Article
Medicine, Research & Experimental
Adam J. Pollak, Luyi Zhao, Stanley T. Crooke
Summary: This study reveals the activation of TLR9 by single-stranded phosphorothioate oligonucleotides (PS-oligos) and uncovers the phenomenon of cooperative activation of TLR9. The researchers find that PS-oligos can bind to different sites on TLR9 and that certain PS-oligos can prime TLR9 for activation by other PS-oligos. However, further investigation is needed to determine the binding sites of specific PS-oligos on TLR9.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2023)
Editorial Material
Chemistry, Medicinal
Rohit Kumar Tiwari, Chhedi Lal Gupta, Preeti Bajpai
Summary: Recent trends in immunotherapy have shown interest in using Toll-like receptors (TLRs) for designing therapeutical interventions against deadly diseases. TLR9, a critical member of TLRs, is associated with inflammatory response to intruders. CG motifs from prokaryotic origin have been found to activate TLR9, leading to the expression of NF kappa B. This article discusses the utilization of TLR9 activation with novel parasitic CpG islands as potential adjuvants against visceral leishmaniasis caused by Leishmania donovani.
DRUG DEVELOPMENT RESEARCH
(2022)
Article
Chemistry, Multidisciplinary
Peiru Chen, Dali Wang, Yuyan Wang, Lei Zhang, Qiwei Wang, Lanxia Liu, Jiahe Li, Xin Sun, Mengqi Ren, Ruoxuan Wang, Yang Fang, Jean J. Zhao, Ke Zhang
Summary: This study demonstrates that a carrier-free spherical nucleic acid-based self-adjuvanting system can serve as a potent anticancer vaccine by enhancing adaptive immunity and significantly inhibiting tumor growth and metastasis.
Editorial Material
Cell Biology
Rohit Kumar Tiwari, Sarika Singh, Chhedi Lal Gupta, Preeti Bajpai
Summary: Understanding and activating pattern recognition receptors (PRRs) like Toll-like receptors (TLRs) can provide insights critical for managing neurological health disorders. Glioblastoma multiforme often expresses members of the TLR family, and activating TLR9 with unmethylated CG sequences may hold promise for therapeutic interventions against this type of brain tumor.
CELLULAR AND MOLECULAR NEUROBIOLOGY
(2021)
Article
Medicine, Research & Experimental
Irina Ushach, Ren Zhu, Elen Rosler, Rajendra K. Pandey, N. Tilani S. De Costa, Soheil Pourshahian, Qinglin Han, Chris Li, Leonid Beigelman, Sergei M. Gryaznov, Theodore Yun
Summary: The study aimed to design a novel immunomodulator to subvert immune tolerance to HBV, showing promising results in inducing strong immune responses against the virus by targeting CpG oligonucleotide to lymphoid organs in a mouse model of chronic HBV infection.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Article
Dentistry, Oral Surgery & Medicine
Alejandra Fernandez, Jessica Astorga, Maria Jose Bordagaray, Maria Jesus Lira, Peter J. Gebicke-Haerter, Marcela Hernandez
Summary: This study explores the methylation pattern and its impact on gene transcription of the TLR9 gene in chronic periapical inflammation. The results show that demethylation of certain CpG sites in the TLR9 promoter region enhances transcriptional activity. Additionally, age and smoking were found to affect the overall methylation status of the gene.
INTERNATIONAL ENDODONTIC JOURNAL
(2022)
Review
Endocrinology & Metabolism
Christopher R. Shepard
Summary: TLR9 plays a crucial role in regulating homeostasis under acute stress, but chronic activation in obesity can drive the pathogenesis of NASH and associated fibrosis. Research has focused on the contributions of parenchymal and non-parenchymal cells in various tissues, with elevated levels of circulating mtDNA observed in obesity, MAFLD, and NASH. Clinical evidence supports TLR9 overactivation as a driver of disease progression in NASH.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Adam J. Pollak, Luyi Zhao, Timothy A. Vickers, Ian J. Huggins, Xue-Hai Liang, Stanley T. Crooke
Summary: Non-CpG PS-ASOs can activate the innate immune system, but may lead to undesired outcomes. The innate immune responses of PS-ASOs can vary depending on their modifications and sequence. Pro-inflammatory PS-ASOs require TLR9 signaling, but their innate immunity is not correlated with their binding affinity with TLR9. Additionally, non-inflammatory PS-ASOs can reduce the innate immune responses of pro-inflammatory PS-ASOs, suggesting interaction with TLR9.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Virology
Agathe M. G. Colmant, Jody Hobson-Peters, Teun A. P. Slijkerman, Jessica J. Harrison, Gorben P. Pijlman, Monique M. van Oers, Peter Simmonds, Roy A. Hall, Jelke J. Fros
Summary: The study found that the zinc-finger antiviral protein (ZAP) in vertebrate cells effectively prevents insect-specific flaviviruses (ISF) from replicating in vertebrate cells. This research reveals how ISFs are inhibited, providing new insights into flavivirus evolution and mechanisms associated with host switching.
Article
Hematology
Emma Kennedy, Eve Coulter, Emma Halliwell, Nuria Profitos-Peleja, Elisabeth Walsby, Barnaby Clark, Elizabeth H. Phillips, Thomas A. Burley, Simon Mitchell, Stephen Devereux, Christopher D. Fegan, Christopher Jones, Rosalynd Johnston, Tim Chevassut, Ralph Schulz, Martina Seiffert, Angelo Agathanggelou, Ceri Oldreive, Nicholas Davies, Tatjana Stankovic, Triantafillos Liloglou, Chris Pepper, Andrea G. S. Pepper
Summary: Despite the advancements in B-cell receptor-targeted inhibitors, CLL remains incurable. TLR9 activation by unmethylated DNA is associated with disease progression in CLL. High TLR9 expression promotes CLL cell migration and disease progression, while dual targeting of TLR9 and BTK shows strong synergism as a potential treatment strategy for this incurable disease.
Article
Multidisciplinary Sciences
Olimpia Alessandra Buoninfante, Bas Pilzecker, Aldo Spanjaard, Daniel de Groot, Stefan Prekovic, Ji-Ying Song, Cor Lieftink, Matilda Ayidah, Colin E. J. Pritchard, Judith Vivie, Kathleen E. Mcgrath, Ivo J. Huijbers, Sjaak Philipsen, Marieke von Lindern, Wilbert Zwart, Roderick L. Beijersbergen, James Palish, Paul C. M. van den Berk, Heinz Jacobs
Summary: DNA damage poses a threat to genomic integrity and leads to stem cell failure. Cells use DNA damage tolerance (DDT), regulated by PCNA ubiquitination and REV1, to bypass genotoxic lesions during replication. While DDT is conserved in all domains of life, its relevance in mammals has been unclear. Our study demonstrates that inactivation of both PCNA ubiquitination and REV1 results in embryonic and adult lethality, as well as accumulation of DNA damage in hematopoietic stem and progenitor cells (HSPCs) which ultimately leads to their depletion. This highlights the crucial importance of DDT in the maintenance of stem cell compartments and mammalian life under unperturbed conditions.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Medicine, Research & Experimental
Ling Bai, Lei Zhou, Wei Han, Jingtao Chen, Xiaoyi Gu, Zheng Hu, Yongguang Yang, Wei Li, Xiaoying Zhang, Chao Niu, Yongchong Chen, Hui Li, Jiuwei Cui
Summary: This study investigated the direct effects of TLR9 agonists on B-ALL cells and found that high expression of TLR9 in B-ALL patients is associated with good prognosis. Additionally, CpG 685 was found to induce apoptosis in B-ALL cells by activating C-MYC and BAX. Combination therapy of CpG 685 and imatinib reversed resistance and showed promising results. Therefore, TLR9 and CpG 685 could be potential targets and drugs for B-ALL therapy.
JOURNAL OF TRANSLATIONAL MEDICINE
(2023)
Article
Multidisciplinary Sciences
Aartik Sarma, Stephanie A. Christenson, Ashley Byrne, Eran Mick, Angela Oliveira Pisco, Catherine DeVoe, Thomas Deiss, Rajani Ghale, Beth Shoshana Zha, Alexandra Tsitsiklis, Alejandra Jauregui, Farzad Moazed, Angela M. Detweiler, Natasha Spottiswoode, Pratik Sinha, Norma Neff, Michelle Tan, Paula Hayakawa Serpa, Andrew Willmore, K. Mark Ansel, Jennifer G. Wilson, Aleksandra Leligdowicz, Emily R. Siegel, Marina Sirota, Joseph L. DeRisi, Michael A. Matthay, Carolyn M. Hendrickson, Kirsten N. Kangelaris, Matthew F. Krummel, Prescott G. Woodruff, David J. Erle, Carolyn S. Calfee, Charles R. Langelier
Summary: The authors performed transcriptional profiling on tracheal aspirates of adults with SARS-CoV2-induced ARDS and found a dysregulated host response that could potentially be modulated by dexamethasone. They also observed distinct immunological features in COVID-19 ARDS compared to ARDS from other causes, including reduced proinflammatory gene expression and increased PTEN signaling. In addition, in silico analysis identified candidate drugs, such as dexamethasone and granulocyte colony stimulating factor, that may modulate gene expression in COVID-19 ARDS.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Medicinal
Nirmal Das, Purbita Bandopadhyay, Swarnali Roy, Bishnu Prasad Sinha, Uddipta Ghosh Dastidar, Oindrila Rahaman, Sourav Pal, Dipyaman Ganguly, Arindam Talukdar
Summary: This study identifies a new chemotype for targeting TLR7 and TLR9 with dual antagonism. The researchers established the minimal pharmacophoric features in the core structure and optimized the lead candidate based on in vitro and in vivo assays. The oral absorption and efficacy of the lead candidate were demonstrated through pharmacokinetic and pharmacodynamic studies.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Weikang Sun, Hao Li, Yuehong Zhao, Longwei Bai, Yukai Qin, Qun Wang, Weiwei Li
Summary: The study identified three conserved VG domains in the Chinese mitten crab, highlighting functional similarities of Vg in vertebrates and invertebrates. Among these domains, DUF1943 and VWD showed bacterial binding activity, with only the VWD domain inhibiting bacterial proliferation. Furthermore, the study demonstrated that EsVg regulates hemocyte phagocytosis by binding with EspIgR through the DUF1943 domain, promoting bacterial clearance and protecting the host from infection.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Microbiology
Jason M. Shapiro, Marcel R. de Zoete, Noah W. Palm, Yaro Laenen, Rene Bright, Meaghan Mallette, Kevin Bu, Agata A. Bielecka, Fang Xu, Andres Hurtado-Lorenzo, Samir A. Shah, Judy H. Cho, Neal S. LeLeiko, Bruce E. Sands, Richard A. Flavell, J. C. Clemente
Summary: The immunopathogenesis of inflammatory bowel disease (IBD) is linked to host genetics and intestinal dysbiosis. Investigating IgA responses to microbiota can reveal potential disease-modifying taxa and improved biomarkers of clinical course in IBD.
CELL HOST & MICROBE
(2021)
Article
Gastroenterology & Hepatology
Eelco C. Brand, Marjolein A. Y. Klaassen, Ranko Gacesa, Arnau Vich Vila, Hiren Ghosh, Marcel R. de Zoete, Dorret Boomsma, Frank Hoentjen, Carmen S. Horjus Talabur Horje, Paul C. van de Meeberg, Gonneke Willemsen, Jingyuan Fu, Cisca Wijmenga, Femke van Wijk, Alexandra Zhernakova, Bas Oldenburg, Rinse K. Weersma
Summary: The gut microbiome of healthy cotwins from IBD-discordant twin pairs displays IBD-like signatures, potentially preceding the onset of IBD. However, longitudinal follow-up studies are needed to infer a causal relationship.
Article
Microbiology
Xinyue Li, Richard W. Wubbolts, Nancy M. C. Bleumink-Pluym, Jos P. M. van Putten, Karin Strijbis
Summary: MUC1 at the host-microbe interface facilitates bacterial invasion through beta 1 integrins, involving a concerted action of the MUC1 O-glycosylated extracellular domain and cytoplasmic tail.
Article
Immunology
R. Villarreal, H. S. Manzer, A. M. Keestra-Gounder, K. S. Doran
Summary: The study on the pathogenesis of GBS meningitis reveals the critical roles of vimentin and NOD2 in mediating inflammatory responses induced by GBS. Vimentin is essential for regulating the inflammation process, while NOD2 promotes chemokine induction in response to GBS infection, highlighting their importance in host immune responses against GBS invasion.
INFECTION AND IMMUNITY
(2021)
Article
Microbiology
Jiannan Cui, Coco Duizer, Lieneke Bouwman, Kristel S. van Rooijen, Carlos G. P. Voogdt, Jos P. M. van Putten, Marcel R. de Zoete
Summary: Authors identified ADP-heptose and/or related heptose phosphates released by Campylobacter jejuni as a potent activator of inflammation in intestinal epithelial cells, signaling through the ALPK1 receptor. These results suggest a potential therapeutic target to treat Campylobacter infection and elucidate the virulence mechanisms involved in the development of bacterial enteritis.
Article
Microbiology
Mostafa Asadpoor, Georgia-Nefeli Ithakisiou, Jos P. M. van Putten, Roland J. Pieters, Gert Folkerts, Saskia Braber
Summary: AOS and COS affect the growth of GBS V and S. aureus wood 46, functioning as anti-biofilm agents. The combination of AOS and COS with different antibiotics may provide new opportunities to combat antimicrobial resistance.
FRONTIERS IN MICROBIOLOGY
(2021)
Article
Immunology
Michiel M. Kroes, Alberto Miranda-Bedate, Elise S. Hovingh, Ronald Jacobi, Corrie Schot, Elder Pupo, Rene H. M. Raeven, Arno A. J. van der Ark, Jos P. M. van Putten, Jelle de Wit, Rob Mariman, Elena Pinelli
Summary: Despite high pertussis vaccination coverage, respiratory infections caused by Bordetella pertussis are reemerging. Studies show that strains lacking pertactin (Prn) component of the vaccine induce stronger immune activation. The findings highlight the role of pathogen adaptation and vaccine pressure in the resurgence of pertussis.
EMERGING MICROBES & INFECTIONS
(2021)
Article
Immunology
Lydia A. Sweet, Sharon K. Kuss-Duerkop, A. Marijke Keestra-Gounder
Summary: ER stress and the IRE1 alpha pathway play crucial roles in inducing inflammation during bacterial infection.
INFECTION AND IMMUNITY
(2022)
Article
Engineering, Biomedical
Yang Cai, Jos P. M. S. van Putten, Myrthe S. Gilbert, Walter J. J. Gerrits, Gert Folkerts, Saskia Braber
Summary: The emergence of antimicrobial resistance in infections has created a need for new intervention strategies. Galacto-oligosaccharides (GOS) show potential as an alternative to antibiotics due to their anti-inflammatory and anti-adhesive properties. Mannheimia haemolytica is a major bacteria associated with bovine lung infections, and the study demonstrates that GOS can reduce its viability and enhance the efficacy of antibiotics. GOS also exhibit anti-adhesive and anti-invasive activities in primary bronchial epithelial cells, which can be attributed to their downregulation of toll-like receptor 4/nuclear factor-kappa B pathway. Furthermore, GOS have been shown to relieve lung infections/inflammation and reduce M. haemolytica positivity in vivo without altering clinical performance. These findings highlight the anti-inflammatory mechanisms of GOS and its potential as a promising agent for preventing infections.
Article
Multidisciplinary Sciences
M. M. Kroes, A. Miranda-Bedate, R. H. J. Jacobi, E. van Woudenbergh, G. den Hartog, J. P. M. van Putten, J. de Wit, E. Pinelli
Summary: This study investigated the response of human airway epithelial cells to Bordetella pertussis infection. The infection resulted in reduced epithelial barrier integrity and disrupted mucociliary transport. The study suggests that B. pertussis only induces mild immunological activation in the epithelial cells and requires communication with local immune cells for a broad immune response.
SCIENTIFIC REPORTS
(2022)
Article
Gastroenterology & Hepatology
Xuefeng Cao, Chris H. A. van de Lest, Liane Z. X. Huang, Jos P. M. van Putten, Marc M. S. M. Wosten
Summary: Research reveals that lysophospholipids of Campylobacter jejuni have toxicity to host cells, especially the short-chain lysoPEs (C:14) may be considered as a novel virulence factor.
Article
Microbiology
Maitrayee Chatterjee, Liane Z. X. L. Huang, Anna Mykytyn, Chunyan Wang, Mart B. Lamers, Bart Westendorp, Richard B. Wubbolts, Jos P. M. van Putten, Berend-Jan B. Bosch, Bart Haagmans, Karin B. Strijbis
Summary: In this study, the role of host mucins and mucin glycans on SARS-CoV-2 entry into airway epithelial cells was investigated. The removal of mucins from the surface of cells increased the binding of the virus and enhanced infection. This study demonstrates the important role of glycosylated extracellular mucin domains in the entry of SARS-CoV-2.
Article
Gastroenterology & Hepatology
Noortje Ijssennagger, Kristel S. van Rooijen, Stefania Magnusdottir, Jose M. Ramos Pittol, Ellen C. L. Willemsen, Marcel R. de Zoete, Matthijs J. D. Baars, Paul B. Stege, Carolina Colliva, Roberto Pellicciari, Sameh A. Youssef, Alain de Bruin, Yvonne Vercoulen, Folkert Kuipers, Saskia W. C. van Mil
Summary: This study highlights the importance of liver-to-gut communication for intestinal health, with a focus on colon functioning. Elimination of Fxr in the liver significantly affects colonic gene expression and enhances the protective capacity of the mucus barrier.
Article
Gastroenterology & Hepatology
Guus H. van Muijlwijk, Guido van Mierlo, Pascal W. T. C. Jansen, Michiel Vermeulen, Nancy M. C. Bleumink-Pluym, Noah W. Palm, Jos P. M. van Putten, Marcel R. de Zoete
Summary: The human gut microbiota plays a key role in intestinal health and disease, with some bacteria linked to human diseases exploiting the inner mucus layer as an important niche. A newly identified IBD-associated species, Allobaculum mucolyticum, was found to carry up to 60 genes encoding putative Carbohydrate Active Enzymes (CAZymes) that may contribute to mucosal colonization. Mass spectrometry revealed the presence of 49 CAZymes, with 26 significantly enriched in its secretome, suggesting that A. mucolyticum's CAZyme secretion may facilitate bacterial colonization and degradation of the mucus layer.
