scholarly journals VapBC22 toxin-antitoxin system from Mycobacterium tuberculosis is required for pathogenesis and modulation of host immune response

2020 ◽  
Vol 6 (23) ◽  
pp. eaba6944
Author(s):  
Sakshi Agarwal ◽  
Arun Sharma ◽  
Rania Bouzeyen ◽  
Amar Deep ◽  
Harsh Sharma ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Mutant Strain ◽  
Transcriptome Analysis ◽  
Regulatory Network ◽  
Ribosomal Proteins ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Associated Proteins ◽  
Precise Role

Virulence-associated protein B and C toxin-antitoxin (TA) systems are widespread in prokaryotes, but their precise role in physiology is poorly understood. We have functionally characterized the VapBC22 TA system from Mycobacterium tuberculosis. Transcriptome analysis revealed that overexpression of VapC22 toxin in M. tuberculosis results in reduced levels of metabolic enzymes and increased levels of ribosomal proteins. Proteomics studies showed reduced expression of virulence-associated proteins and increased levels of cognate antitoxin, VapB22 in the ΔvapC22 mutant strain. Furthermore, both the ΔvapC22 mutant and VapB22 overexpression strains of M. tuberculosis were susceptible to killing upon exposure to oxidative stress and showed attenuated growth in guinea pigs and mice. Host transcriptome analysis suggests upregulation of the transcripts involved in innate immune responses and tissue remodeling in mice infected with the ΔvapC22 mutant strain. Together, we demonstrate that the VapBC22 TA system belongs to a key regulatory network and is essential for M. tuberculosis pathogenesis.

scholarly journals Effect of Vitamin D Supplementation on Mycobacterium tuberculosis-Induced Innate Immune Responses in a Canadian Dené First Nations Cohort

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e40692 ◽  
Author(s):  
Linda Larcombe ◽  
Pamela Orr ◽  
Emily Turner-Brannen ◽  
Caroline R. Slivinski ◽  
Peter W. Nickerson ◽  
...  
Keyword(s):  
Vitamin D ◽  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
First Nations ◽  
Vitamin D Supplementation ◽  
Innate Immune ◽  
Innate Immune Responses

scholarly journals Mycobacterium tuberculosis Rv2224c modulates innate immune responses

2008 ◽  
Vol 105 (1) ◽  
pp. 264-269 ◽  
Author(s):  
J. Rengarajan ◽  
E. Murphy ◽  
A. Park ◽  
C. L. Krone ◽  
E. C. Hett ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses

scholarly journals Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Bin Zhou ◽  
Fei Qi ◽  
Fangyi Wu ◽  
Hongbo Nie ◽  
Yifan Song ◽  
...  
Keyword(s):  
Immune Responses ◽  
Transcriptome Analysis ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Innate Immune ◽  
Endogenous Retroviruses ◽  
Innate Immune Responses ◽  
Antiviral Responses ◽  
Positive Regulator ◽  
Deficient Mice

ABSTRACT Endogenous retroviruses (ERVs) are transposable elements that cause host genome instability and usually play deleterious roles in disease such as tumorigenesis. Recent advances also suggest that this “enemy within” may encode a viral mimic to induce antiviral immune responses through viral sensors. Here, through whole-genome transcriptome analysis with RNA sequencing (RNA-Seq), we discovered that a full-length ERV-derived long noncoding RNA (lncRNA), designated lnc-EPAV (ERV-derived lncRNA positively regulates antiviral responses), was a positive regulator of NF-κB signaling. lnc-EPAV expression was rapidly upregulated by viral RNA mimics or RNA viruses to facilitate the expression of RELA, an NF-κB subunit that plays a crucial role in antiviral responses. Transcriptome analysis of lnc-EPAV-silenced macrophages showed that lnc-EPAV was critical for RELA target gene expression and innate immune responses. Consistently, lnc-EPAV-deficient mice exhibited reduced expression of type I interferons (IFNs) and, consequently, increased viral loads and mortality following lethal RNA virus infection. Mechanistically, lnc-EPAV promoted expression of RELA by competitively binding to and displacing SFPQ, a transcriptional repressor of Rela. Altogether, our work demonstrates an alternative mechanism by which ERVs regulate antiviral immune responses. IMPORTANCE Endogenous retroviruses are transposable genetic elements comprising 8% to 10% of the human and mouse genomes. Although most ERVs have been inactivated due to deleterious mutations, some are still transcribed. However, the biological functions of transcribed ERVs are largely unknown. Here, we identified a full-length ERV-derived lncRNA, designated lnc-EPAV, as a positive regulator of host innate immune responses. We found that silencing lnc-EPAV impaired virus-induced cytokine production, resulting in increased viral replication in cells. The lnc-EPAV-deficient mice exhibited enhanced susceptibility to viral challenge. We also found that lnc-EPAV regulated expression of RELA, an NF-κB subunit that plays a critical role in antiviral responses. ERV-derived lncRNA coordinated with a transcription repressor, SFPQ, to control Rela transcription. Our report provides new insights into the previously unrecognized immune gene regulatory mechanism of ERV-derived lncRNAs.

scholarly journals HIV-1 Infection of Macrophages Dysregulates Innate Immune Responses to Mycobacterium tuberculosis by Inhibition of Interleukin-10

2013 ◽  
Vol 209 (7) ◽  
pp. 1055-1065 ◽  
Author(s):  
Gillian S. Tomlinson ◽  
Lucy C. K. Bell ◽  
Naomi F. Walker ◽  
Jhen Tsang ◽  
Jeremy S. Brown ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Interleukin 10 ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Hiv 1

Early Clearance of Mycobacterium tuberculosis Is Associated With Increased Innate Immune Responses

2019 ◽  
Author(s):  
Ayesha J Verrall ◽  
Marion Schneider ◽  
Bachti Alisjahbana ◽  
Lika Apriani ◽  
Arjan van Laarhoven ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Cellular Response ◽  
Ex Vivo ◽  
Interferon Γ ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Cytokine Responses ◽  
Protection Against Infection

AbstractBackgroundA proportion of tuberculosis (TB) case contacts do not become infected, even when heavily exposed. We studied the innate immune responses of TB case contacts to understand their role in protection against infection with Mycobacterium tuberculosis, termed “early clearance.”MethodsIndonesian household contacts of TB cases were tested for interferon-γ release assay (IGRA) conversion between baseline and 14 weeks post recruitment. Blood cell populations and ex vivo innate whole blood cytokine responses were measured at baseline and, in a subgroup, flow cytometry was performed at weeks 2 and 14. Immunological characteristics were measured for early clearers, defined as a persistently negative IGRA at 3 months, and converters, whose IGRA converted from negative to positive.ResultsAmong 1347 case contacts, 317 were early clearers and 116 were converters. Flow cytometry showed a resolving innate cellular response from 2 to 14 weeks in persistently IGRA-negative contacts but not converters. There were no differences in cytokine responses to mycobacterial stimuli, but compared to converters, persistently IGRA-negative contacts produced more proinflammatory cytokines following heterologous stimulation with Escherichia coli and Streptococcus pneumoniae.ConclusionsEarly clearance of M. tuberculosis is associated with enhanced heterologous innate immune responses similar to those activated during induction of trained immunity.

scholarly journals Mitochondria: powering the innate immune response to Mycobacterium tuberculosis infection

2021 ◽  
Author(s):  
Kristin L. Patrick ◽  
Robert O. Watson
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Bacterial Pathogen ◽  
Tuberculosis Patient ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Type I ◽  
Innate Immune Responses ◽  
Mycobacterium Tuberculosis Infection

Within the last decade, we have learned that damaged mitochondria activate many of the same innate immune pathways that evolved to sense and respond to intracellular pathogens. These shared responses include cytosolic nucleic acid sensing and type I interferon (IFN) expression, inflammasome activation that leads to pyroptosis, and selective autophagy (called mitophagy when mitochondria are the cargo). Because mitochondria were once bacteria, parallels between how cells respond to mitochondrial and bacterial ligands are not altogether surprising. However, the potential for crosstalk or synergy between bacteria- and mitochondria-driven innate immune responses during infection remains poorly understood. This interplay is particularly striking—and intriguing—in the context of infection with the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb). Multiple studies point to a role for Mtb infection and/or specific Mtb virulence factors in disrupting the mitochondrial network in macrophages leading to metabolic changes and triggering potent innate immune responses. Research from our labs and others argues that mutations in mitochondrial genes can exacerbate mycobacterial disease severity by hyper-activating innate responses or activating them at the wrong time. Indeed, growing evidence supports a model whereby different mitochondrial defects or mutations alter Mtb infection outcomes in distinct ways. By synthesizing the current literature in this minireview, we hope to gain insight into the molecular mechanisms driving, and consequences of, mitochondrial-dependent immune polarization so that we might better predict tuberculosis patient outcomes and develop host-directed therapeutics designed to correct these imbalances.

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