UCLA

The host immune system is required for protection against disease caused by intracellular pathogens, such as mycobacteria. Activated host cells induce a variety of defense mechanisms that coordinate in order to eliminate mycobacteria. Stimulation of toll-like receptors (TLRs) as part of the innate immune system, and T-cell release of IFN-γ as part of the adaptive immune response are both associated with protection against mycobacterial disease progression. However, the various host defense pathways mediated by these two signals in human macrophages still need to be defined. Ligation of TLR2/1 with mycobacteria derived lipoproteins has been shown to trigger anti-mycobacterial activity, with the induction of antimicrobial peptides via a vitamin D-dependent pathway. Here, IFN-γ activation of human macrophages was shown to also induce killing of mycobacteria via a vitamin D-dependent antimicrobial pathway. In addition, IL-32, an IFN-γ inducible protein, was shown to mediate antimicrobial activity against mycobacteria by also inducing the vitamin D pathway.

Since activation via TLR2/1 and IFN-γ converge on at least one common antimicrobial pathway, we further studied the TLR2/1 and IFN-γ inducible gene network by RNA sequencing. Bioinformatics analysis identified “defense response” as a common TLR2/1 and IFN-γ gene ontology term. A subset of genes with previously reported direct or indirect antimicrobial activity was also identified in the common dataset. The role of S100A12, a TLR2/1 and IFN-γ common gene, was further investigated in the context of leprosy, a disease caused by Mycobacterium leprae, in which the clinical manifestations correlate with immune response. S100A12 was more highly expressed in tuberculoid leprosy (T-lep), which is associated with resistance to infection, compared to lepromatous leprosy (L-lep), which is associated with susceptibility to infection. S100A12 was sufficient to kill mycobacteria and was required for the TLR2/1 and IFN-γ inducible antimicrobial activity against M. leprae in human macrophages. Our data further define mechanisms for TLR2/1 and IFN-γ mediated antimicrobial response against mycobacteria.