Article
Multidisciplinary Sciences
Jeremy Di Domizio, Muhammet F. Gulen, Fanny Saidoune, Vivek V. Thacker, Ahmad Yatim, Kunal Sharma, Theo Nass, Emmanuella Guenova, Martin Schaller, Curdin Conrad, Christine Goepfert, Laurence de Leval, Christophe von Garnier, Sabina Berezowska, Anaelle Dubois, Michel Gilliet, Andrea Ablasser
Summary: This study reveals the mechanism behind aberrant type I interferon responses in COVID-19 through the cGAS-STING pathway and demonstrates its importance in severe cases. By using animal and lung-on-chip models, the study provides insights into host-directed therapeutic strategies for COVID-19.
Review
Cell Biology
Emily N. Chin, Ariana Sulpizio, Luke L. Lairson
Summary: Pharmacology-based methods can promote antitumor immunity without causing systemic cytotoxicity like traditional chemotherapies. The activation of type I interferon signaling is crucial for inducing a tumor-specific adaptive immune response, and the cGAS/STING pathway is a principal regulator of this signaling. It is a promising target for developing first-in-class immunotherapies, but it may also have cell type- and pathway-dependent toxicities.
TRENDS IN CELL BIOLOGY
(2023)
Article
Microbiology
Lei Xu, Mengyuan Li, Yadong Yang, Chen Zhang, Zhen Xie, Jingjing Tang, Zhenkun Shi, Shukun Chen, Guangzhe Li, Yanchao Gu, Xiao Wang, Fuhua Zhang, Yao Wang, Xihui Shen
Summary: This study reveals the important role of the cytosolic surveillance pathway cGAS-STING in the activation of the type I interferon response during S. Typhimurium infection, in addition to the TLR4-dependent response. The study also highlights the significance of mtDNA release triggered by S. Typhimurium infection in the induction of type I interferon.
Article
Multidisciplinary Sciences
Hong Yien Tan, Yean Kong Yong, Yuan Chao Xue, Huitao Liu, Tomomi Furihata, Esaki Muthu Shankar, Chen Seng Ng
Summary: Neuroinflammation worsens the development of ALS caused by SOD1 mutation. The mitochondrial damage triggered by ALS leads to the release of mtDNA and RNA:DNA hybrids, activating the IRF3- and IFNAR-dependent IFN-I and interferon-stimulating genes, causing high levels of IFN-I and pro-inflammatory response. Inter-neuronal gap junctions amplify the response through cGAS/DDX41-STING signaling. This highlights the role of a common DNA sensing pathway between SOD1 and TDP-43 in ALS progression.
Article
Multidisciplinary Sciences
Martha Triantafilou, Joshi Ramanjulu, Lee M. Booty, Gisela Jimenez-Duran, Hakan Keles, Ken Saunders, Neysa Nevins, Emma Koppe, Louise K. Modis, G. Scott Pesiridis, John Bertin, Kathy Triantafilou
Summary: Evidence suggests that the signaling mediator STING, which is typically associated with antiviral responses, is actually needed for optimal human rhinovirus infection. The study shows that human rhinovirus can reduce stored Ca2(+) levels to trigger the release of STING in the ER, allowing it to interact with PI4P and facilitate viral replication and transmission. This discovery may have implications for other RNA viruses that rely on replication organelles.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Annemarie Steiner, Katja Hrovat-Schaale, Ignazia Prigione, Chien-Hsiung Yu, Pawat Laohamonthonkul, Cassandra R. Harapas, Ronnie Ren Jie Low, Dominic De Nardo, Laura F. Dagley, Michael J. Mlodzianoski, Kelly L. Rogers, Thomas Zillinger, Gunther Hartmann, Michael P. Gantier, Marco Gattorno, Matthias Geyer, Stefano Volpi, Sophia Davidson, Seth L. Masters
Summary: Deficiency in COPI complex I may lead to aberrant activation of the STING pathway and inflammatory diseases, with cGAS possibly being the upstream immune sensor driving this process. Targeted inhibition of the cGAS/STING pathway can alleviate inflammation in diseases such as COPA syndrome.
NATURE COMMUNICATIONS
(2022)
Review
Biochemistry & Molecular Biology
Khiem C. Lam, Romina E. Araya, April Huang, Quanyi Chen, Martina Di Modica, Richard R. Rodrigues, Amelie Lopes, Sarah B. Johnson, Benjamin Schwarz, Eric Bohrnsen, Alexandria P. Cogdill, Catharine M. Bosio, Jennifer A. Wargo, Maxwell P. Lee, Romina S. Goldszmid
Summary: This study reveals how the microbiota influences the immune components of the TME to improve cancer therapy. Modulating the microbiota can trigger the IFN-I-NK cell-DC axis within tumors, enhancing the efficacy of immune checkpoint blockade (ICB).
Article
Oncology
Razmik Ghukasyan, Keke Liang, Kevin Chau, Luyi Li, Charlotte Chan, Evan R. Abt, Thuc Le, Joon Y. Park, Nanping Wu, Alykhan Premji, Robert Damoiseaux, Tony Luu, Amanda Labora, Khalid Rashid, Jason M. Link, Caius G. Radu, Timothy R. Donahue
Summary: The purpose of this study is to identify combination therapies that can enhance the efficacy of STING agonists for the treatment of pancreatic ductal adenocarcinoma. The researchers found that MEK inhibitors showed the greatest synergy with a specific STING agonist, leading to enhanced tumor cell death. They also discovered that MEK signaling inhibits the NFxB-dependent mechanism of STING-induced cell death.
CLINICAL CANCER RESEARCH
(2023)
Article
Immunology
Luca Occhigrossi, Federica Rossin, Valeria Rachela Villella, Speranza Esposito, Carlo Abbate, Manuela D'Eletto, Maria Grazia Farrace, Antonella Tosco, Roberta Nardacci, Gian Maria Fimia, Valeria Raia, Mauro Piacentini
Summary: Cystic fibrosis (CF) is a rare genetic disease caused by mutations in the CFTR gene, leading to chronic lung infections. This study reveals the link between recurrent infections in CF patients and impaired innate immune response. The use of STING pathway agonists can restore the immune response and potentially be utilized as a new treatment strategy.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Agriculture, Dairy & Animal Science
Xuelan Liu, Dexian Xi, Aiyun Xu, Yuan Wang, Tao Song, Tiantian Ma, Hong Ye, Lin Li, Fazhi Xu, Hao Zheng, Jinnian Li, Feifei Sun
Summary: VP1 protein of chicken anemia virus (CAV) interacts with IRF7 to antagonize the cGAS-STING pathway-mediated IFN-b activation, leading to downregulation of type I interferon production.
Article
Cell Biology
Erika S. Guimaraes, Fabio V. Marinho, Nina M. G. P. de Queiroz, Maisa M. Antunes, Sergio C. Oliveira
Summary: STING, as an immune sensor, plays a crucial role in the early detection of bacterial pathogens. It activates immune responses by detecting bacterial DNA or cyclic dinucleotides, leading to the production of interferons and proinflammatory cytokines and participating in the metabolic reprogramming of macrophages. However, STING-mediated immune responses during bacterial infections can also be detrimental to the host.
Article
Food Science & Technology
Amnart Onsa-Ard, Rungthip Thongboontho, Narongsuk Munkong, Kanokkarn Phromnoi, Atcharaporn Ontawong, Sirinat Pengnet, Arthid Thim-Uam
Summary: This study finds that red rice bran extract may exert anti-inflammatory effects on macrophages through the inhibition of STING signaling pathway. Furthermore, it can reduce the transcription of interferon-stimulated genes, thereby decreasing the production of inflammatory cytokines.
Article
Multidisciplinary Sciences
Mathieu Iampietro, Claire Dumont, Cyrille Mathieu, Julia Spanier, Jonathan Robert, Aude Charpenay, Sebastien Dupichaud, Kevin P. Dhondt, Noemie Aurine, Rodolphe Pelissier, Marion Ferren, Stephane Mely, Denis Gerlier, Ulrich Kalinke, Branka Horvat
Summary: The cGAS/STING pathway plays a critical role in controlling paramyxovirus infection, with cGAS or STING deletion leading to reduced type I interferon production and enhanced viral infection. Phosphorylation and ubiquitination of STING during viral infections confirm the activation of the cGAS/STING pathway by NiV and MeV.
Article
Multidisciplinary Sciences
Zhongshun Liu, Congwei Jiang, Zhangmengxue Lei, Sihan Dong, Linlin Kuang, Chenxu Huang, Ying Gao, Mu Liu, Hui Xiao, Patrick Legembre, Jae U. Jung, Huaping Liang, Xiaozhen Liang
Summary: Type I interferons (IFNs) are the first line of defense against invading pathogens. This study identified a previously unknown protein, PINLYP, that interacts with TBK1 to induce the production of type I IFN. Loss of PINLYP impaired the activation of IRF3 and the production of IFN induced by various viruses and Toll-like receptor ligands. Mice lacking PINLYP were more susceptible to lethal virus infection, highlighting the importance of PINLYP in the host defense against viral infections.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Miaoling Huang, Ting Wu, Rui Liu, Meina Wang, Munan Shi, Jingyu Xin, Shan Shao, Xingqi Zhao, Ying Ma, Lili Gu, Zhigang Guo, Feiyan Pan
Summary: DNA Polymerase fi (Polfi) plays a key role in maintaining the stability and integrity of the genome. Mutant Polfi is closely associated with carcinogenesis. This study discovered that Polfi knockdown led to increased levels of type I interferon in breast cancer cells and made them more susceptible to elimination by NK cells. Similarly, Polfi-mutant mice exhibited chronic inflammation symptoms and elevated type I interferon levels. Further investigation revealed that Polfi deficiency caused the accumulation of DNA damage in cells, triggering the activation of the STING/IRF3 pathway and enhancing the expression of type I interferon and proinflammatory cytokines. These effects could be eliminated by Polfi overexpression, a STING inhibitor, or STING knockdown.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Immunology
Evangelos Andreakos, Laurent Abel, Donald C. Vinh, Elzbieta Kaja, Beth A. Drolet, Qian Zhang, Cliona O'Farrelly, Giuseppe Novelli, Carlos Rodriguez-Gallego, Filomeen Haerynck, Carolina Prando, Aurora Pujol, Helen C. Su, Jean-Laurent Casanova, Andras N. Spaan, Paul Bastard, Catherine M. Biggs, Benedetta Bigio, Bertrand Boisson, Alexandre Bolze, Anastasiia Bondarenko, Petter Brodin, Samya Chakravorty, John Christodoulou, Aurelie Cobat, Antonio Condino-Neto, Stefan N. Constantinescu, Hagit Baris Feldman, Jacques Fellay, Rabih Halwani, Emmanuelle Jouanguy, Yu-Lung Lau, Isabelle Meyts, Trine H. Mogensen, Satoshi Okada, Keisuke Okamoto, Tayfun Ozcelik, Qiang Pan-Hammarstrom, Anna M. Planas, Anne Puel, Lluis Quintana-Murci, Laurent Renia, Igor Resnick, Anna Sediva, Anna Shcherbina, Ondrej Slaby, Ivan Tancevski, Stuart E. Turvey, K. M. Furkan Uddin, Diederik van de Beek, Mayana Zatz, Pawel Zawadzki, Shen-Ying Zhang
Summary: SARS-CoV-2 infections can vary greatly between individuals, with some being asymptomatic while others experience life-threatening disease. While 20% of critical COVID-19 cases are due to inborn errors or autoantibodies, the genetic and immunological factors for resistance to infection itself remain unknown. Studies have shown that autosomal recessive deficiencies in certain genes or enzymes can confer resistance to diseases, suggesting a potential strategy for identifying individuals naturally resistant to SARS-CoV-2 infection.
Review
Immunology
Soren R. Paludan, Trine H. Mogensen
Summary: COVID-19 is a disease characterized by significant dysregulation of the innate immune system. The activation of specific pattern recognition receptors by SARS-CoV-2 and host-derived molecules leads to protective interferon responses and pathological cytokine responses. These pathways are modulated by virus-host interactions and host stress-sensing pathways.
SCIENCE IMMUNOLOGY
(2022)
Article
Immunology
Christopher J. A. Duncan, Morten K. Skouboe, Sophie Howarth, Anne K. Hollensen, Rui Chen, Malene L. Borresen, Benjamin J. Thompson, Jarmila Stremenova Spegarova, Catherine F. Hatton, Frederik F. Staeger, Mette K. Andersen, John Whittaker, Soren R. Paludan, Sofie E. Jorgensen, Martin K. Thomsen, Jacob G. Mikkelsen, Carsten Heilmann, Daniela Buhas, Nina F. Obro, Jakob T. Bay, Hanne Marquart, M. Teresa de la Morena, Joseph A. Klejka, Matthew Hirschfeld, Line Borgwardt, Isabel Forss, Tania Masmas, Anja Poulsen, Francisco Noya, Guy Rouleau, Torben Hansen, Sirui Zhou, Anders Albrechtsen, Reza Alizadehfar, Eric J. Allenspach, Sophie Hambleton, Trine H. Mogensen
Summary: This study investigated five children from Greenland, Canada, and Alaska who carried a homozygous IFNAR2 gene variant, resulting in increased vulnerability to viral infections. This finding highlights the essential role of Type I interferons in viral immunity and suggests the need for further population screening studies.
JOURNAL OF EXPERIMENTAL MEDICINE
(2022)
Article
Biology
Manutea C. Serrero, Virginie Girault, Sebastian Weigang, Todd M. Greco, Ana Ramos-Nascimento, Fenja Anderson, Antonio Piras, Ana Hickford Martinez, Jonny Hertzog, Anne Binz, Anja Pohlmann, Ute Prank, Jan Rehwinkel, Rudolf Bauerfeind, Ileana M. Cristea, Andreas Pichlmair, Georg Kochs, Beate Sodeik, Adam P. Geballe
Summary: This study identifies an interferon-inducible protein, MxB, that can sense herpesviral capsids and disassemble them, thereby restricting viral nuclear targeting and progeny capsid assembly, leading to enhanced innate immune responses.
Article
Clinical Neurology
Jane Agergaard, Benjamin Yamin Ali Khan, Thomas Engell-Sorensen, Berit Schiottz-Christensen, Lars ostergaard, Eva K. Hejbol, Henrik D. Schroder, Henning Andersen, Jakob Udby Blicher, Thomas Holm Pedersen, Thomas Harbo, Hatice Tankisi, M. U. L. T. I. C. O. V. Consortium MULTICOV Consortium
Summary: This study examined 84 patients with long COVID using qEMG and sfEMG, and performed muscle biopsies in a subset of patients. The results showed that the mean MUP duration was decreased in >= 1 muscles in 52% of the patients, and the mean jitter was increased in 17% of the patients in the tibialis anterior and 25% in the extensor digitorum communis. Muscle biopsies revealed damage of terminal nerves and motor endplate with abundant basal lamina material. These findings suggest a muscle pathophysiology behind fatigue in long COVID.
CLINICAL NEUROPHYSIOLOGY
(2023)
Article
Infectious Diseases
Trine H. Mogensen, Morten Kelder Skouboe, Ingolf Molle
Summary: Human infection with parvovirus B19 can lead to various clinical manifestations, and treatment can be challenging. This case report presents a 43-year-old man with persistent parvovirus B19 infection and anaemia. The patient showed resistance to standard treatments but responded well to pegylated interferon alfa-2a. This highlights the potential of interferon alfa-2a as a treatment option for persistent parvovirus B19 infection.
LANCET INFECTIOUS DISEASES
(2023)
Article
Genetics & Heredity
Daniela Matuozzo, Estelle Talouarn, Astrid Marchal, Peng Zhang, Jeremy Manry, Yoann Seeleuthner, Yu Zhang, Alexandre Bolze, Matthieu Chaldebas, Baptiste Milisavljevic, Adrian Gervais, Paul Bastard, Takaki Asano, Lucy Bizien, Federica Barzaghi, Hassan Abolhassani, Ahmad Abou Tayoun, Alessandro Aiuti, Ilad Alavi Darazam, Luis M. Allende, Rebeca Alonso-Arias, Andres Augusto Arias, Gokhan Aytekin, Peter Bergman, Simone Bondesan, Yenan T. Bryceson, Ingrid G. Bustos, Oscar Cabrera-Marante, Sheila Carcel, Paola Carrera, Giorgio Casari, Khalil Chaibi, Roger Colobran, Antonio Condino-Neto, Laura E. Covill, Ottavia M. Delmonte, Loubna El Zein, Carlos Flores, Peter K. Gregersen, Marta Gut, Filomeen Haerynck, Rabih Halwani, Selda Hancerli, Lennart Hammarstroem, Nevin Hatipoglu, Adem Karbuz, Sevgi Keles, Christele Kyheng, Rafael Leon-Lopez, Jose Luis Franco, Davood Mansouri, Javier Martinez-Picado, Ozge Metin Akcan, Isabelle Migeotte, Pierre-Emmanuel Morange, Guillaume Morelle, Andrea Martin-Nalda, Giuseppe Novelli, Antonio Novelli, Tayfun Ozcelik, Figen Palabiyik, Qiang Pan-Hammarstroem, Rebeca Perez de Diego, Laura Planas-Serra, Daniel E. Pleguezuelo, Carolina Prando, Aurora Pujol, Luis Felipe Reyes, Jacques G. Riviere, Carlos Rodriguez-Gallego, Julian Rojas, Patrizia Rovere-Querini, Agatha Schlueter, Mohammad Shahrooei, Ali Sobh, Pere Soler-Palacin, Yacine Tandjaoui-Lambiotte, Imran Tipu, Cristina Tresoldi, Jesus Troya, Diederik van de Beek, Mayana Zatz, Pawel Zawadzki, Saleh Zaid Al-Muhsen, Mohammed Faraj Alosaimi, Fahad M. Alsohime, Hagit Baris-Feldman, Manish J. Butte, Stefan N. Constantinescu, Megan A. Cooper, Clifton L. Dalgard, Jacques Fellay, James R. Heath, Yu-Lung Lau, Richard P. Lifton, Tom Maniatis, Trine H. Mogensen, Horst von Bernuth, Alban Lermine, Michel Vidaud, Anne Boland, Jean-Francois Deleuze, Robert Nussbaum, Amanda Kahn-Kirby, France Mentre, Sarah Tubiana, Guy Gorochov, Florence Tubach, Pierre Hausfater, C. O. V. I. D. Human Genetic Effort, Isabelle Meyts, Shen-Ying Zhang, Anne Puel, Luigi D. Notarangelo, Stephanie Boisson-Dupuis, Helen C. Su, Bertrand Boisson, Emmanuelle Jouanguy, Jean-Laurent Casanova, Qian Zhang, Laurent Abel, Aurelie Cobat
Summary: Through a genome-wide rare variant burden association analysis, it was found that there is an association between at-risk variants in the TLR7 gene and rare loss-of-function variants in TLR3-dependent type I interferon immunity genes. These findings suggest that rare variants in TLR3- and TLR7-dependent type I interferon immunity genes may underlie life-threatening COVID-19 in patients under 60 years old.
Review
Microbiology
Morten Kelder Skouboe, Marvin Werner, Trine H. Mogensen
Summary: Herpesvirus infections can cause severe clinical manifestations in the central nervous system, but the understanding of the underlying host factors is incomplete. Defects in innate immune pathways and interferon production have been found to predispose individuals to herpes simplex encephalitis. Recent evidence suggests that IFN-independent intrinsic mechanisms play a crucial role in restricting herpesvirus replication and protecting against CNS infection. This review discusses clinical manifestations, host-pathogen interactions, and inborn errors of immunity that increase susceptibility to HSV CNS infection, highlighting the unanswered questions and future research directions in the pathogenesis of these diseases.
Article
Biology
Giorgia Marino, Baocun Zhang, Alexander Schmitz, Hanna V. F. Schwensen, Line S. Reinert, Soren R. Paludan
Summary: Critical COVID-19 is characterized by a lack of early antiviral defense and excessive lung inflammation. The aberrant activation of immune cells has been suggested to contribute to the pathology, with the DNA-sensing cGAS-STING pathway being implicated. However, this study using a mouse model found no evidence supporting a role for STING in COVID-19 pathology, as STING deficiency did not alter disease development or immune response.
LIFE SCIENCE ALLIANCE
(2023)
Article
Oncology
Justin V. Joseph, Mathilde S. Blaavand, Huiqiang Cai, Fabienne Vernejoul, Rasmus W. Knopper, Thomas B. Lindhardt, Kristian A. Skipper, Esben Axelgaard, Line Reinert, Jacob G. Mikkelsen, Per Borghammer, Soren E. Degn, Eric Perouzel, Henrik Hager, Brian Hansen, Joanna M. Kalucka, Mikkel Vendelbo, Soren R. Paludan, Martin K. Thomsen
Summary: This study focused on glioblastoma and investigated the activation of the innate immune system through long-term STING activation as a potential treatment approach. The results showed that this approach reduced tumor progression and prolonged survival. Additionally, prolonged STING activation led to alterations in tumor vasculature and activation of VEGFR. Combination treatment with anti-PD1 did not provide any additional benefits, suggesting that STING activation alone is sufficient to hinder tumor development.
Article
Biochemistry & Molecular Biology
Fanghui Ren, Ryo Narita, Ahmad S. Rashidi, Stefanie Fruhwurth, Zongliang Gao, Rasmus O. Bak, Martin K. Thomsen, Georges M. G. M. Verjans, Line S. Reinert, Soren R. Paludan
Summary: Neurotropic viruses such as herpes simplex virus (HSV) can infect neurons and cause severe diseases. HSV-induced neuronal cell death is mediated by gasdermin E (GSDME) and involves endoplasmic reticulum stress, caspase activation, and mitochondria-dependent apoptosis. The necrotic neurons release alarmins, triggering inflammatory responses in microglia.
Article
Virology
Kristoffer Skaalum Hansen, Sofie Eg Jorgensen, Morten Kelder Skouboe, Jane Agergaard, Berit Schiottz-Christensen, Line Khalidan Vibholm, Martin Tolstrup, Lars Ostergaard, Steffen Leth, Trine H. Mogensen
Summary: Long COVID is an emerging global health concern, and its underlying mechanism and pathophysiology are still unclear. This study found that autoantibodies against type 1 interferons in patients with Long COVID do not contribute to the symptoms.
JOURNAL OF MEDICAL VIROLOGY
(2023)
Article
Multidisciplinary Sciences
Stefanie Fruhwurth, Line S. Reinert, Carl Oberg, Marcelina Sakr, Marcus Henricsson, Henrik Zetterberg, Soren R. Paludan
Summary: Immunological control of viral infections in the brain, especially through the TREM2 pathway, is crucial for protection against herpes simplex virus type 1 (HSV1) infection and maintenance of brain integrity. The down-regulation of TREM2 expression in HSV1-infected microglia leads to impaired antiviral response and decreased ability to phagocytose infected neurons. This study highlights the importance of TREM2 in the immune defense against viral infections and raises questions about its role in neurological pathologies.
Article
Medicine, Research & Experimental
Azadeh Reyahi, Marie Studahl, Morten K. Skouboe, Stefanie Fruhwurth, Ryo Narita, Fanghui Ren, Moa Bjerhem Viklund, Marie B. Iversen, Mette Christiansen, Alexandra Svensson, Trine H. Mogensen, Kristina Eriksson, Soren R. Paludan
Summary: This study reveals the importance of the IKBKE gene and the cGAS/STING pathway in protecting against recurrent HSV-2 meningitis. A monoallelic variant in the IKBKE gene was identified in a patient with multiple episodes of HSV-2 meningitis, leading to impaired induction of IFN genes and decreased antiviral activity. The patient allele encoded a truncated IKK epsilon protein with loss of kinase activity and dominant-negative activity. Reintroducing wild-type IKBKE into patient cells restored IFN induction and antiviral activity. These findings highlight the nonredundant role of the cGAS/STING pathway in human antiviral immunity.
