Type I Interferon Suppresses Type II Interferon–Triggered Human Anti-Mycobacterial Responses

Abstract

Type I interferons (IFN-α and IFN-β) are important for protection against many viral infections, whereas type II interferon (IFN-γ) is essential for host defense against some bacterial and parasitic pathogens. Study of IFN responses in human leprosy revealed an inverse correlation between IFN-β and IFN-γ gene expression programs. IFN-γ and its downstream vitamin D–dependent antimicrobial genes were preferentially expressed in self-healing tuberculoid lesions and mediated antimicrobial activity against the pathogen Mycobacterium leprae in vitro. In contrast, IFN-β and its downstream genes, including interleukin-10 (IL-10), were induced in monocytes by M. leprae in vitro and preferentially expressed in disseminated and progressive lepromatous lesions. The IFN-γ–induced macrophage vitamin D–dependent antimicrobial peptide response was inhibited by IFN-β and by IL-10, suggesting that the differential production of IFNs contributes to protection versus pathogenesis in some human bacterial infections.

Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy

“…The T-lep and RR forms of the disease clustered together, which prevented separation of the two forms by clustering, in line with previous results (16). Although the gene expression profiles of these subforms of leprosy overlapped, the RR samples showed a greater heterogeneity, as indicated by the size of the ellipsoid that represents the 95% confidence interval.…”

“…MMP-12 contributes to cell migration (33) of DC and leukocytes (31,34). The ability of MMP-12 to cleave off IFN-α receptor 2-binding sites (35) blocks the action of type I IFN, which in previous work we showed blocks antimicrobial responses in leprosy (16). The presence of MMP-12 in T-lep and RR granulomas, as well as other granulomatous diseases such as sarcoidosis (36), suggests that MMP-12 is part of a tissue remodeling and inflammation gene network that contributes to granuloma formation and/or maintenance.…”

“…ENL, erythema nodosum leprosum; L-lep, lepromatous leprosy; RR, reversal reaction; T-lep, tuberculoid leprosy. using frozen robust multiarray average (fRMA), as previously described (16).…”

Importance of the immune response to Mycobacterium leprae in the skin

“…The most recent studies have included interferon (Teles et al 2013), vitamin D-dependent antimicrobial pathways (Liu et al 2012), NOD2-mediated signalling (Netea et al 2010) and the role of T regulatory cells, Th-17/IL17a/IL-17F cytokines, CD163 and galectin-3 (Polycarpou et al 2013). A deeper understanding of the M. leprae genome will provide insight into the mechanism by which this organism avoids immune surveillance.…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…Interestingly, this historical view was revised recently by placing type I IFN as a central regulator determining the outcome of M. leprae infection. Lepromatous leprosy is associated with the development of an IFN-b-inducible gene signature in the blood (94). Importantly, type I IFNs are shown to increase bacterial burden and tissue pathology by limiting IFN-g-dependent antimicrobial activity through production of the immunosuppressive cytokine IL-10 (94).…”