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Toward a monogenic architecture of human infections: From 1996 to 2026
Jean-Laurent Casanova1,2,3,4,5
1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, NY, USA.
Abstract:
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.
Insights
Life-threatening infections can stem from simple single-gene defects, making individuals susceptible to specific microbes. These genetic variations also reveal links to autoimmunity, impacting host defense mechanisms.
Area of Science:
- Genetics and immunology
- Infectious disease research
- Human health and disease
Background:
- Over 30 years, research has increasingly identified single-gene lesions as causes of lethal infections.
- Monogenic predispositions can render individuals vulnerable to microbes harmless to the general population.
Purpose of the Study:
- To explore the concept of a monogenic architecture underlying life-threatening infectious diseases.
- To discuss the biological and public health implications of these genetic underpinnings.
Main Methods:
- Review of documented cases of single-gene lesions predisposing to infections.
- Analysis of the interplay between monogenic susceptibility and autoimmunity in infectious diseases.
Main Results:
- Single-gene mutations can cause severe susceptibility to specific pathogens in otherwise healthy individuals.
- The same host defense components targeted by monogenic susceptibility can also be targets of autoimmunity, linked to different mutations.
- These genetic lesions exhibit pleiotropy and incomplete penetrance, influenced by microbial challenges and age.
Conclusions:
- A monogenic architecture significantly contributes to life-threatening infectious diseases.
- Understanding these genetic bases is crucial for both basic biology and public health strategies.
- Further research into these genetic variants can illuminate host-pathogen interactions and autoimmune disease mechanisms.
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