microbes will inevitably remain refractory to, or escape vaccination, or chemotherapy, or both. The solution also is important biologically, because the emergence and evolution of eukaryotes alongside more rapidly evolving prokaryotes, archaea, and viruses posed immunological challenges of an ecological and evolutionary nature. We need to study these challenges in natural, as opposed to experimental, conditions, and also at the molecular and cellular levels. According to the human genetic theory of infectious diseases, inborn variants underlie life-threatening infectious diseases. Here I review the history of the field of human genetics of infectious diseases from the turn of the 19th century to the second half of the 20th century. This paper thus sets the scene, providing the background information required to understand and appreciate the more recently described monogenic forms of resistance or predisposition to specific infections discussed in a second paper in this issue.

Keywords: human genetics; immunology; infectious diseases; pediatrics; primary immunodeficiency.

Fig. 1.

Human mortality curves. Mortality curves at various periods of human history, from the Paleolithic period (<10,000 BC) to modern times (2000 AD). Contemporary data for the United Kingdom and Mozambique are available from the WHO site (www.who.int/topics/global_burden_of_disease). Older data were obtained from ref. . Life tables for the Paleolithic and Neolithic periods are based on examinations of skeletons, assuming that 60% of newborn infants survived to the age of 5 y, because few very young skeletons were found in the burial grounds. For most of human prehistory and history worldwide (i.e., until the end of the 19th century), as many as half of all children died before the age of 15 y, and life expectancy at birth averaged only 20–25 y. Fever was by far the greatest killer. The gradual adjustment of the immune system by natural selection did not increase life expectancy because of the coevolution of microorganisms and the emergence of new infectious threats. Thus, the increase in life expectancy in the 20th century does not reflect the sudden and global natural selection of high-quality immune genes. It reflects the conquests that accompanied the germ theory of disease: hygiene, aseptic surgery, vaccines, and the development of drugs to treat infection. The area between the four ancient curves and the curve for the United Kingdom in 2000 corresponds to ∼65% of the individuals currently alive. Most of these individuals have retained immunodeficiencies against one or more infectious agents that are masked by medical progress. Reproduced from ref. .

Fig. 2.

The genetic component of human infectious diseases, according to age. Schematic representation of a hypothetical, age-dependent, human genetic architecture of infectious diseases. We suggest that single-gene human variants make an important contribution to the determinism of life-threatening infectious diseases in the course of primary infection, which occurs most often in childhood. In this model, single-gene inborn errors of immunity are more often monogenic than Mendelian, with incomplete penetrance and variable expressivity accounting for infectious diseases being sporadic more often than familial. By contrast, predisposition to severe infectious diseases in the course of microbial reactivation from latency or secondary infection, typically in adults, is less influenced by germline human genetic variations, resulting in a more complex and less monogenic component. Somatic and epigenetic processes are likely to play a greater role in older individuals. Reproduced from ref. .