Lethal Infectious Diseases as Inborn Errors of Immunity: Toward a Synthesis of the Germ and Genetic Theories

Abstract

It was first demonstrated in the late nineteenth century that human deaths from fever were typically due to infections. As the germ theory gained ground, it replaced the old, unproven theory that deaths from fever reflected a weak personal or even familial constitution. A new enigma emerged at the turn of the twentieth century, when it became apparent that only a small proportion of infected individuals die from primary infections with almost any given microbe. Classical genetics studies gradually revealed that severe infectious diseases could be driven by human genetic predisposition. This idea gained ground with the support of molecular genetics, in three successive, overlapping steps. First, many rare inborn errors of immunity were shown, from 1985 onward, to underlie multiple, recurrent infections with Mendelian inheritance. Second, a handful of rare and familial infections, also segregating as Mendelian traits but striking humans resistant to other infections, were deciphered molecularly beginning in 1996. Third, from 2007 onward, a growing number of rare or common sporadicinfections were shown to result from monogenic, but not Mendelian, inborn errors. A synthesis of the hitherto mutually exclusive germ and genetic theories is now in view.

Keywords: Mendelian infection; human genetics of infectious diseases; inborn error of immunity; monogenic infection; primary immunodeficiency.

Figure 1.

Pedigrees for primary immunodeficiencies for the three modes of inheritance: Autosomal recessive (AR), with the example of severe combined immunodeficiency (SCID) due to RAG1 deficiency; X-linked recessive (XR), with the example of agammaglobulinemia due to BTK deficiency; Autosomal dominant (AD), with the example of severe congenital neutropenia due to ELANE deficiency. Primary immunodeficiencies (PIDs) are typically characterized by multiple infections, overt immunological abnormalities and a high penetrance (see Table 1).

Figure 2.

Pedigrees for Mendelian infections, for the three modes of inheritance: Autosomal recessive (AR), with the example of epidermodysplasia verruciformis (EV) following β-Human papilloma virus (HPV) infection due to CIB1 deficiency; X-linked recessive (XR), with the example of X-lymphoproliferative disease (XLP) following Epstein-Barr virus (EBV) infection due to SAP deficiency; Autosomal dominant (AD), with the example of Mendelian susceptibility to mycobacterial diseases (MSMD) following BCG infection due to IFN-γR1 deficiency. Mendelian infections are typically characterized by severe, “idiopathic” infection with a single, rare pathogen, the absence of classic immunological abnormalities, and a high penetrance (see Table 1).

Figure 3.

Pedigrees for monogenic infections, for the three modes of inheritance: Autosomal recessive (AR), with the example of severe influenza pneumonitis due to IRF7 deficiency; X-linked recessive (XR), with the example of invasive pneumococcal infection due to NEMO deficiency; Autosomal dominant (AD), with the example of herpes simplex virus-1 (HSV-1) encephalitis due to TLR3 deficiency. Monogenic infections are characterized by severe, unexplained infection with a single, common pathogen, the absence of classic immunological abnormalities, and a low penetrance. Vertical bars indicate healthy carriers of the deleterious genotype (see Table 1).