{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTLR3 functions as a critical sensor for viral double‐stranded RNA in several cell types that are key to host antiviral defense. In respiratory and central nervous system cells, TLR3 detects dsRNA intermediates generated during viral replication—such as in influenza A virus and herpes simplex virus 1 infections—and induces type I interferon and proinflammatory cytokine production. In humans, defects in TLR3 signaling have been linked to fatal HSV-1 encephalitis and aberrant responses to viruses including Zika, as demonstrated in both in vivo studies and in stem cell–derived neural models, highlighting its indispensable role in central nervous system immunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in detecting exogenous viral RNA, TLR3 also senses endogenous RNA released by damaged, necrotic, or stressed cells, thereby modulating inflammatory responses in tissues such as the skin and lung. Activation of TLR3 in keratinocytes, for example, contributes to normal postinjury inflammation that can be modulated by commensal microbial products, while in mesenchymal stem cells and lung epithelial cells TLR3 engagement by tumor‐derived exosomal RNA influences cytokine secretion, cell death, and even metastatic niche formation. These findings underscore the dual role of TLR3 in innate responses that can either promote antiviral and antitumor immunity or, when dysregulated, contribute to immunopathology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, TLR3’s ability to recognize dsRNA is mediated by its horseshoe-shaped ectodomain, which dimerizes upon ligand binding and recruits the TRIF adaptor to activate divergent downstream pathways leading to NF-κB and IRF3 activation. Detailed mutagenesis and structural studies have mapped key residues and glycosylation sites essential for dsRNA binding and have elucidated how tyrosine phosphorylation events, c-Src recruitment, and subsequent activation of kinases such as TBK1 and PI3K/Akt fully potentiate interferon responses. Moreover, comparative investigations in epithelial, dendritic, and cancer cells—as well as studies of TLR3 promoter regulation and signaling crosstalk with other pattern recognition receptors—have broadened our understanding of how TLR3 orchestrates innate and adaptive immunity, influencing cellular outcomes ranging from antiviral defense and inflammatory cytokine secretion to apoptosis and autophagy. These mechanistic insights lay the groundwork for novel therapeutic strategies targeting TLR3 in infectious diseases, cancer, and immune disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "39"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Loïc Guillot, Ronan Le Goffic, Sarah Bloch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M410592200"}], "href": "https://doi.org/10.1074/jbc.M410592200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15579900"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15579900"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Shen-Ying Zhang, Emmanuelle Jouanguy, Sophie Ugolini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TLR3 deficiency in patients with herpes simplex encephalitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1139522"}], "href": "https://doi.org/10.1126/science.1139522"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17872438"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17872438"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Qiong Wang, Deepti R Nagarkar, Emily R Bowman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of double-stranded RNA pattern recognition receptors in rhinovirus-induced airway epithelial cell responses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.0901386"}], "href": "https://doi.org/10.4049/jimmunol.0901386"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19890046"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19890046"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Fabien G Lafaille, Itai M Pessach, Shen-Ying Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature11583"}], "href": "https://doi.org/10.1038/nature11583"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23103873"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23103873"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jason Dang, Shashi Kant Tiwari, Gianluigi Lichinchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Stem Cell (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.stem.2016.04.014"}], "href": "https://doi.org/10.1016/j.stem.2016.04.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27162029"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27162029"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Katalin Karikó, Houping Ni, John Capodici, et al. "}, {"type": "b", "children": [{"type": "t", "text": "mRNA is an endogenous ligand for Toll-like receptor 3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M310175200"}], "href": "https://doi.org/10.1074/jbc.M310175200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14729660"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14729660"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Bruno Salaun, Isabelle Coste, Marie-Clotilde Rissoan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TLR3 can directly trigger apoptosis in human cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.176.8.4894"}], "href": "https://doi.org/10.4049/jimmunol.176.8.4894"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16585585"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16585585"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Francesco Liotta, Roberta Angeli, Lorenzo Cosmi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cells (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1634/stemcells.2007-0454"}], "href": "https://doi.org/10.1634/stemcells.2007-0454"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17962701"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17962701"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Yuping Lai, Anna Di Nardo, Teruaki Nakatsuji, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm.2062"}], "href": "https://doi.org/10.1038/nm.2062"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19966777"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19966777"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Alenka Kuznik, Mojca Bencina, Urban Svajger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1000702"}], "href": "https://doi.org/10.4049/jimmunol.1000702"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21398612"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21398612"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Yanfang Liu, Yan Gu, Yanmei Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor Exosomal RNAs Promote Lung Pre-metastatic Niche Formation by Activating Alveolar Epithelial TLR3 to Recruit Neutrophils."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccell.2016.06.021"}], "href": "https://doi.org/10.1016/j.ccell.2016.06.021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27505671"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27505671"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Zhengfan Jiang, Tak W Mak, Ganes Sen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0308496101"}], "href": "https://doi.org/10.1073/pnas.0308496101"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14982987"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14982987"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Katalin Karikó, Prakash Bhuyan, John Capodici, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.172.11.6545"}], "href": "https://doi.org/10.4049/jimmunol.172.11.6545"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15153468"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15153468"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Saumendra N Sarkar, Kristi L Peters, Christopher P Elco, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Struct Mol Biol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nsmb847"}], "href": "https://doi.org/10.1038/nsmb847"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15502848"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15502848"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Kui Li, Zihong Chen, Nobuyuki Kato, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Distinct poly(I-C) and virus-activated signaling pathways leading to interferon-beta production in hepatocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M414139200"}], "href": "https://doi.org/10.1074/jbc.M414139200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15737993"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15737993"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Jorma Tissari, Jukka Sirén, Seppo Meri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IFN-alpha enhances TLR3-mediated antiviral cytokine expression in human endothelial and epithelial cells by up-regulating TLR3 expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.174.7.4289"}], "href": "https://doi.org/10.4049/jimmunol.174.7.4289"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15778392"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15778392"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Jungwoo Choe, Matthew S Kelker, Ian A Wilson "}, {"type": "b", "children": [{"type": "t", "text": "Crystal structure of human toll-like receptor 3 (TLR3) ectodomain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1115253"}], "href": "https://doi.org/10.1126/science.1115253"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15961631"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15961631"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Jessica K Bell, Istvan Botos, Pamela R Hall, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The molecular structure of the Toll-like receptor 3 ligand-binding domain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0505077102"}], "href": "https://doi.org/10.1073/pnas.0505077102"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16043704"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16043704"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Odette de Bouteiller, Estelle Merck, Uzma A Hasan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Recognition of double-stranded RNA by human toll-like receptor 3 and downstream receptor signaling requires multimerization and an acidic pH."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M507163200"}], "href": "https://doi.org/10.1074/jbc.M507163200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16144834"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16144834"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Christopher A Hewson, Alice Jardine, Michael R Edwards, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Toll-like receptor 3 is induced by and mediates antiviral activity against rhinovirus infection of human bronchial epithelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Virol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/JVI.79.19.12273-12279.2005"}], "href": "https://doi.org/10.1128/JVI.79.19.12273-12279.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16160153"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16160153"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Malika Bsibsi, Carla Persoon-Deen, Ronald W H Verwer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Glia (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/glia.20328"}], "href": "https://doi.org/10.1002/glia.20328"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16482523"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16482523"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Ingvild Bjellmo Johnsen, Thuy Thanh Nguyen, Monika Ringdal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to initiate antiviral signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.emboj.7601222"}], "href": "https://doi.org/10.1038/sj.emboj.7601222"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16858407"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16858407"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Misako Matsumoto, Tsukasa Seya "}, {"type": "b", "children": [{"type": "t", "text": "TLR3: interferon induction by double-stranded RNA including poly(I:C)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Adv Drug Deliv Rev (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.addr.2007.11.005"}], "href": "https://doi.org/10.1016/j.addr.2007.11.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18262679"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18262679"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Jason W Upton, William J Kaiser, Edward S Mocarski "}, {"type": "b", "children": [{"type": "t", "text": "Cytomegalovirus M45 cell death suppression requires receptor-interacting protein (RIP) homotypic interaction motif (RHIM)-dependent interaction with RIP1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.C800051200"}], "href": "https://doi.org/10.1074/jbc.C800051200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18442983"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18442983"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Behnam Naderi Kalali, Gabriele Köllisch, Jörg Mages, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Double-stranded RNA induces an antiviral defense status in epidermal keratinocytes through TLR3-, PKR-, and MDA5/RIG-I-mediated differential signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.181.4.2694"}], "href": "https://doi.org/10.4049/jimmunol.181.4.2694"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18684960"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18684960"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Zhenglin Yang, Charity Stratton, Peter J Francis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Toll-like receptor 3 and geographic atrophy in age-related macular degeneration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa0802437"}], "href": "https://doi.org/10.1056/NEJMoa0802437"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18753640"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18753640"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Pierre-Yves Bochud, Jason W Chien, Kieren A Marr, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa0802629"}], "href": "https://doi.org/10.1056/NEJMoa0802629"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18946062"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18946062"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Caroline Ospelt, Fabia Brentano, Yvonne Rengel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: toll-like receptor expression in early and longstanding arthritis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arthritis Rheum (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/art.24140"}], "href": "https://doi.org/10.1002/art.24140"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19035519"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19035519"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Yi-Ting Tsai, Sui-Yuan Chang, Chun-Nan Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human TLR3 recognizes dengue virus and modulates viral replication in vitro."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Microbiol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1462-5822.2008.01277.x"}], "href": "https://doi.org/10.1111/j.1462-5822.2008.01277.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19134117"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19134117"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Nan Wang, Yuqiong Liang, Santhana Devaraj, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Toll-like receptor 3 mediates establishment of an antiviral state against hepatitis C virus in hepatoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Virol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/JVI.01125-09"}], "href": "https://doi.org/10.1128/JVI.01125-09"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19625408"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19625408"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Alexander Panda, Feng Qian, Subhasis Mohanty, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.0901022"}], "href": "https://doi.org/10.4049/jimmunol.0901022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20100933"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20100933"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Rebeca Pérez de Diego, Vanessa Sancho-Shimizu, Lazaro Lorenzo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunity (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.immuni.2010.08.014"}], "href": "https://doi.org/10.1016/j.immuni.2010.08.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20832341"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20832341"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Salomé González-Reyes, Laura Marín, Lucía González, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Cancer (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2407-10-665"}], "href": "https://doi.org/10.1186/1471-2407-10-665"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21129170"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21129170"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "A M A Nasirudeen, Hui Hui Wong, Peiling Thien, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Activation of chemokine and inflammatory cytokine response in hepatitis C virus-infected hepatocytes depends on Toll-like receptor 3 sensing of hepatitis C virus double-stranded RNA intermediates."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hepatology (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/hep.24763"}], "href": "https://doi.org/10.1002/hep.24763"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22030901"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22030901"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Melina Herman, Michael Ciancanelli, Yi-Hung Ou, et al. 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