Modern Clinical Mycobacterium tuberculosis Strains Leverage Type I IFN Pathway for a Pro-Inflammatory Response in the Host

2019 ◽  
Author(s):  
Deepthi Shankaran ◽  
Prabhakar Arumugam ◽  
Ankur Bothra ◽  
Sheetal Gandotra ◽  
Vivek Rao
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Inflammatory Response ◽  
Type I ◽  
Type I Ifn

scholarly journals TRIM14 Is a Key Regulator of the Type I IFN Response during Mycobacterium tuberculosis Infection

2020 ◽  
Vol 205 (1) ◽  
pp. 153-167 ◽  
Author(s):  
Caitlyn T. Hoffpauir ◽  
Samantha L. Bell ◽  
Kelsi O. West ◽  
Tao Jing ◽  
Allison R. Wagner ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Tuberculosis Infection ◽  
Type I ◽  
Type I Ifn ◽  
Mycobacterium Tuberculosis Infection

scholarly journals Modern clinical Mycobacterium tuberculosis strains leverage type I IFN pathway for a pro-inflammatory response in the host

2019 ◽  
Author(s):  
Deepthi Shankaran ◽  
Prabhakar Arumugam ◽  
Ankur Bothra ◽  
Sheetal Gandotra ◽  
Vivek Rao
Keyword(s):  
Inflammatory Response ◽  
Defense Mechanisms ◽  
Cholesterol Metabolism ◽  
Intervention Strategy ◽  
Cell Physiology ◽  
Type I ◽  
Type I Ifn ◽  
Innate Defense ◽  
Proinflammatory Responses ◽  
Regulatory Loop

ABSTRACTHost phagocytes respond to infections by innate defense mechanisms through metabolic shuffling in order to restrict the invading pathogen. However, this very plasticity of the host provides an ideal platform for pathogen mediated manipulation. By employing the macrophage model of Mtb infection, we identify an important strategy employed by modern clinical lineages in regulating the host immune–metabolism axis. The potent ability of these strains to specifically elicit a strong and early macrophage type I IFN response (in contrast to the protracted response to ancient Mtb), was dependent on an increased ability to localize in acidified phagosomes; this higher transit via acidified compartments is important for stimulation of the DNA dependent signaling in infected macrophages. The augmented IFN signaling provided a positive regulatory loop for enhanced expression of the cellular oxysterol-CH25H which in turn facilitated higher levels of IL6 in macrophages infected with the modern Mtb strains. Requirement of type I IFN signaling in mycobacterial intracellular growth highlights another unique ability of Mtb to manipulate host cell physiology and proinflammatory responses.Significance StatementCo-evolution with humans has enabled the development of novel adaptive mechanisms for survival in host specific environments in the human TB pathogen-Mtb. We present one such mechanism of modern Mtb strains harnessing the type I IFN immune axis to regulate the host pro-inflammatory response. Our results highlight the use of host intracellular endosomal transit as a mechanism by these strains to ensure a strong type I IFN response in macrophages. We also demonstrate the ability of Mtb to regulate macrophage cholesterol metabolism in order to fine tune the host innate responses. These findings lay the foundation of the future development of a host axis directed intervention strategy against this pathogen.

scholarly journals IFN-β signalling regulates RAW 264.7 macrophage activation, cytokine production, and killing activity

2019 ◽  
Vol 26 (3) ◽  
pp. 172-182
Author(s):  
Yalda Karimi ◽  
Elizabeth C Giles ◽  
Fatemeh Vahedi ◽  
Marianne V Chew ◽  
Tina Nham ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Critical Role ◽  
Raw 264.7 ◽  
Type I ◽  
Type I Ifn ◽  
Killing Activity ◽  
Raw 264.7 Macrophage

Type I IFN holds a critical role in host defence, providing protection against pathogenic organisms through coordinating a pro-inflammatory response. Type I IFN provides additional protection through mitigating this inflammatory response, preventing immunopathology. Within the context of viral infections, type I IFN signalling commonly results in successful viral clearance. Conversely, during bacterial infections, the role of type I IFN is less predictable, leading to either detrimental or beneficial outcomes. The factors responsible for the variability in the role of type I IFN remain unclear. Here, we aimed to elucidate differences in the effect of type I IFN signalling on macrophage functioning in the context of TLR activation. Using RAW 264.7 macrophages, we observed the influence of type I IFN to be dependent on the type of TLR ligand, length of TLR exposure and the timing of IFN-β signalling. However, in all conditions, IFN-β increased the production of the anti-inflammatory cytokine IL-10. Examination of RAW 264.7 macrophage function showed type I IFN to induce an activated phenotype by up-regulating MHC II expression and enhancing killing activity. Our results support a context-dependent role for type I IFN in regulating RAW 264.7 macrophage activity.

scholarly journals Type I interferon signaling mediates Mycobacterium tuberculosis–induced macrophage death

2020 ◽  
Vol 218 (2) ◽  
Author(s):  
Li Zhang ◽  
Xiuju Jiang ◽  
Daniel Pfau ◽  
Yan Ling ◽  
Carl F. Nathan
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Critical Role ◽  
Type I ◽  
Type I Ifn ◽  
Paracrine Signaling ◽  
Type I Ifns ◽  
Genome Wide ◽  
Mouse Macrophages ◽  
Definition Of

Macrophages help defend the host against Mycobacterium tuberculosis (Mtb), the major cause of tuberculosis (TB). Once phagocytized, Mtb resists killing by macrophages, replicates inside them, and leads to their death, releasing Mtb that can infect other cells. We found that the death of Mtb-infected mouse macrophages in vitro does not appear to proceed by a currently known pathway. Through genome-wide CRISPR-Cas9 screening, we identified a critical role for autocrine or paracrine signaling by macrophage-derived type I IFNs in the death of Mtb-infected macrophages in vitro, and blockade of type I IFN signaling augmented the effect of rifampin, a first-line TB drug, in Mtb-infected mice. Further definition of the pathway of type I IFN–mediated macrophage death may allow for host-directed therapy of TB that is more selective than systemic blockade of type I IFN signaling.

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

2021 ◽  
Vol 11 ◽  
Author(s):  
Fanli Yi ◽  
Jing Hu ◽  
Xiaoyan Zhu ◽  
Yue Wang ◽  
Qiuju Yu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Glutamic Acid ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Type I ◽  
Type I Ifn ◽  
Rna Seq ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

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.

scholarly journals Matrix metalloproteinase 28 is regulated by TRIF- and type I IFN-dependent signaling in macrophages

2018 ◽  
Vol 24 (6) ◽  
pp. 357-365 ◽  
Author(s):  
Matthew E. Long ◽  
Ke-Qin Gong ◽  
Joseph S. Volk ◽  
William E. Eddy ◽  
Mary Y. Chang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Macrophage Polarization ◽  
Experimental Models ◽  
Multiple Roles ◽  
Poly I:C ◽  
Type I ◽  
Type I Ifn ◽  
Wild Type ◽  
Coordinate Regulation ◽  
Data Support

Matrix metalloproteinases (MMPs) are transcriptionally regulated proteases that have multiple roles in modifying the extracellular matrix (ECM) and inflammatory response. Our previous work identified Mmp28 as a key regulator of inflammation and macrophage polarization during experimental models of pulmonary infection, fibrosis, and chronic smoke exposure. However, the signaling pathways responsible for regulation of macrophage Mmp28 expression remain undefined. This study utilized murine macrophages obtained from wild type, Tlr2−/−, Tlr4−/−, MyD88−/−, Ticam1 Lps2 ( Trifmutant), and Ifnar1−/− mice to test the hypothesis that macrophage Mmp28 expression was dependent on TRIF and type I IFN. Our results support the hypothesis, demonstrating that increased macrophage Mmp28 expression was dependent on type I IFN after LPS and poly(I:C) stimulation. To gain further insight into the function of MMP28, we explored the inflammatory response of macrophages derived from wild type or Mmp28−/− mice to stimulation with poly(I:C). Our data support a role for MMP28 in regulating the macrophage inflammatory response to poly(I:C) because expression of Ccl2, Ccl4, Cxcl10, and Il6 were increased in Mmp28−/− macrophages. Together, these data support a model in which macrophages integrate TRIF- and type I IFN-dependent signaling to coordinate regulation of proteins with the capacity to modify the ECM.

scholarly journals Mycobacterium tuberculosis MmsA (Rv0753c) Interacts with STING and Blunts the Type I Interferon Response

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Yifan Sun ◽  
Wei Zhang ◽  
Chunsheng Dong ◽  
Sidong Xiong
Keyword(s):  
Mass Spectrometry ◽  
Mycobacterium Tuberculosis ◽  
Proteomic Analysis ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn ◽  
Content Type ◽  
C Terminus ◽  
Autophagic Degradation

ABSTRACT Type I interferon (IFN) plays an important role in Mycobacterium tuberculosis persistence and disease pathogenesis. M. tuberculosis has evolved a number of mechanisms to evade host immune surveillance. However, it is unclear how the type I IFN response is tightly regulated by the M. tuberculosis determinants. Stimulator of interferon genes (STING) is an essential adaptor for type I IFN production triggered by M. tuberculosis genomic DNA or cyclic dinucleotides upon infection. To investigate how the type I IFN response is regulated by M. tuberculosis determinants, immunoprecipitation-mass spectrometry-based (IP-MS) proteomic analysis was performed to screen proteins interacting with STING in the context of M. tuberculosis infection. Among the many predicted candidates interacting with STING, the M. tuberculosis coding protein Rv0753c (MmsA) was identified. We confirmed that MmsA binds and colocalizes with STING, and the N-terminal regions of MmsA (amino acids [aa] 1 to 251) and STING (aa 1 TO 190) are responsible for MmsA-STING interaction. Type I IFN production was impaired with exogenous expression of MmsA in RAW264.7 cells. MmsA inhibited the STING-TBK1-IRF3 pathway, as evidenced by reduced STING levelS and subsequent IRF3 activation. Furthermore, MmsA facilitated p62-mediated STING autophagic degradation by binding p62 with its C terminus (aa 252 to 455), which may account for the negative regulation of M. tuberculosis MmsA in STING-mediated type I IFN production. Additionally, the M. tuberculosis mmsA R138W mutation, detected in a hypervirulent clinical isolate, enhanced the degradation of STING, implying the important relevance of MmsA in disease outcome. Together, we report a novel mechanism where M. tuberculosis MmsA serves as an antagonist of type I IFN response by targeting STING with p62-mediated autophagic degradation. IMPORTANCE It is unclear how the type I IFN response is regulated by mycobacterial determinants. Here, we characterized the previously unreported role of M. tuberculosis MmsA in immunological regulation of type I IFN response by targeting the central adaptor STING in the DNA sensing pathway. We identified STING-interacting MmsA by coimmunoprecipitation-mass spectrometry-based (IP-MS) proteomic analysis and showed MmsA interacting with STING and autophagy receptor p62 via its N terminus and C terminus, respectively. We also showed that MmsA downregulated type I IFN by promoting p62-mediated STING degradation. Moreover, the MmsA mutant R138W is potentially associated with the virulence of M. tuberculosis clinical strains owing to the modulation of STING protein. Our results provide novel insights into the regulatory mechanism of type I IFN response manipulated by mycobacterial MmsA and the additional cross talk between autophagy and STING in M. tuberculosis infection, wherein a protein from microbial pathogens induces autophagic degradation of host innate immune molecules.

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