Transcriptional Profiling of Human Peripheral Blood Mononuclear Cells Stimulated by Mycobacterium tuberculosis PPE57 Identifies Characteristic Genes Associated With Type I Interferon Signaling

Abstract

Proline-glutamic acid (PE)- and proline-proline-glutamic acid (PPE)-containing proteins are exclusive to Mycobacterium tuberculosis (MTB), the leading cause of tuberculosis (TB). In this study, we performed global transcriptome sequencing (RNA-Seq) on PPE57-stimulated peripheral blood mononuclear cells (PBMCs) and control samples to quantitatively measure the expression level of key transcripts of interest. A total of 1367 differentially expressed genes (DEGs) were observed in response to a 6 h exposure to PPE57, with 685 being up-regulated and 682 down-regulated. Immune-related gene functions and pathways associated with these genes were evaluated, revealing that the type I IFN signaling pathway was the most significantly enriched pathway in our RNA-seq dataset, with 14 DEGs identified therein including ISG15, MX2, IRF9, IFIT3, IFIT2, OAS3, IFIT1, IFI6, OAS2, OASL, RSAD2, OAS1, IRF7, and MX1. These PPE57-related transcriptomic profiles have implications for a better understanding of host global immune mechanisms underlying MTB infection outcomes. However, more studies regarding these DEGs and type I IFN signaling in this infectious context are necessary to more fully clarify the underlying mechanisms that arise in response to PPE57 during MTB infection.

Gene signature discovery and systematic validation across diverse clinical cohorts for TB prognosis and response to treatment

“…The connections between genes may indicate physical interaction between some of the encoded proteins, or that the proteins jointly contribute to a shared function [ 39 ]. Proteins IFIT2 and IFIT3 centered in the network are IFN-α/β induced proteins and highly expressed during cell-intrinsic immune response to Mtb infection [ 40 ]. Further, we observed that STAT1 forms associations with many proteins in the network ( n = 17); STAT1 is known to be an immunoregulatory factor that regulates both IFN-α/β and IFN-γ -mediated responses [ 7 , 41 , 42 ].…”

Construction of Immune-Related Diagnostic Model for Latent Tuberculosis Infection and Active Tuberculosis

“… 32 In addition, overexpression of MX1 was identified in human peripheral blood mononuclear cells stimulated with M. tb PPE57. 33 IFIH1 is a novel regulator for promoting M1 macrophage polarization. 34 STAT1 is a member of the STAT protein family and a key component that mediates interferon signaling.…”

“… 45 Similar to MX1, overexpressed IRF7 was also detected in human peripheral blood mononuclear cells stimulated by M. tb PPE57. 33 …”

In-depth systems biological evaluation of bovine alveolar macrophages suggests novel insights into molecular mechanisms underlying Mycobacterium bovis infection

“…In addition to the pink module, we identified several critical functional terms related to inflammation and immune response, such as “NF-kappa B signaling pathway,” “TNF signaling pathway,” and “B cell receptor signaling pathway” in the tan module, as well as terms such as “cytokine-mediated signaling pathway (GO:0019221),” “negative regulation of programmed cell death (GO:0043069),” “toll-like receptor 2 signaling pathway (GO:0034134),” and “negative regulation of epithelial cell apoptotic process (GO:1904036)” in the salmon module. Moreover, several hub-central genes/TFs of the tan module such as CD40 ( Khan et al, 2016 ), CD274 ( Petrilli et al, 2020 ), CTNNB1 ( Subuddhi et al, 2020 ), IKBKE ( Killick et al, 2014 ), IL23R ( Jiang et al, 2015 ), MAPK7 ( María Irene et al, 2021 ), TRAF2 ( Killick et al, 2014 ), NFKB1 ( Meade et al, 2007 ), NFKB2 ( Magee et al, 2012 ), and STAT6 ( Cronan et al, 2021 ), as well as hub-central genes of the salmon module, such as CASP4 ( Malone et al, 2018 ), DHX58 ( Nalpas et al, 2015 ), IL10 ( Wang et al, 2011 ), MX1 , MX2 , IFIT2 ( Yi et al, 2021 ), RIPK2 ( Widdison et al, 2011 ), TRAF1 ( Li H. et al, 2017 ), and USP18 ( Carranza et al, 2020 ), have been reported to be involved in the host immunity and M. bovis pathogenesis. The NFKB1 hub-central TF is a major mediator of the proinflammatory immune response that stimulates the transcription of proinflammatory cytokines and chemokines and has shown a significant reduction in the response to M. bovis infection ( Meade et al, 2007 ).…”