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 Changes in Transcript, Metabolite, and Antibody Reactivity During the Early Protective Immune Response in Humans to Mycobacterium tuberculosis Infection

2019 ◽  
Vol 71 (1) ◽  
pp. 30-40 ◽  
Author(s):  
January Weiner ◽  
Teresa Domaszewska ◽  
Simon Donkor ◽  
Stefan H E Kaufmann ◽  
Philip C Hill ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Latent Tuberculosis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Tuberculosis Infection ◽  
Type I ◽  
Infection Status ◽  
Mycobacterium Tuberculosis Infection ◽  
Vitamin B5 ◽  
Negative Reading

Abstract Background Strategies to prevent Mycobacterium tuberculosis (Mtb) infection are urgently required. In this study, we aimed to identify correlates of protection against Mtb infection. Methods Two groups of Mtb-exposed contacts of tuberculosis (TB) patients were recruited and classified according to their Mtb infection status using the tuberculin skin test (TST; cohort 1) or QuantiFERON (QFT; cohort 2). A negative reading at baseline with a positive reading at follow-up classified TST or QFT converters and a negative reading at both time points classified TST or QFT nonconverters. Ribonucleic acid sequencing, Mtb proteome arrays, and metabolic profiling were performed. Results Several genes were found to be differentially expressed at baseline between converters and nonconverters. Gene set enrichment analysis revealed a distinct B-cell gene signature in TST nonconverters compared to converters. When infection status was defined by QFT, enrichment of type I interferon was observed. A remarkable area under the curve (AUC) of 1.0 was observed for IgA reactivity to Rv0134 and an AUC of 0.98 for IgA reactivity to both Rv0629c and Rv2188c. IgG reactivity to Rv3223c resulted in an AUC of 0.96 and was markedly higher compared to TST nonconverters. We also identified several differences in metabolite profiles, including changes in biomarkers of inflammation, fatty acid metabolism, and bile acids. Pantothenate (vitamin B5) was significantly increased in TST nonconverters compared to converters at baseline (q = 0.0060). Conclusions These data provide new insights into the early protective response to Mtb infection and possible avenues to interfere with Mtb infection, including vitamin B5 supplementation. Analysis of blood from highly exposed household contacts from The Gambia who never develop latent Mycobacterium tuberculosis infection shows distinct transcriptomic, antibody, and metabolomic profiles compared to those who develop latent tuberculosis infection but prior to any signs of infection.

scholarly journals TRIM14 is a key regulator of the type I interferon response during Mycobacterium tuberculosis infection

2019 ◽  
Author(s):  
Caitlyn T. Hoffpauir ◽  
Samantha L. Bell ◽  
Kelsi O. West ◽  
Tao Jing ◽  
Sylvia Torres-Odio ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Nucleic Acid ◽  
Type I Interferon ◽  
Negative Regulator ◽  
Interferon Response ◽  
Cytokine Signaling ◽  
Type I ◽  
Type I Ifn ◽  
Mycobacterium Tuberculosis Infection ◽  
Innate Immune Signaling

ABSTRACTTripartite motif-containing proteins (TRIMs) play a variety of recently described roles in innate immunity. While many TRIMs regulate type I interferon (IFN) expression following cytosolic nucleic acid sensing of viruses, their contribution to innate immune signaling and gene expression during bacterial infection remains largely unknown. Because Mycobacterium tuberculosis is a potent activator of cGAS-dependent cytosolic DNA sensing, we set out to investigate a role for TRIM proteins in regulating macrophage responses to M. tuberculosis. Here we demonstrate that TRIM14, a non-canonical TRIM that lacks an E3 ligase RING domain, is a critical negative regulator of the type I IFN response in macrophages. We show that TRIM14 physically interacts with both cGAS and TBK1 and that macrophages lacking TRIM14 dramatically hyperinduce interferon stimulated gene (ISG) expression following cytosolic nucleic acid transfection, IFN-β treatment, and M. tuberculosis infection. Consistent with a defect in resolution of the type I IFN response, Trim14 knockout (KO) macrophages have more phospho-Ser754 STAT3 relative to phospho-727 and fail to upregulate the STAT3 target Socs3 (Suppressor of Cytokine Signaling 3), which is required to turn off IFNAR signaling. These data support a model whereby TRIM14 acts as a scaffold between TBK1 and STAT3 to promote phosphorylation of STAT3 at Ser727 and enhance negative regulation of ISG expression. Remarkably, Trim14 KO macrophages hyperinduce antimicrobials like Inos2 and are significantly better than control cells at limiting M. tuberculosis replication. Collectively, these data reveal a previously unappreciated role for TRIM14 in resolving type I IFN responses and controlling M. tuberculosis infection.

scholarly journals Type I interferons in tuberculosis: Foe and occasionally friend

2018 ◽  
Vol 215 (5) ◽  
pp. 1273-1285 ◽  
Author(s):  
Lúcia Moreira-Teixeira ◽  
Katrin Mayer-Barber ◽  
Alan Sher ◽  
Anne O’Garra
Keyword(s):  
Mouse Models ◽  
Infection Type ◽  
Protective Role ◽  
Tuberculosis Infection ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Mycobacterium Tuberculosis Infection ◽  
Protective Mechanisms ◽  
Experimental Mouse

Tuberculosis remains one of the leading causes of mortality worldwide, and, despite its clinical significance, there are still significant gaps in our understanding of pathogenic and protective mechanisms triggered by Mycobacterium tuberculosis infection. Type I interferons (IFN) regulate a broad family of genes that either stimulate or inhibit immune function, having both host-protective and detrimental effects, and exhibit well-characterized antiviral activity. Transcriptional studies have uncovered a potential deleterious role for type I IFN in active tuberculosis. Since then, additional studies in human tuberculosis and experimental mouse models of M. tuberculosis infection support the concept that type I IFN promotes both bacterial expansion and disease pathogenesis. More recently, studies in a different setting have suggested a putative protective role for type I IFN. In this study, we discuss the mechanistic and contextual factors that determine the detrimental versus beneficial outcomes of type I IFN induction during M. tuberculosis infection, from human disease to experimental mouse models of tuberculosis.

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