Toward a monogenic architecture of human infections: From 1996 to 2026

The provocative idea that a process as apparently complex as a lethal infection can be due to a cause as simple as a rare or common germline single-gene lesion has been documented over the last 30 years for a growing number of infections, and such variants have been diagnosed in an even larger number of patients. A monogenic lesion can predispose a healthy person, who has fended off other microbes, to death following infection with a specific microbe that has proved harmless in most other infected individuals. Remarkably, studies of monogenic infections led to the discovery that autoimmunity targeting the same component of host defense, sometimes due to another type of single-gene mutation, can also underlie the same infection. Both types of single-gene lesions are highly pleiotropic, depending on microbial challenges, and incompletely penetrant, depending on age. I discuss here the roots and implications of a monogenic architecture of life-threatening human infectious diseases, in terms of both basic biology and public health.