Mitochondrial DNA: A Key Regulator of Anti-Microbial Innate Immunity

During the last few years, mitochondrial DNA has attained much attention as a modulator of immune responses. Due to common evolutionary origin, mitochondrial DNA shares various characteristic features with DNA of bacteria, as it consists of a remarkable number of unmethylated DNA as 2′-deoxyribose cytidine-phosphate-guanosine (CpG) islands. Due to this particular feature, mitochondrial DNA seems to be recognized as a pathogen-associated molecular pattern by the innate immune system. Under the normal physiological situation, mitochondrial DNA is enclosed in the double membrane structure of mitochondria. However, upon pathological conditions, it is usually released into the cytoplasm. Growing evidence suggests that this cytosolic mitochondrial DNA induces various innate immune signaling pathways involving NLRP3, toll-like receptor 9, and stimulator of interferon genes (STING) signaling, which participate in triggering downstream cascade and stimulating to produce effector molecules. Mitochondrial DNA is responsible for inflammatory diseases after stress and cellular damage. In addition, it is also involved in the anti-viral and anti-bacterial innate immunity. Thus, instead of entire mitochondrial importance in cellular metabolism and energy production, mitochondrial DNA seems to be essential in triggering innate anti-microbial immunity. Here, we describe existing knowledge on the involvement of mitochondrial DNA in the anti-microbial immunity by modulating the various immune signaling pathways.

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Pathogen-Associated Molecular Pattern Recognition of Hepatitis C Virus Transmitted/Founder Variants by RIG-I Is Dependent on U-Core Length

Journal of Virology ◽

10.1128/jvi.01964-15 ◽

2015 ◽

Vol 89 (21) ◽

pp. 11056-11068 ◽

Cited By ~ 19

Author(s):

Alison Kell ◽

Mark Stoddard ◽

Hui Li ◽

Joe Marcotrigiano ◽

George M. Shaw ◽

...

Keyword(s):

Innate Immunity ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Acute Infection ◽

Innate Immune ◽

Hcv Infection ◽

Immune Signaling ◽

Molecular Pattern ◽

Innate Immune Signaling ◽

Acute Hcv

ABSTRACTDespite the introduction of direct-acting antiviral (DAA) drugs against hepatitis C virus (HCV), infection remains a major public health concern because DAA therapeutics do not prevent reinfection and patients can still progress to chronic liver disease. Chronic HCV infection is supported by a variety of viral immune evasion strategies, but, remarkably, 20% to 30% of acute infections spontaneously clear prior to development of adaptive immune responses, thus implicating innate immunity in resolving acute HCV infection. However, the virus-host interactions regulating acute infection are unknown. Transmission of HCV involves one or a few transmitted/founder (T/F) variants. In infected hepatocytes, the retinoic acid-inducible gene I (RIG-I) protein recognizes 5′ triphosphate (5′ppp) of the HCV RNA and a pathogen-associated molecular pattern (PAMP) motif located within the 3′ untranslated region consisting of poly-U/UC. PAMP binding activates RIG-I to induce innate immune signaling and type 1 interferon antiviral defenses. HCV poly-U/UC sequences can differ in length and complexity, suggesting that PAMP diversity in T/F genomes could regulate innate immune control of acute HCV infection. Using 14 unique poly-U/UC sequences from HCV T/F genomes recovered from acute-infection patients, we tested whether RIG-I recognition and innate immune activation correlate with PAMP sequence characteristics. We show that T/F variants are recognized by RIG-I in a manner dependent on length of the U-core motif of the poly-U/UC PAMP and are recognized by RIG-I to induce innate immune responses that restrict acute infection. PAMP recognition of T/F HCV variants by RIG-I may therefore impart innate immune signaling and HCV restriction to impact acute-phase-to-chronic-phase transition.IMPORTANCERecognition of nonself molecular patterns such as those seen with viral nucleic acids is an essential step in triggering the immune response to virus infection. Innate immunity is induced by hepatitis C virus infection through the recognition of viral RNA by the cellular RIG-I protein, where RIG-I recognizes a poly-uridine/cytosine motif in the viral genome. Variation within this motif may provide an immune evasion strategy for transmitted/founder viruses during acute infection. Using 14 unique poly-U/UC sequences from HCV T/F genomes recovered from acutely infected HCV patients, we demonstrate that RIG-I binding and activation of innate immunity depend primarily on the length of the uridine core within this motif. T/F variants found in acute infection contained longer U cores within the motif and could activate RIG-I and induce innate immune signaling sufficient to restrict viral infection. Thus, recognition of T/F variants by RIG-I could significantly impact the transition from acute to chronic infection.

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When Rab GTPases meet innate immune signaling pathways

Cytokine & Growth Factor Reviews ◽

10.1016/j.cytogfr.2021.01.002 ◽

2021 ◽

Author(s):

Chenhe Su ◽

Chunfu Zheng

Keyword(s):

Signaling Pathways ◽

Innate Immune ◽

Rab Gtpases ◽

Immune Signaling ◽

Innate Immune Signaling

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Are innate immune signaling pathways in plants and animals conserved?

Nature Immunology ◽

10.1038/ni1253 ◽

2005 ◽

Vol 6 (10) ◽

pp. 973-979 ◽

Cited By ~ 584

Author(s):

Frederick M Ausubel

Keyword(s):

Signaling Pathways ◽

Innate Immune ◽

Immune Signaling ◽

Innate Immune Signaling

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Essential role of HCMV deubiquitinase in promoting oncogenesis by targeting anti-viral innate immune signaling pathways

Cell Death and Disease ◽

10.1038/cddis.2017.461 ◽

2017 ◽

Vol 8 (10) ◽

pp. e3078-e3078 ◽

Cited By ~ 17

Author(s):

Puja Kumari ◽

Irene Saha ◽

Athira Narayanan ◽

Sathish Narayanan ◽

Akinori Takaoka ◽

...

Keyword(s):

Signaling Pathways ◽

Essential Role ◽

Innate Immune ◽

Immune Signaling ◽

Innate Immune Signaling

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Toll-like receptor-mediated innate immunity against herpesviridae infection: a current perspective on viral infection signaling pathways

Virology Journal ◽

10.1186/s12985-020-01463-2 ◽

2020 ◽

Vol 17 (1) ◽

Cited By ~ 1

Author(s):

Wenjin Zheng ◽

Qing Xu ◽

Yiyuan Zhang ◽

Xiaofei E ◽

Wei Gao ◽

...

Keyword(s):

Innate Immunity ◽

Immune System ◽

Signaling Pathways ◽

Critical Role ◽

Innate Immune ◽

Host Cells ◽

Main Body ◽

Current Perspective ◽

Viral Components

Abstract Background In the past decades, researchers have demonstrated the critical role of Toll-like receptors (TLRs) in the innate immune system. They recognize viral components and trigger immune signal cascades to subsequently promote the activation of the immune system. Main body Herpesviridae family members trigger TLRs to elicit cytokines in the process of infection to activate antiviral innate immune responses in host cells. This review aims to clarify the role of TLRs in the innate immunity defense against herpesviridae, and systematically describes the processes of TLR actions and herpesviridae recognition as well as the signal transduction pathways involved. Conclusions Future studies of the interactions between TLRs and herpesviridae infections, especially the subsequent signaling pathways, will not only contribute to the planning of effective antiviral therapies but also provide new molecular targets for the development of antiviral drugs.

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Myeloperoxidase Modulates Hydrogen Peroxide Mediated Cellular Damage in Murine Macrophages

Antioxidants ◽

10.3390/antiox9121255 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1255

Author(s):

Chaorui Guo ◽

Inga Sileikaite ◽

Michael J. Davies ◽

Clare L. Hawkins

Keyword(s):

Hydrogen Peroxide ◽

Hypochlorous Acid ◽

Cell Function ◽

Inflammatory Diseases ◽

Innate Immune ◽

Cellular Damage ◽

Enzymatic System ◽

Therapeutic Approaches ◽

Macrophage Cell

Myeloperoxidase (MPO) is involved in the development of many chronic inflammatory diseases, in addition to its key role in innate immune defenses. This is attributed to the excessive production of hypochlorous acid (HOCl) by MPO at inflammatory sites, which causes tissue damage. This has sparked wide interest in the development of therapeutic approaches to prevent HOCl-induced cellular damage including supplementation with thiocyanate (SCN−) as an alternative substrate for MPO. In this study, we used an enzymatic system composed of glucose oxidase (GO), glucose, and MPO in the absence and presence of SCN−, to investigate the effects of generating a continuous flux of oxidants on macrophage cell function. Our studies show the generation of hydrogen peroxide (H2O2) by glucose and GO results in a dose- and time-dependent decrease in metabolic activity and cell viability, and the activation of stress-related signaling pathways. Interestingly, these damaging effects were attenuated by the addition of MPO to form HOCl. Supplementation with SCN−, which favors the formation of hypothiocyanous acid, could reverse this effect. Addition of MPO also resulted in upregulation of the antioxidant gene, NAD(P)H:quinone acceptor oxidoreductase 1. This study provides new insights into the role of MPO in the modulation of macrophage function, which may be relevant to inflammatory pathologies.

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How to rewire the host cell: A home improvement guide for intracellular bacteria

The Journal of Cell Biology ◽

10.1083/jcb.201701095 ◽

2017 ◽

Vol 216 (12) ◽

pp. 3931-3948 ◽

Cited By ~ 29

Author(s):

Elias Cornejo ◽

Philipp Schlaermann ◽

Shaeri Mukherjee

Keyword(s):

Host Cell ◽

Signaling Pathways ◽

Membrane Trafficking ◽

Defense Mechanisms ◽

Bacterial Pathogens ◽

Innate Immune ◽

Intracellular Bacteria ◽

Immune Signaling ◽

Innate Immune Signaling ◽

The Unfolded Protein Response

Intracellular bacterial pathogens have developed versatile strategies to generate niches inside the eukaryotic cells that allow them to survive and proliferate. Making a home inside the host offers many advantages; however, intracellular bacteria must also overcome many challenges, such as disarming innate immune signaling and accessing host nutrient supplies. Gaining entry into the cell and avoiding degradation is only the beginning of a successful intracellular lifestyle. To establish these replicative niches, intracellular pathogens secrete various virulence proteins, called effectors, to manipulate host cell signaling pathways and subvert host defense mechanisms. Many effectors mimic host enzymes, whereas others perform entirely novel enzymatic functions. A large volume of work has been done to understand how intracellular bacteria manipulate membrane trafficking pathways. In this review, we focus on how intracellular bacterial pathogens target innate immune signaling, the unfolded protein response, autophagy, and cellular metabolism and exploit these pathways to their advantage. We also discuss how bacterial pathogens can alter host gene expression by directly modifying histones or hijacking the ubiquitination machinery to take control of several host signaling pathways.

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Mitochondrial DNA Is a Pro-Inflammatory Damage-Associated Molecular Pattern Released During Active IBD

Inflammatory Bowel Diseases ◽

10.1093/ibd/izy095 ◽

2018 ◽

Vol 24 (10) ◽

pp. 2113-2122 ◽

Cited By ~ 23

Author(s):

Ray K Boyapati ◽

David A Dorward ◽

Arina Tamborska ◽

Rahul Kalla ◽

Nicholas T Ventham ◽

...

Keyword(s):

Mitochondrial Dna ◽

Inflammatory Diseases ◽

Quantitative Polymerase Chain Reaction ◽

White Cell Count ◽

Primary Source ◽

Inflammatory Cells ◽

Mitochondrial Damage ◽

Inflammatory Factor ◽

Inflammatory Damage ◽

Molecular Pattern

Abstract Background Due to common evolutionary origins, mitochondrial DNA (mtDNA) shares many similarities with immunogenic bacterial DNA. MtDNA is recognized as a pro-inflammatory damage-associated molecular pattern (DAMP) with a pathogenic role in several inflammatory diseases. We hypothesised that mtDNA is released during active disease, serving as a key pro-inflammatory factor in inflammatory bowel disease (IBD). Methods Between 2014 and 2015, we collected plasma separated within 2 hours of sampling from 97 prospectively recruited IBD patients (67 ulcerative colitis [UC] and 30 Crohn’s disease [CD]) and 40 non-IBD controls. We measured circulating mtDNA using quantitative polymerase chain reaction (amplifying mitochondria COXIII/ND2 genes) and also in mouse colitis induced by dextran sulfate-sodium (DSS). We used a mass spectometry approach to detect free plasma mitochondrial formylated peptides. Furthermore, we examined for mitochondrial damage using electron microscopy (EM) and TLR9 expression, the target for mtDNA, in human intestinal IBD mucosa. Results Plasma mtDNA levels were increased in UC and CD (both P < 0.0001) compared with non-IBD controls. These levels were significantly correlated to blood (C-reactive protein, albumin, white cell count), clinical and endoscopic markers of severity, and disease activity. In active UC, we identified 5 mitochondrial formylated peptides (the most abundant being fMMYALF with known chemoattractant function) in plasma. We observed mitochondrial damage in inflamed UC mucosa and significantly higher fecal MtDNA levels (vs non-IBD controls [P < 0.0001]), which supports gut mucosal mitochondrial DAMP release as the primary source. In parallel, plasma mtDNA levels increased during induction of acute DSS colitis and were associated with more severe colitis (P < 0.05). In active IBD, TLR9+ lamina propria inflammatory cells were significantly higher in UC and CD compared with controls (P < 0.05). Conclusions We present the first evidence to show that mtDNA is released during active IBD. MtDNA is a potential mechanistic biomarker, and our data point to mtDNA-TLR9 as a therapeutic target in IBD.

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