Molecular immunity to mycobacteria: knowledge from the mutation and phenotype spectrum analysis of Mendelian susceptibility to mycobacterial diseases

Abstract

Understanding molecular immunity against mycobacterial infection is critical for the development of effective strategies to control tuberculosis (TB), which is a major health issue in the developing world. Host immunogenetic studies represent an indispensable approach to understand the molecular mechanisms against mycobacterial infection. A superb paradigm is the identification of rare mutations causing Mendelian susceptibility to mycobacterial diseases (MSMD). Mutations in the interferon-gamma (IFN-γ) receptor genes are highly specific (although not exclusive) for mycobacterial infection. Only dominant negative mutations of STAT1 have specific susceptibility to mycobacterial infection. Mutations in the interleukin-12 (IL-12) signaling genes have phenotypes with non-specificity. Current studies highlight a complex molecular network in antimycobacterial immunity, centered on IFN-γ signaling.

Figure 1

The proteins involved in interferon-gamma (IFN-γ) signaling. Without the binding of IFN-γ, the IFN-γ receptor subunits are not associated with each other. IFNγR1 binds with JAK-1, and IFNγR2 binds with JAK-2. STAT1 exists in the cytoplasm as a homodimer through the interaction of N-terminal domains.

Figure 2

The critical components involved in interleukin-12 (IL-12) signaling. IL12R.β1 is associated with TYK-2, and IL12Rβ2 is associated with JAK-2. STAT4 exists in the cytoplasm as a homodimer through the interaction of the N-terminal domains. The active form of STAT4 is a tetramer.

Figure 3

Nuclear factor kappa B essential modulator (NEMO) and NF-κB activation. NEMO is a critical regulatory component of IκB kinase (IKK), which receives cell surface signals and activates the IKK catalytic subunits Ikk-1 and Ikk-2. Activated IKK phosphorylates IκB, and induces the degradation of IκB. Released by the inhibitory IκB, active NF-κB dimer translocates to the nucleus and regulates the transcription of target genes.

Figure 4

Molecular mechanisms of immunity to mycobacteria revealed by immunogenetic studies.