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Inherited and acquired immunodeficiencies underlying tuberculosis in childhood
Stéphanie Boisson-Dupuis1, Jacinta Bustamante, Jamila El-Baghdadi
1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, INSERM-U1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France.
Abstract:
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN-γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey.
Insights
Tuberculosis (TB) pathogenesis is complex, with few infected individuals developing disease. Understanding genetic predispositions, especially in children, is crucial for developing new TB treatments.
Area of Science:
- Immunology
- Genetics
- Infectious Diseases
Background:
- Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a major global health threat, yet its pathogenesis remains poorly understood.
- Clinical TB disease develops in only a fraction of infected individuals, with childhood TB often presenting differently and linked to immunodeficiencies.
- Studying infections with less virulent mycobacteria has illuminated genetic factors in TB.
Purpose of the Study:
- To review conditions predisposing individuals, particularly children, to mycobacterial infections, including TB.
- To explore insights gained from studying rare mycobacterial infections and their underlying immunodeficiencies.
- To highlight the role of host genetics in TB susceptibility.
Main Methods:
- Literature review of conditions associated with mycobacterial infections.
- Analysis of genetic and immunological studies on TB and related infections.
- Examination of findings from inborn errors of immunity, such as IFN-γ pathway defects.
Main Results:
- Single-gene defects in interferon-gamma (IFN-γ) immunity explain severe childhood TB cases.
- Acquired and inherited immunodeficiencies are key factors in susceptibility to mycobacterial diseases.
- Weakly virulent mycobacteria infections offer insights into TB pathogenesis.
Conclusions:
- Host genetic factors play a significant role in determining TB susceptibility and disease severity in children.
- Further human genetic studies in high-incidence regions are expected to yield novel findings on TB predisposition.
- Understanding immunodeficiencies is critical for managing and preventing childhood TB.
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