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REVIEW
Yixuan Wang, Wenwei Shao
Viral vectors play a pivotal role in the field of gene therapy, with several related drugs having already gained clinical approval from the EMA and FDA. However, numerous viral gene therapy vectors are currently undergoing pre-clinical research or participating in clinical trials. Despite advancements, the innate response remains a significant barrier impeding the clinical development of viral gene therapy. The innate immune response to viral gene therapy vectors and transgenes is still an important reason hindering its clinical development...
August 24, 2023: Viruses
#22
JOURNAL ARTICLE
Nicole DeFoor, Swagatika Paul, Shuang Li, Erwin K Gudenschwager Basso, Valentina Stevenson, Jack L Browning, Anna K Prater, Samantha Brindley, Ge Tao, Alicia M Pickrell
SARS-CoV-2 causes the severe respiratory disease COVID-19. Remdesivir (RDV) was the first fast-tracked FDA approved treatment drug for COVID-19. RDV acts as an antiviral ribonucleoside (adenosine) analogue that becomes active once it accumulates intracellularly. It then diffuses into the host cell and terminates viral RNA transcription. Previous studies have shown that certain nucleoside analogues unintentionally inhibit mitochondrial RNA or DNA polymerases or cause mutational changes to mitochondrial DNA (mtDNA)...
September 15, 2023: Scientific Reports
#23
JOURNAL ARTICLE
Cason R King, Yiping Liu, Katherine A Amato, Grace A Schaack, Clayton Mickelson, Autumn E Sanders, Tony Hu, Srishti Gupta, Ryan A Langlois, Judith A Smith, Andrew Mehle
Host:pathogen interactions dictate the outcome of infection, yet the limitations of current approaches leave large regions of this interface unexplored. Here, we develop a novel fitness-based screen that queries factors important during the middle to late stages of infection. This is achieved by engineering influenza virus to direct the screen by programming dCas9 to modulate host gene expression. Our genome-wide screen for pro-viral factors identifies the cytoplasmic DNA exonuclease TREX1. TREX1 degrades cytoplasmic DNA to prevent inappropriate innate immune activation by self-DNA...
September 13, 2023: Cell Host & Microbe
#24
JOURNAL ARTICLE
Joseph W Guarnieri, Joseph M Dybas, Hossein Fazelinia, Man S Kim, Justin Frere, Yuanchao Zhang, Yentli Soto Albrecht, Deborah G Murdock, Alessia Angelin, Larry N Singh, Scott L Weiss, Sonja M Best, Marie T Lott, Shiping Zhang, Henry Cope, Victoria Zaksas, Amanda Saravia-Butler, Cem Meydan, Jonathan Foox, Christopher Mozsary, Yaron Bram, Yared Kidane, Waldemar Priebe, Mark R Emmett, Robert Meller, Sam Demharter, Valdemar Stentoft-Hansen, Marco Salvatore, Diego Galeano, Francisco J Enguita, Peter Grabham, Nidia S Trovao, Urminder Singh, Jeffrey Haltom, Mark T Heise, Nathaniel J Moorman, Victoria K Baxter, Emily A Madden, Sharon A Taft-Benz, Elizabeth J Anderson, Wes A Sanders, Rebekah J Dickmander, Stephen B Baylin, Eve Syrkin Wurtele, Pedro M Moraes-Vieira, Deanne Taylor, Christopher E Mason, Jonathan C Schisler, Robert E Schwartz, Afshin Beheshti, Douglas C Wallace
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis. We analyzed mitochondrial gene expression in nasopharyngeal and autopsy tissues from patients with coronavirus disease 2019 (COVID-19). In nasopharyngeal samples with declining viral titers, the virus blocked the transcription of a subset of nuclear DNA (nDNA)-encoded mitochondrial OXPHOS genes, induced the expression of microRNA 2392, activated HIF-1α to induce glycolysis, and activated host immune defenses including the integrated stress response...
August 9, 2023: Science Translational Medicine
#25
JOURNAL ARTICLE
Ashutosh Tripathi, Alona Bartosh, Carl Whitehead, Anilkumar Pillai
Inflammation and social behavior deficits are associated with a number of neuropsychiatric disorders. Chronic stress, a major risk factor for depression and other mental health conditions is known to increase inflammatory responses and social behavior impairments. Disturbances in mitochondria function have been found in chronic stress conditions, however the mechanisms that link mitochondrial dysfunction to stress-induced social behavior deficits are not well understood. In this study, we found that chronic restraint stress (RS) induces significant increases in serum cell-free mitochondrial DNA (cf-mtDNA) levels in mice, and systemic Deoxyribonuclease I (DNase I) treatment attenuated RS-induced social behavioral deficits...
August 1, 2023: Molecular Psychiatry
#26
JOURNAL ARTICLE
Chloe Wick, Seyed Arad Moghadasi, Jordan T Becker, Elisa Fanunza, Sunwoo Oh, Elodie Bournique, Rémi Buisson, Reuben S Harris
APOBEC3A is an antiviral DNA deaminase often induced by virus infection. APOBEC3A is also a source of cancer mutation in viral and nonviral tumor types. It is therefore critical to identify factors responsible for APOBEC3A upregulation. Here, we test the hypothesis that leaked mitochondrial (mt) double-stranded (ds)RNA is recognized as foreign nucleic acid, which triggers innate immune signaling, APOBEC3A upregulation, and DNA damage. Knockdown of an enzyme responsible for degrading mtdsRNA, the exoribonuclease polynucleotide phosphorylase, results in mtdsRNA leakage into the cytosol and induction of APOBEC3A expression...
September 2023: Journal of Biological Chemistry
#27
JOURNAL ARTICLE
Tian Zhao, Jiaojiao Zhang, Hong Lei, Yuanyuan Meng, Hongcheng Cheng, Yanping Zhao, Guangfeng Geng, Chenglong Mu, Linbo Chen, Qiangqiang Liu, Qian Luo, Chuanmei Zhang, Yijia Long, Jingyi Su, Yinhao Wang, Zhuoya Li, Jiaxing Sun, Guo Chen, Yanjun Li, Xudong Liao, Yingli Shang, Gang Hu, Quan Chen, Yushan Zhu
Mitochondrial biogenesis is the process of generating new mitochondria to maintain cellular homeostasis. Here, we report that viruses exploit mitochondrial biogenesis to antagonize innate antiviral immunity. We found that nuclear respiratory factor-1 (NRF1), a vital transcriptional factor involved in nuclear-mitochondrial interactions, is essential for RNA (VSV) or DNA (HSV-1) virus-induced mitochondrial biogenesis. NRF1 deficiency resulted in enhanced innate immunity, a diminished viral load, and morbidity in mice...
July 6, 2023: EMBO Journal
#28
JOURNAL ARTICLE
Ruilin Zheng, Danyang Chen, Jingyao Su, Jia Lai, Chenyang Wang, Haitian Chen, Zhihui Ning, Xia Liu, Xingui Tian, Yinghua Li, Bing Zhu
BACKGROUND: Human Adenovirus (HAdV) can cause severe respiratory symptoms in people with low immunity and there is no targeted treatment for adenovirus infection. Anti-adenoviral drugs have high clinical significance for inhibiting adenovirus infection. Selenium (Se) plays an important role in anti-oxidation, redox signal transduction, and redox homeostasis. The excellent biological activity of Se is mainly achieved by being converted into selenocystine (SeC). Se participates in the active sites of various selenoproteins in the form of SeC...
May 18, 2023: Journal of Trace Elements in Medicine and Biology
#29
REVIEW
Ana R Gomes, Carla L Varela, Ana S Pires, Elisiário J Tavares-da-Silva, Fernanda M F Roleira
Guanidines are fascinating small nitrogen-rich organic compounds, which have been frequently associated with a wide range of biological activities. This is mainly due to their interesting chemical features. For these reasons, for the past decades, researchers have been synthesizing and evaluating guanidine derivatives. In fact, there are currently on the market several guanidine-bearing drugs. Given the broad panoply of pharmacological activities displayed by guanidine compounds, in this review, we chose to focus on antitumor, antibacterial, antiviral, antifungal, and antiprotozoal activities presented by several natural and synthetic guanidine derivatives, which are undergoing preclinical and clinical studies from January 2010 to January 2023...
May 11, 2023: Bioorganic Chemistry
#30
JOURNAL ARTICLE
Xinyuan Wang, Huabin Zhang, Yuqin Wang, Laylan Bramasole, Kai Guo, Fatima Mourtada, Thomas Meul, Qianjiang Hu, Valeria Viteri, Ilona Kammerl, Melanie Konigshoff, Mareike Lehmann, Thomas Magg, Fabian Hauck, Isis E Fernandez, Silke Meiners
The immunoproteasome is a specialized type of proteasome involved in MHC class I antigen presentation, antiviral adaptive immunity, autoimmunity, and is also part of a broader response to stress. Whether the immunoproteasome is regulated by DNA stress, however, is not known. We here demonstrate that mitochondrial DNA stress upregulates the immunoproteasome and MHC class I antigen presentation pathway via cGAS/STING/type I interferon signaling resulting in cell autonomous activation of CD8+ T cells. The cGAS/STING-induced adaptive immune response is also observed in response to genomic DNA and is conserved in epithelial and mesenchymal cells of mice and men...
March 13, 2023: EMBO Journal
#31
JOURNAL ARTICLE
Ilaria Montali, Camilla Ceccatelli Berti, Marco Morselli, Greta Acerbi, Valeria Barili, Giuseppe Pedrazzi, Barbara Montanini, Carolina Boni, Arianna Alfieri, Marco Pesci, Alessandro Loglio, Elisabetta Degasperi, Marta Borghi, Riccardo Perbellini, Amalia Penna, Diletta Laccabue, Marzia Rossi, Andrea Vecchi, Camilla Tiezzi, Valentina Reverberi, Chiara Boarini, Gianluca Abbati, Marco Massari, Pietro Lampertico, Gabriele Missale, Carlo Ferrari, Paola Fisicaro
BACKGROUND & AIMS: In chronic HBV infection, elevated reactive oxygen species levels derived from dysfunctional mitochondria can cause increased protein oxidation and DNA damage in exhausted virus-specific CD8 T cells. The aim of this study was to understand how these defects are mechanistically interconnected to further elucidate T cell exhaustion pathogenesis and, doing so, to devise novel T cell-based therapies. METHODS: DNA damage and repair mechanisms, including parylation, CD38 expression, and telomere length were studied in HBV-specific CD8 T cells from chronic HBV patients...
July 2023: Journal of Hepatology
#32
JOURNAL ARTICLE
Xuecheng Shen, Caiyu Sun, Yeping Cheng, Dapeng Ma, Yanlin Sun, Yueke Lin, Yunxue Zhao, Min Yang, Weiqiang Jing, Xiuling Cui, Lihui Han
Cyclic GMP-AMP synthase (cGAS), as a cytosolic DNA sensor, plays a crucial role in antiviral immunity, and its overactivation induces excess inflammation and tissue damage. Macrophage polarization is critically involved in inflammation; however, the role of cGAS in macrophage polarization during inflammation remains unclear. In this study, we demonstrated that cGAS was upregulated in the LPS-induced inflammatory response via the TLR4 pathway, and cGAS signaling was activated by mitochondria DNA in macrophages isolated from C57BL/6J mice...
March 1, 2023: Journal of Immunology
#33
REVIEW
Joon Park, Noe Baruch-Torres, Y Whitney Yin
Human mitochondrial DNA (mtDNA) is a 16.9 kbp double-stranded, circular DNA, encoding subunits of the oxidative phosphorylation electron transfer chain and essential RNAs for mitochondrial protein translation. The minimal human mtDNA replisome is composed of the DNA helicase Twinkle, DNA polymerase γ, and mitochondrial single-stranded DNA-binding protein. While the mitochondrial RNA transcription is carried out by mitochondrial RNA polymerase, mitochondrial transcription factors TFAM and TFB2M, and a transcription elongation factor, TEFM, both RNA transcriptions, and DNA replication machineries are intertwined and control mtDNA copy numbers, cellular energy supplies, and cellular metabolism...
February 14, 2023: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
#34
Cason R King, Yiping Liu, Katherine A Amato, Grace A Schaack, Tony Hu, Judith A Smith, Andrew Mehle
Intracellular pathogens interact with host factors, exploiting those that enhance replication while countering those that suppress it. Genetic screens have begun to define the host:pathogen interface and establish a mechanistic basis for host-directed therapies. Yet, limitations of current approaches leave large regions of this interface unexplored. To uncover host factors with pro-pathogen functions, we developed a novel fitness-based screen that queries factors important during the middle-to-late stages of infection...
February 7, 2023: bioRxiv
#35
JOURNAL ARTICLE
Huawei Li, Xiaotian Yang, Yuzhen Song, Qingguo Zhu, Ziqian Liao, Yixuan Liang, Jianghao Guo, Bo Wan, Dengke Bao
Porcine reproductive and respiratory syndrome virus (PRRSV) infection causes severe interstitial pneumonia and inflammatory response in piglets and growing pigs. IL-1β is implicated in PRRSV-mediated inflammatory response and the pathogenesis of PRRSV infection. Mitochondria are critical intracellular organelles which is served as signaling platform for antiviral immunity response to participate in immune response of virus infection. The role of mitochondria in PRRSV-mediated inflammatory response and the pathogenesis of PRRSV infection has not been elucidated...
April 2023: Veterinary Microbiology
#36
REVIEW
Owen Davis Sanders
Oxidative stress, inflammation, and amyloid-β are Alzheimer's disease (AD) hallmarks that cause each other and other AD hallmarks. Most amyloid-β-lowering, antioxidant, anti-inflammatory, and antimicrobial AD clinical trials failed; none stopped or reversed AD. Although signs suggest an infectious etiology, no pathogen accumulated consistently in AD patients. Neuropathology, neuronal cell culture, rodent, genome-wide association, epidemiological, biomarker, and clinical studies, plus analysis using Hill causality criteria and revised Koch's postulates, indicate that the virus-like oxidative damage-associated molecular-pattern (DAMP) cytosolic and cell-free nucleic acids accumulated in AD patients' brains likely drive neuroinflammation, synaptotoxicity, and neurotoxicity...
2023: JAD Reports
#37
JOURNAL ARTICLE
Joe Nassour, Lucia Gutierrez Aguiar, Adriana Correia, Tobias T Schmidt, Laura Mainz, Sara Przetocka, Candy Haggblom, Nimesha Tadepalle, April Williams, Maxim N Shokhirev, Semih C Akincilar, Vinay Tergaonkar, Gerald S Shadel, Jan Karlseder
Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis-an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and other cancer-relevant chromosomal aberrations1,2 . However, little is known about the molecular events that regulate the onset of this important tumour-suppressive barrier. Here we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as a regulator of the crisis program...
February 8, 2023: Nature
#38
JOURNAL ARTICLE
Huisheng Liu, Zixiang Zhu, Qiao Xue, Fan Yang, Zongqiang Li, Zhaoning Xue, Weijun Cao, Jijun He, Jianhong Guo, Xiangtao Liu, Andrew E Shaw, Donald P King, Haixue Zheng
Cyclic GMP-AMP synthase (cGAS) plays a key role in the innate immune responses to both DNA and RNA virus infection. Here, we found that enterovirus 71 (EV-A71), Seneca Valley virus (SVV), and foot-and-mouth disease virus (FMDV) infection triggered mitochondria damage and mitochondrial DNA (mtDNA) release in vitro and vivo. These responses were mediated by picornavirus 2B proteins which induced mtDNA release during viral replication. SVV infection caused the opening of mitochondrial permeability transition pore (mPTP) and led to voltage-dependent anion channel 1 (VDAC1)- and BCL2 antagonist/killer 1 (Bak) and Bak/BCL2-associated X (Bax)-dependent mtDNA leakage into the cytoplasm, while EV-A71 and FMDV infection induced mPTP opening and resulted in VDAC1-dependent mtDNA release...
February 6, 2023: PLoS Pathogens
#39
REVIEW
Lauren E Fritsch, Colin Kelly, Alicia M Pickrell
The cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase-Stimulator of Interferon Genes (cGAS-STING) pathway is a critical innate immune mechanism for detecting the presence of double-stranded DNA (dsDNA) and prompting a robust immune response. Canonical cGAS-STING activation occurs when cGAS, a predominantly cytosolic pattern recognition receptor, binds microbial DNA to promote STING activation. Upon STING activation, transcription factors enter the nucleus to cause the production of Type I interferons, inflammatory cytokines whose primary function is to prime the host for viral infection by producing a number of antiviral interferon-stimulated genes...
January 12, 2023: WIREs Mech Dis
#40
JOURNAL ARTICLE
Kai Mao, Peter Breen, Gary Ruvkun
Surveillance of Caenorhabditis elegans mitochondrial status is coupled to defense responses such as drug detoxification, immunity, antiviral RNA interference (RNAi), and regulation of life span. A cytochrome p540 detoxification gene, cyp-14A4 , is specifically activated by mitochondrial dysfunction. The nuclear hormone receptor NHR-45 and the transcriptional Mediator component MDT-15/MED15 are required for the transcriptional activation of cyp-14A4 by mitochondrial mutations, gene inactivations, or toxins. A genetic screen for mutations that fail to activate this cytochrome p450 gene upon drug or mutation-induced mitochondrial dysfunction identified a DNA helicase ARIP-4 that functions in concert with the NHR-45 transcriptional regulatory cascade...
December 6, 2022: Proceedings of the National Academy of Sciences of the United States of America
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