IL-32 is a molecular marker of a host defense network in human tuberculosis

Abstract

Tuberculosis is a leading cause of infectious disease–related death worldwide; however, only 10% of people infected with Mycobacterium tuberculosis develop disease. Factors that contribute to protection could prove to be promising targets for M. tuberculosis therapies. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify potential human candidate markers of host defense by studying gene expression profiles of macrophages, cells that, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene coexpression network analysis revealed an association between the cytokine interleukin-32 (IL-32) and the vitamin D antimicrobial pathway in a network of interferon-γ– and IL-15–induced “defense response” genes. IL-32 induced the vitamin D–dependent antimicrobial peptides cathelicidin and DEFB4 and to generate antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. In addition, the IL-15–induced defense response macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent compared with active tuberculosis or healthy controls and a coexpression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15–induced gene network. As maintaining M. tuberculosis in a latent state and preventing transition to active disease may represent a form of host resistance, these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis.

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

“…WGCNA analysis identified 17 modules of coexpressed genes ( Figure 3, y axis). To determine which modules were associated with each disease subtype, we performed module eigengene correlation of the samples clustering within the main subtype branch by coding traits as a binary matrix of zeros and ones: each sample had a value of "1" for its corresponding subtype and a value of "0" for all other subtypes (30).…”

“…In order to identify genes and functional pathways associated with leprosy subtypes, we performed weighted gene correlation network analysis (WGCNA) on the filtered leprosy gene expression profiles (29,30). WGCNA is a clustering approach that identifies the typical pattern of each cluster (the eigengene).…”

Dendritic Cell–Derived IL-32α: A Novel Inhibitory Cytokine of NK Cell Function

“…Particularly, there have been limited studies on the roles of each specific isoform. One important study links IL-32 to IL-15-induced defense response against Mycobacterium tuberculosis in macrophages (30). Interestingly, we found that skin LCs and dermal CD1a dim CD141…”

“…IL-32g can trigger TNF-a and IL-6 production, the maturation of DCs (24), and the activation of NK cell cytotoxicity through cell death receptor 3 (44). Furthermore, IL-32g has been shown to be protective in tuberculosis (30,45,46). In contrast, little is known about the IL-32a isoform, except that it was indicated to have a regulatory function by inhibiting the production of TNF-a or IL-6 in PBMCs (25).…”

“…In contrast, little is known about the IL-32a isoform, except that it was indicated to have a regulatory function by inhibiting the production of TNF-a or IL-6 in PBMCs (25). Understanding the biology of the different IL-32 isoforms is important to understand why in some diseases, including cancer (47)(48)(49), HIV (50), tuberculosis (30), and leprosy (24,51), IL-32 presence in patients was associated with either a positive or a negative outcome. In this work, we focus on the biology of the a isoform of IL-32, which we found to be expressed in two skin DC subsets.…”