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.

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

“…In recent years, it has emerged that inborn errors in genes encoding proteins of innate or cell-intrinsic immunity can underlie specific infections in otherwise healthy individuals (15,16). In this work we describe 4 patients with severe VZV infections who carried missense mutations in POLR3A and/or POLR3C, which encode subunits of the innate DNA sensor POL III.…”

“…In recent years, it has emerged that single-gene inborn errors of innate or cell-intrinsic immunity can underlie enhanced susceptibility to specific (viral) infections in otherwise healthy individuals (15,16). A striking example is that mutations in genes controlling Toll-like receptor (TLR) 3-dependent type I and III IFN-mediated immunity confer susceptibility to herpes simplex encephalitis (HSE) (17)(18)(19)(20)(21)(22).…”

Effects of allelic variations in the human myxovirus resistance protein A on its antiviral activity

“…Host genetics plays an important role in inter-individual variability in the course of viral infection (37)(38)(39). The aim of the present study was to investigate potential effects of naturally occurring allelic variations in MX1 on the function of the broadly acting antiviral factor MxA, that plays a key role in FLUAV restriction (26).…”

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

“…Patients with autosomal dominant (AD) hyper-IgE syndrome (HIES), caused by heterozygous dominant negative mutations of STAT3, display fewer infections, and patients with autosomal recessive (AR) autoimmune polyendocrine syndrome type 1 (APS-1) are not prone to other infections (2, 3). Finally, rare patients with inherited but idiopathic forms of CMC, referred to as CMC disease (CMCD), have been described since the late 1960s (4)(5)(6)(7)(8). These patients may display isolated CMC, but they often also display cutaneous staphylococcal disease (nonetheless referred to as CMCD) or other infectious and/or autoimmune clinical manifestations (syndromic CMCD).…”