Control of human host immunity to mycobacteria

Infection with Mycobacterium tuberculosis results in disease in 5–10% of exposed individuals, whereas the remainder controls infection effectively. Similar inter-individual differences in disease susceptibility are characteristic features of leprosy, typhoid fever, leishmaniasis and other chronic in...

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Published in:	Tuberculosis (Edinburgh, Scotland) Scotland), 2005-01, Vol.85 (1), p.53-64
Main Authors:	Ottenhoff, Tom H.M., Verreck, Frank A.W., Hoeve, Marieke A., Vosse, Esther van de
Format:	Article
Language:	eng
Subjects:	Adjuvants, Immunologic - genetics Cytokines - genetics Cytokines - immunology Genetic Predisposition to Disease - genetics Genetic susceptibility Humans IFN- γ (receptor) IL-12 (receptor) IL-23 (receptor) Immunity, Cellular - genetics Immunity, Cellular - immunology Interferon-gamma - genetics Interferon-gamma - immunology Interleukin-12 - genetics Interleukin-12 - immunology Interleukin-23 Interleukin-23 Subunit p19 Interleukins - genetics Interleukins - immunology Mycobacterium Infections - genetics Mycobacterium Infections - immunology Receptors, Interferon - genetics Receptors, Interferon - immunology Receptors, Interleukin - genetics Receptors, Interleukin - immunology Salmonella Infections - genetics Salmonella Infections - immunology Signal Transduction - genetics Signal Transduction - immunology Tuberculosis Tuberculosis - genetics Tuberculosis - immunology
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Summary:	Infection with Mycobacterium tuberculosis results in disease in 5–10% of exposed individuals, whereas the remainder controls infection effectively. Similar inter-individual differences in disease susceptibility are characteristic features of leprosy, typhoid fever, leishmaniasis and other chronic infectious diseases, including viral infections. Although the outcome of infection is influenced by many factors, it is clear that genetic host factors play an important role in controlling disease susceptibility to intracellular pathogens. Knowledge of the genes involved and their downstream cellular pathways will provide new insights for the design of improved and rationalized strategies to enhance host-resistance, e.g. by vaccination. In addition, this knowledge will aid in identifying better biomarkers of protection and disease, which are essential tools for the monitoring of vaccination and other intervention trials. The recent identification of patients with deleterious mutations in genes that encode major proteins in the type-1 cytokine (IL-12/IL23-IFN- γ) axis, that suffered from severe infections due to otherwise poorly pathogenic mycobacteria (non-tuberculous mycobacteria (NTM) or M. bovis Bacille Calmette-Guérin (BCG)) or Salmonella species has revealed the major role of this system in innate and adaptive immunity to mycobacteria and salmonellae. Clinical tuberculosis has now been described in a number of patients with IL-12/IL23-IFN- γ system defects. Moreover, unusual mycobacterial infections were reported in several patients with genetic defects in NEMO, a key regulatory molecule in the NFκB pathway. These new findings will be discussed since they provide further insights into the role of type-1 cytokines in immunity to mycobacteria, including M. tuberculosis.
ISSN:	1472-9792 1873-281X