RESUMEN
Toll-like receptors (TLRs) play an important role in innate immune through recognizes pathogens. In order to reveal the evolutionary patterns and adaptive evolution of avian TLRs, we examined 66 representative bird species in 26 orders. Phylogenetic results indicated that TLR1A and TLR1B may have differentiated functionally. Evolutionary analysis showed that the TLR genes in birds under strong Purification selection (0.165-0.4265). A total of 126 common positively selected codons were identified in 10 TLR genes of avian, and most sites were located in the extracellular leucine-rich repeat (LRR) functional domains, and both environment and feeding habits were external factors driving the evolution of avian TLR genes. Environmental pressures had a greater effect on TLR1B, TLR2B, TLR3 and TLR4, while feeding habits were active in affecting TLR2A, TLR2B, TLR15 and TLR21. Our data suggested that TLR genes have been subjected to different selective pressures in the diversification of birds and that these changes enabled them to respond differently to pathogens from diverse sources.
Asunto(s)
Adaptación Fisiológica/genética , Proteínas Aviares/genética , Aves/genética , Evolución Molecular , Duplicación de Gen , Receptores Toll-Like/genética , Animales , Secuencia de Bases , Ecosistema , Conducta Alimentaria , Filogenia , Conformación Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Selección Genética , Homología de Secuencia de Ácido Nucleico , Receptor Toll-Like 1/química , Receptor Toll-Like 1/genética , Receptores Toll-Like/química , Receptores Toll-Like/clasificaciónRESUMEN
Head and neck squamous cell carcinoma (HNSCC) is a group of tumours which exhibit low 5 year survival rates. Thus, there is an urgent need to identify biomarkers that may improve the clinical utility of patients with HNSCC. Emerging studies support a role of toll-like receptors (TLRs) in carcinogenesis. Therefore, this systematic review and meta-analysis was performed to assess the prognostic value of TLR immunoexpression in HNSCC patients. We compiled the results of thirteen studies comprising 1825 patients, of which six studies were deemed qualified for quantitative synthesis. The higher immunoexpression of TLR-1 to 5 and 9 was associated with a worsening of the clinical parameters of patients with HNSCC. Furthermore, induced levels of TLR-3, 4, 5, 7 and 9 were found to predict the patients' survival time. The meta-analysis revealed that TLR-7 overexpression is associated with a decreased mortality risk in HNSCC patients (HR 0.51; 95%CI 0.13-0.89; I2 34.6%), while a higher expression of TLR-5 predicted shorter, but non-significant, survival outcome. In conclusion, this review suggests that TLRs may represent some prognostic value for patients with HNSCC. However, due to small sample sizes and other inherent methodological limitations, more well designed studies across different populations are still needed before TLRs can be recommended as a reliable clinical risk-stratification tool.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Receptor Toll-Like 5/genética , Receptor Toll-Like 7/genética , Supervivencia sin Enfermedad , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/epidemiología , Tasa de Supervivencia , Receptores Toll-Like/clasificación , Receptores Toll-Like/genéticaRESUMEN
Coronavirus disease-2019 (COVID-19) outbreak due to novel coronavirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has come out as a major threat for mankind in recent times. It is continually taking an enormous toll on mankind by means of increasing number of deaths, associated comorbidities, and socioeconomic loss around the globe. Unavailability of chemotherapeutics/vaccine has posed tremendous challenges to scientists and doctors for developing an urgent therapeutic strategy. In this connection, the present in silico study aims to understand the sequence divergence of spike protein (the major infective protein of SARS-CoV-2), its mode of interaction with the angiotensin-converting enzyme-2 receptor (ACE2) receptor of human and related animal hosts/reservoir. Moreover, the involvement of the human Toll-like receptors (TLRs) against the spike protein has also been demonstrated. Our data indicated that the spike glycoprotein of SARS-CoV-2 is phylogenetically close to bat coronavirus and strongly binds with ACE2 receptor protein from both human and bat origin. We have also found that cell surface TLRs, especially TLR4 is most likely to be involved in recognizing molecular patterns from SARS-CoV-2 to induce inflammatory responses. The present study supported the zoonotic origin of SARS-CoV-2 from a bat and also revealed that TLR4 may have a crucial role in the virus-induced inflammatory consequences associated with COVID-19. Therefore, selective targeting of TLR4-spike protein interaction by designing competitive TLR4-antagonists could pave a new way to treat COVID-19. Finally, this study is expected to improve our understanding on the immunobiology of SARS-CoV-2 and could be useful in adopting spike protein, ACE2, or TLR-guided intervention strategy against COVID-19 shortly.
Asunto(s)
Alphacoronavirus/química , Enzima Convertidora de Angiotensina 2/química , Receptores Virales/química , SARS-CoV-2/química , Glicoproteína de la Espiga del Coronavirus/química , Receptores Toll-Like/química , Alphacoronavirus/clasificación , Alphacoronavirus/metabolismo , Alphacoronavirus/patogenicidad , Enzima Convertidora de Angiotensina 2/clasificación , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Sitios de Unión , COVID-19/inmunología , COVID-19/virología , Quirópteros/inmunología , Quirópteros/virología , Minería de Datos , Euterios/inmunología , Euterios/virología , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Modelos Moleculares , Filogenia , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Receptores Virales/clasificación , Receptores Virales/genética , Receptores Virales/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/clasificación , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Termodinámica , Receptores Toll-Like/clasificación , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Viverridae/inmunología , Viverridae/virologíaRESUMEN
Toll-like receptors (TLRs) are a complex family of innate immune genes that are well characterized in mammals and birds but less well understood in nonavian sauropsids (reptiles). The advent of highly contiguous draft genomes of nonmodel organisms enables study of such gene families through analysis of synteny and sequence identity. Here, we analyze TLR genes from the genomes of 22 tetrapod species. Findings reveal a TLR8 gene expansion in crocodilians and turtles (TLR8B), and a second duplication (TLR8C) specifically within turtles, followed by pseudogenization of that gene in the nonfreshwater species (desert tortoise and green sea turtle). Additionally, the Mojave desert tortoise (Gopherus agassizii) has a stop codon in TLR8B (TLR8-1) that is polymorphic among conspecifics. Revised orthology further reveals a new TLR homolog, TLR21-like, which is exclusive to lizards, snakes, turtles, and crocodilians. These analyses were made possible by a new draft genome assembly of the desert tortoise (gopAga2.0), which used chromatin-based assembly to yield draft chromosomal scaffolds (L50 = 26 scaffolds, N50 = 28.36 Mb, longest scaffold = 107 Mb) and an enhanced de novo genome annotation with 25,469 genes. Our three-step approach to orthology curation and comparative analysis of TLR genes shows what new insights are possible using genome assemblies with chromosome-scale scaffolds that permit integration of synteny conservation data.
Asunto(s)
Cromosomas/genética , Genoma/genética , Receptores Toll-Like/genética , Animales , Filogenia , Reptiles/genética , Reptiles/metabolismo , Sintenía/genética , Receptor Toll-Like 8/clasificación , Receptor Toll-Like 8/genética , Receptores Toll-Like/clasificación , TortugasRESUMEN
Adaptation to a wide range of pathogenic environments is a major aspect of the ecological adaptations of vertebrates during evolution. Toll-like receptors (TLRs) are ancient membrane-bound sensors in animals and are best known for their roles in detecting and defense against invading pathogenic microorganisms. To understand the evolutionary history of the vertebrate TLR gene family, we first traced the origin of single-cysteine cluster TLRs that share the same protein architecture with vertebrate TLRs in early-branching animals and then analyzed all members of the TLR family in over 200 species covering all major vertebrate clades. Our results indicate that although the emergence of single-cysteine cluster TLRs predates the separation of bilaterians and cnidarians, most vertebrate TLR members originated shortly after vertebrate emergence. Phylogenetic analyses divided 1,726 vertebrate TLRs into 8 subfamilies, and TLR3 may represent the most ancient subfamily that emerged before the branching of deuterostomes. Our analysis reveals that purifying selection predominated in the evolution of all vertebrate TLRs, with mean dN/dS (ω) values ranging from 0.082 for TLR21 in birds to 0.434 for TLR11 in mammals. However, we did observe patterns of positive selection acting on specific codons (527 of 60,294 codons across all vertebrate TLRs, 8.7), which are significantly concentrated in ligand-binding extracellular domains and suggest host-pathogen coevolutionary interactions. Additionally, we found stronger positive selection acting on nonviral compared with viral TLRs, indicating the more essential nonredundant function of viral TLRs in host immunity. Taken together, our findings provide comprehensive insight into the complex evolutionary processes of the vertebrate TLR gene family, involving gene duplication, pseudogenization, purification, and positive selection.
Asunto(s)
Evolución Molecular , Familia de Multigenes , Receptores Toll-Like/genética , Vertebrados/genética , Animales , Filogenia , Selección Genética , Receptores Toll-Like/clasificaciónRESUMEN
Toll-like receptors (TLRs) are the most well studied pattern recognition receptors (PRRs) that play a crucial role in both innate and adaptive immunity in animals. In the present study, a novel toll-like receptor (McTLRj) was identified and characterised in thick shell mussel Mytilus coruscus. McTLRj possessed a signal peptide, a transmembrane domain, leucine-rich repeats and an intracellular Toll/interleukin-1 receptor domain that were conserved in typical TLRs. McTLRj transcripts were constitutively expressed in all of the examined tissues with high expression level in immune-related tissues, and significantly induced in haemocytes upon live Vibrio alginolyticus, lipopolysaccharide, polyinosinic-polycytidylic acid and peptidoglycans challenge. The overexpression of the McTLRj TLR fragment in Drosophila S2 cells could induce the expression of Drosophila attacin A, drosomycin, cecropin A, and metchnikowin expression. The expression of McTLRj was obviously repressed by dsRNA-mediated RNA interference, and downstream TLR pathway factors, such as MyD88a, IRAK4, and TRAF6 were significantly repressed in McTLRj-silenced mussels upon LPS challenge. These results collectively indicated that McTLRj is a TLR family member that may play a potential PRR role in TLR-mediated signalling pathway. This research contributed to the clarification of innate immune response in molluscs.
Asunto(s)
Inmunidad/inmunología , Mytilus/inmunología , Transducción de Señal/inmunología , Receptores Toll-Like/inmunología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Línea Celular , Clonación Molecular , Perfilación de la Expresión Génica/métodos , Hemocitos/inmunología , Hemocitos/metabolismo , Hemocitos/virología , Inmunidad/genética , Mytilus/genética , Filogenia , Interferencia de ARN , Análisis de Secuencia de ADN , Transducción de Señal/genética , Receptores Toll-Like/clasificación , Receptores Toll-Like/genética , Vibrio alginolyticus/inmunología , Vibrio alginolyticus/fisiologíaRESUMEN
The innate immune system governed by toll-like receptors (TLRs) provides the first line of defense against pathogens. Surface-localized TLR1 and TLR6 are known to detect parasite components. TLR encoding genes wereshown to display signatures of recent positive selection in Europeans and might be involved in local adaptation at immune-related genes. To verify the influence of Brazilian population admixture on the distribution of polymorphisms in TLRs, we analyzed the genotype frequencies of 24 polymorphisms distributed across five TLRgenes in a Southeastern Brazilian population where autochthonous cases of malaria occur in small foci oftransmission. The estimation of ancestry showed mainly European ancestry (63%) followed by African ancestry(22%). Mean proportions of European ancestry differed significantly between the genotypes of the TLR1 (I602S) gene and in the TLR6 (P249S) gene. The chance of having the G allele in TLR1 gene increases as Europeanancestry increases as well as the chance of having the T allele in the TLR6 gene. The 602S allele is related to ahypo-responsiveness possibly explaining the high prevalence of asymptomatic malaria cases in areas of Southeastern Brazil. Our results underline the necessity to include informative ancestry markers in genetic association studies in order to avoid biased results...
Asunto(s)
Humanos , Polimorfismo Genético/genética , Receptores Toll-Like/análisis , Receptores Toll-Like/clasificación , Receptores Toll-Like/genéticaRESUMEN
OBJECTIVE: To show experimentally induced renal stone disease and to evaluate secondary inflammatory responses in vivo, and to characterize changes in the expression of Toll-like receptor (TLR) subtypes in this model. METHODS: Twenty 5- to 6-week-old male Wistar rats were divided into control and hyperoxaluria groups (n = 10 per group) and were supplied with normal water or 1% ethylene glycol, respectively, for 16 weeks. The animals were then placed in metabolic cages, and urine was collected for a 24-hour urine oxalate level evaluation. Following sacrifice, rats were subjected to bilateral nephrectomy and both kidneys were histopathologically evaluated. A 1-mm3 biopsy section from the right kidney of each rat was subjected to real-time polymerase chain reaction of the TLR expression. RESULTS: At the end of week 16, the hyperoxaluria group had a higher mean 24-hour urine oxalate level (1.91) than the control group (0.29) (P <.05) and a remarkably increased deposition of renal CaOx crystals (15/20) than the control group (0/20) (P <.05), which was universally accompanied by inflammation (15/15). Twelve and no rats in the hyperoxaluria and control groups, respectively, had macroscopically visible renal pelvic stones (P <.05). Quantitative real-time polymerase chain reaction revealed significant decreases in the expression of several TLRs, particularly TLR11 and TLR7. Decreases in TLR1, TLR3, and TLR6 expressions and an increase in the TLR2 expression did not differ significantly between the groups. CONCLUSION: We believe that is the first evaluation of TLR expression associated with renal stone formation in an animal model of inflammation. These results might lead to novel TLR-based treatments for nephrolithiasis and related inflammatory renal damage.
Asunto(s)
Cálculos Renales/etiología , Nefritis/etiología , Receptores Toll-Like/clasificación , Receptores Toll-Like/fisiología , Animales , Modelos Animales de Enfermedad , Masculino , Ratas WistarRESUMEN
The Toll-like receptor (TLR) gene family is a class of conserved pattern recognition receptors, which play an essential role in innate immunity providing efficient defense against invading microbial pathogens. Although TLRs have been extensively characterized in both invertebrates and vertebrates, a comprehensive analysis of TLRs in common carp is lacking. In the present study, we have conducted the first genome-wide systematic analysis of common carp (Cyprinus carpio) TLR genes. A set of 27 common carp TLR genes were identified and characterized. Sequence similarity analysis, functional domain prediction and phylogenetic analysis supported their annotation and orthologies. By examining the gene copy number of TLR genes across several vertebrates, gene duplications and losses were observed. The expression patterns of TLR genes were examined during early developmental stages and in various healthy tissues, and the results showed that TLR genes were ubiquitously expressed, indicating a likely role in maintaining homeostasis. Moreover, the differential expression of TLRs was examined after Aeromons hydrophila infection, and showed that most TLR genes were induced, with diverse patterns. TLR1, TLR4-2, TLR4-3, TLR22-2, TLR22-3 were significantly up-regulated at minimum one timepoint, whereas TLR2-1, TLR4-1, TLR7-1 and TLR7-2 were significantly down-regulated. Our results suggested that TLR genes play critical roles in the common carp immune response. Collectively, our findings provide fundamental genomic resources for future studies on fish disease management and disease-resistance selective breeding strategy development.
Asunto(s)
Aeromonas hydrophila/inmunología , Carpas/genética , Enfermedades de los Peces/inmunología , Infecciones por Bacterias Gramnegativas/inmunología , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Animales , Carpas/inmunología , Dosificación de Gen , Genoma/genética , Genoma/inmunología , Infecciones por Bacterias Gramnegativas/veterinaria , Especificidad de Órganos , Filogenia , Receptores Toll-Like/clasificaciónRESUMEN
Toll-like receptors (TLRs) are germline-encoded, non-clonal innate immune receptors, which are often the first receptors to recognize the molecular patterns on pathogens. Therefore, the immune response initiated by TLRs has far-reaching consequences on the outcome of an infection. As soon as the cell surface TLRs and other receptors recognize a pathogen, the pathogen is phagocytosed. Inclusion of TLRs in the phagosome results in quicker phagosomal maturation and stronger adaptive immune response, as TLRs influence co-stimulatory molecule expression and determinant selection by major histocompatibility complex (MHC) class II and MHC class I for cross-presentation. The signals delivered by the TCR-peptide-MHC complex and co-stimulatory molecules are indispensable for optimal T cell activation. In addition, the cytokines induced by TLRs can skew the differentiation of activated T cells to different effector T cell subsets. However, the potential of TLRs to influence adaptive immune response into different patterns is severely restricted by multiple factors: gross specificity for the molecular patterns, lack of receptor rearrangements, sharing of limited number of adaptors that assemble signalling complexes and redundancy in ligand recognition. These features of apparent redundancy and regulation in the functioning of TLRs characterize them as important and probable contributory factors in the resistance or susceptibility to an infection.
Asunto(s)
Leishmania/inmunología , Leishmaniasis/inmunología , Receptores Toll-Like/inmunología , Inmunidad Adaptativa , Animales , Reactividad Cruzada , Regulación de la Expresión Génica , Humanos , Inmunidad Innata , Ratones , Moléculas de Patrón Molecular Asociado a Patógenos/inmunología , Fagocitosis , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/fisiología , Receptores Toll-Like/clasificación , Receptores Toll-Like/deficiencia , Receptores Toll-Like/genéticaRESUMEN
TLR2-dependent cellular signaling in Mycobacterium tuberculosis-infected macrophages causes apoptosis and inhibits class II major histocompatibility complex (MHC-II) molecules antigen processing, leading to evasion of surveillance. Mycobacterium tuberculosis (MTB) lipoproteins are an important class of Toll-like receptor (TLR) ligand, and identified as specific components that mediate these effects. In this study, we identified and characterized MTB lipoprotein Rv1016c (lpqT) as a cell wall associated-protein that was exposed on the cell surface and enhanced the survival of recombinants M. smegmatis_Rv1016c under stress conditions. We found that Rv1016c lipoprotein was a novel TLR2 ligand and able to induce macrophage apoptosis in a both dose- and time-dependent manner. Additionally, apoptosis induced by Rv1016c was reserved in THP-1 cells blocked with anti-TLR-2 Abs or in TLR2-/- mouse macrophages, indicating that Rv1016c-induced apoptosis is dependent on TLR2. Moreover, we demonstrated that Rv1016c lipoprotein inhibited IFN-γ-induced MHC-II expression and processing of soluble antigens in a TLR2 dependent manner. Class II transactivator (CIITA) regulates MHC II expression. In this context, Rv1016c lipoprotein diminished IFN-γ-induced expression of CIITA IV through TLR2 and MAPK Signaling. TLR2-dependent apoptosis and inhibition of MHC-II Ag processing induced by Rv1016c during mycobacteria infection may promote the release of residual bacilli from apoptotic cells and decrease recognition by CD4+ T cells. These mechanisms may allow intracellular MTB to evade immune surveillance and maintain chronic infection.
Asunto(s)
Presentación de Antígeno/efectos de los fármacos , Apoptosis/efectos de los fármacos , Proteínas Bacterianas/farmacología , Antígenos de Histocompatibilidad Clase II/efectos de los fármacos , Lipoproteínas/genética , Macrófagos/microbiología , Mycobacterium tuberculosis/metabolismo , Proteínas Recombinantes/farmacología , Receptor Toll-Like 2/metabolismo , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Línea Celular , Pared Celular/química , ADN Bacteriano , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Genes Bacterianos/genética , Humanos , Interferón gamma/efectos de los fármacos , Lipoproteínas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mycobacterium smegmatis , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/inmunología , Proteínas Nucleares/efectos de los fármacos , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Receptores de Superficie Celular/fisiología , Proteínas Recombinantes/genética , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia , Receptor Toll-Like 2/genética , Receptores Toll-Like/clasificación , Receptores Toll-Like/metabolismo , Transactivadores/efectos de los fármacos , Tuberculosis/microbiologíaRESUMEN
Notothenia coriiceps, a typical Antarctic notothenioid teleost, has evolved to adapt to the extreme Antarctic marine environment. We previously reported an extensive analysis of the Antarctic notothenioid transcriptome. In this study, we focused on a key component of the innate immune system, the Toll-like receptors (TLRs). We cloned the full-length sequence of 12 TLRs of N. coriiceps. The N. coriiceps transcriptome for TLR homologue (ncTLR) genes encode a typical TLR structure, with multiple extracellular leucine-rich regions and an intracellular Toll/IL-1 receptor (TIR) domain. Using phylogenetic analysis, we established that all of the cloned ncTLR genes could be classified into the same orthologous clade with other teleost TLRs. ncTLRs were widely expressed in various organs, with the highest expression levels observed in immune-related tissues, such as the skin, spleen, and kidney. A subset of the ncTLR genes was expressed at higher levels in fish exposed to pathogen-mimicking agonists, heat-killed Escherichia coli, and polyinosinic-polycytidylic acid (poly(I:C)). However, the mechanism involved in the upregulation of TLR expression following pathogen exposure in fish is currently unknown. Further research is required to elucidate these mechanisms and to thereby increase our understanding of vertebrate immune system evolution.
Asunto(s)
Escherichia coli/patogenicidad , Enfermedades de los Peces/genética , Peces/genética , Peces/inmunología , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno/genética , Receptores Toll-Like/genética , Secuencia de Aminoácidos , Animales , Biomarcadores/metabolismo , Infecciones por Escherichia coli/genética , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/microbiología , Enfermedades de los Peces/microbiología , Peces/microbiología , Perfilación de la Expresión Génica , Datos de Secuencia Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos , Filogenia , Poli I-C/farmacología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de Aminoácido , Receptores Toll-Like/clasificaciónRESUMEN
The immune system (IS) cells are capable of recognizing a wide variety of microorganisms, through receptors that are expressed and distributed throughout the cell architecture. The interaction between the pathogen-associated molecular patterns or damage-associated molecular patterns (PAMPs or DAMPs) and pattern recognition receptors (PRR), present in host cells, is a critical event that involves intracellular signaling processes that end up in the expression of both, proinflammatory and antiviral mediators. Accordingly, the proper functioning of the different mechanisms of signal transduction from the cell membrane to the cytoplasm will depend on the integrity of these receptors (PRR); and therefore, the IS response triggered against pathogens including viral agents. Hence, in this review we discuss the role of toll-like receptors (TLRs) and nucleotide-binding oligomerization domain receptors (NLRs) in viral infections, using as evidence the studies in humans and mice known to date.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD/fisiología , Interacciones Huésped-Patógeno/inmunología , Proteína Adaptadora de Señalización NOD2/fisiología , Receptores Toll-Like/fisiología , Virosis/inmunología , Animales , Proteínas Portadoras/fisiología , Citocinas/biosíntesis , Citocinas/genética , Evolución Molecular , Predicción , Humanos , Inmunidad Innata , Ratones , Modelos Inmunológicos , Familia de Multigenes , Proteína con Dominio Pirina 3 de la Familia NLR , Proteína Adaptadora de Señalización NOD1/fisiología , Estructura Terciaria de Proteína , Transducción de Señal , Receptores Toll-Like/química , Receptores Toll-Like/clasificaciónRESUMEN
Las células del sistema inmunitario (SI) son capaces de reconocer una gran variedad de microorganismos, a través de los receptores que se encuentran expresados y distribuidos a lo largo de su arquitectura celular. La interacción entre los patrones moleculares asociados a microorganismos o a daño (PMAM o PMAD) y los receptores reconocedores de patrones (RRP) presentes en las células del hospedero es un evento crítico que implica procesos intracelulares de señalización que finalizan en la expresión de mediadores tanto proinflamatorios como antivirales. Por consiguiente, de la integridad de estos receptores dependerá el buen funcionamiento de los distintos mecanismos de transducción de señal desde las membranas celulares al citoplasma y por ende, de la respuesta que el SI desencadene contra los patógenos entre ellos los agentes virales. De allí que, en esta revisión se discutirá el papel de los receptores tipo toll (TLRs) y receptores para dominios de oligomerización para la unión a nucleótidos (NLRs) en las infecciones virales, tomando como evidencia los estudios en humanos y ratones que a la fecha se conocen.
The immune system (IS) cells are capable of recognizing a wide variety of microorganisms, through receptors that are expressed and distributed throughout the cell architecture. The interaction between the pathogen-associated molecular patterns or damage-associated molecular patterns (PAMPs or DAMPs) and pattern recognition receptors (PRR), present in host cells, is a critical event that involves intracellular signaling processes that end up in the expression of both, proinflammatory and antiviral mediators. Accordingly, the proper functioning of the different mechanisms of signal transduction from the cell membrane to the cytoplasm will depend on the integrity of these receptors (PRR); and therefore, the IS response triggered against pathogens including viral agents. Hence, in this review we discuss the role of toll-like receptors (TLRs) and nucleotide-binding oligomerization domain receptors (NLRs) in viral infections, using as evidence the studies in humans and mice known to date.
Asunto(s)
Animales , Humanos , Ratones , Proteínas Adaptadoras de Señalización CARD/fisiología , Interacciones Huésped-Patógeno/inmunología , /fisiología , Receptores Toll-Like/fisiología , Virosis/inmunología , Proteínas Portadoras/fisiología , Citocinas/biosíntesis , Citocinas/genética , Evolución Molecular , Predicción , Inmunidad Innata , Modelos Inmunológicos , Familia de Multigenes , Proteína Adaptadora de Señalización NOD1/fisiología , Estructura Terciaria de Proteína , Transducción de Señal , Receptores Toll-Like/química , Receptores Toll-Like/clasificaciónRESUMEN
Like other vertebrate Toll-like receptors (TLRs), the TLRs of teleost fish can be subdivided into six major families, each of which recognize a general class of molecular patterns. However, there also are a number of Tlrs with unknown function, the presence of which seems unique to the bony fish, among which is Tlr20. We identified full-length complementary DNA (cDNA) sequences for tlr20 of zebrafish and common carp, two closely related fish species. Zebrafish have six copies of tlr20, whereas carp express only a single copy. Both zebrafish Tlr20 (at least Tlr20a-d) and carp Tlr20 have 26 leucine-rich repeats (LRRs). Three-dimensional modeling indicates a best fit to the crystal structure of TLR8. Phylogenetic analyses place Tlr20 in the TLR11 family closest to Tlr11 and Tlr12, which sense ligands from protozoan parasites in the mouse. Conservation of genes on zebrafish chromosome 9, which carries tlr20, with genes on mouse chromosome 14, which carries tlr11, indicates Tlr11 could be a possible ortholog of Tlr20. Confocal microscopy suggests a subcellular localization of Tlr20 at the endoplasmatic reticulum. Although in vitro reporter assays could not identify a ligand unique to Tlr20, in vivo infection experiments indicate a role for Tlr20 in the immune response of carp to protozoan parasites (Trypanoplasma borreli). Carp tlr20 is mainly expressed in peripheral blood leukocytes (PBL) with B lymphocytes, in particular, expressing relatively high levels of Tlr20. In vitro stimulation of PBL with T. borreli induces an upregulation of tlr20, supportive of a role for Tlr20 in the immune response to protozoan parasites.
Asunto(s)
Linfocitos B/inmunología , Carpas/inmunología , Enfermedades de los Peces/inmunología , Receptores Toll-Like/genética , Tripanosomiasis/veterinaria , Pez Cebra/inmunología , Secuencia de Aminoácidos , Animales , Linfocitos B/parasitología , Carpas/genética , Carpas/parasitología , Evolución Molecular , Enfermedades de los Peces/genética , Enfermedades de los Peces/parasitología , Regulación de la Expresión Génica/inmunología , Genes Reporteros , Proteínas Fluorescentes Verdes , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Filogenia , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Receptores Toll-Like/clasificación , Receptores Toll-Like/inmunología , Trypanosoma/inmunología , Tripanosomiasis/genética , Tripanosomiasis/inmunología , Tripanosomiasis/parasitología , Pez Cebra/genética , Pez Cebra/parasitologíaRESUMEN
Toll-like receptors (TLRs) are a major class of innate immune pattern recognition receptors that have a key role in immune homeostasis and the defense against infections. The research explosion that followed the discovery of TLRs more than a decade ago has boosted fundamental knowledge on the function of the immune system and the resistance against disease, providing a rational for clinical modulation of the immune response. In addition, the conserved nature of the ancient TLR system throughout the animal kingdom has enabled a comparative biology approach to understand the evolution, structural architecture, and function of TLRs. In the present review we focus on TLR biology in the avian species, and, especially, on the unique functional properties of the chicken TLR repertoire.
Asunto(s)
Pollos/inmunología , Inmunidad Innata , Receptores Toll-Like/inmunología , Animales , Evolución Biológica , Citocinas/genética , Citocinas/inmunología , Flagelina/inmunología , Flagelina/metabolismo , Regulación de la Expresión Génica , Humanos , Ligandos , Mamíferos/inmunología , Especificidad de Órganos , Transducción de Señal , Receptores Toll-Like/clasificación , Receptores Toll-Like/genéticaRESUMEN
A comprehensive survey of channel catfish Toll-like receptors (TLRs) was undertaken following a genomic PCR approach based on degenerate primers. Twenty different TLRs were identified in channel catfish. Channel catfish TLR sequences were characterized by phylogenetic analysis based on their conserved Toll/interleukin-1 receptor domain and by in-depth analysis of leucine-rich repeat (LRR) motifs of the ligand binding extracellular domain (ECD). The catfish have representatives of all the TLR types defined in vertebrates with the exception of TLR6, TLR10, TLR11, TLR12, TLR13, TLR15, TLR23, and TLR24. Additionally, two new types were discovered: TLR25 and TLR26. TLR25 is also present in cyprinids, cichlids, plecoglossids, and adrianichthyids, suggesting its presence early in fish evolution. To date, TLR26 was found only in channel catfish. Like TLR18-23, TLR25 and TLR26 were not found in any other vertebrate classes and appear to be fish specific. Data mining using the catfish TLR sequences revealed that in addition to ictalurids and cyprinids, TLR4 is also present in salmonids. TLR19 and TLR20 were both found in ictalurids, cyprinids, and salmonids, demonstrating a wider range than previously known. The LRR structure within ECDs appeared generally well conserved. TLR7 demonstrated a very high identity to human TLR7 strongly suggesting that ligand specificity maybe conserved. Finally, expression profiling confirmed that most TLRs are widely expressed in a diversity of tissues and revealed marked differences of expression level.
Asunto(s)
Ictaluridae/genética , Receptores Toll-Like/genética , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Secuencia de Consenso , Secuencia Conservada , ADN Complementario , Evolución Molecular , Exones/genética , Peces/genética , Expresión Génica , Humanos , Ictaluridae/inmunología , Datos de Secuencia Molecular , Familia de Multigenes , Especificidad de Órganos , Filogenia , Estructura Terciaria de Proteína , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Especificidad de la Especie , Receptores Toll-Like/clasificación , Receptores Toll-Like/inmunología , Vertebrados/genéticaRESUMEN
TLR- and MyD88-related sequences have been previously investigated in Mytibase and then in new transcript reads obtained by Illumina technology from the mussel, Mytilus galloprovincialis. Based on full cds and domain organizations of virtual translations, we identified 23 Toll-like receptors (TLRs) and 3 MyD88 adaptors. MgTLRs can be arranged in 4 clusters according to extra-cellular LRR domain content. MgTLR-b, -i and -k were the only ones containing a multiple cysteine cluster (mccTLR), a domain composition also found in Drosophila Toll-1 and 18-wheeler. The 3 MyD88 we identified in M. galloprovincialis were also retrieved from Mytilus edulis, as well as MgTLR-b and -i. All MgTLRs were constitutively expressed in digestive gland whereas only 4 of them were also present in hemocytes. On the opposite, the 3 MgMyD88s were constitutively expressed in all the tissues. In vivo challenge of M. galloprovincialis with bacteria caused the up regulation of only MgTLR-i, but of all the 3 MgMyD88s. Highest response was induced by Gram-negative Vibrio anguillarum at 9h p.i. Injection of filamentous fungus, Fusarium oxysporum, resulted in up regulation of MgTLR-i and MgMyD88-c at 9h p.i. Such similar pattern of responses suggested MgMyD88-c represents the intra cytoplasm partner of MgTLR-i. Their interaction constituted the first cellular event revealing the existence of a Toll-signaling pathway in Lophotrochozoa.
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Factor 88 de Diferenciación Mieloide/metabolismo , Mytilus/metabolismo , Receptores Toll-Like/metabolismo , Secuencia de Aminoácidos , Animales , Análisis por Conglomerados , Expresión Génica , Regulación de la Expresión Génica/inmunología , Branquias/metabolismo , Hemocitos/metabolismo , Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata , Datos de Secuencia Molecular , Factor 88 de Diferenciación Mieloide/genética , Mytilus/inmunología , Mytilus/microbiología , Especificidad de Órganos , Filogenia , Estructura Terciaria de Proteína , Transducción de Señal/inmunología , Receptores Toll-Like/clasificación , Receptores Toll-Like/genética , Transcriptoma , Vibrio/inmunologíaRESUMEN
Human blood DCs encompass pDCs and two subsets of mDCs: CD1c(+) mDCs and CD141(+) mDCs. The rare CD141(+) DC population is thought to be the equivalent of mouse CD8α(+) cDCs that play a significant role in antigen cross-presentation. Here, we analyzed by Q-PCR TLR1-10 expression in blood DC subsets. Whereas CD1c(+) DCs express all TLR except TLR9, CD141(+) DCs present a more restricted pattern with high expression of TLR3 and -10, expression of TLR1,-2, -6, and -8, and lack of TLR4, -5, -7, and -9. The in vitro analysis of isolated mDC subset reponsiveness to an extensive panel of TLR ligands confirmed these results, with CD141(+) DCs responding only to TLR1/2, -3, and -7/8. The cytokine/chemokine production profile of isolated CD141(+) DCs was also more restricted, as they produced mainly proinflammatory cytokines but no IL-12 and to a lower level, in comparison with CD1c(+) DCs, except for CXCL10, CCL5, and IFN-ß. In contrast, with the use of a whole blood assay, we found that CD141(+) DCs produce IL-12 in response to TLR1/2, -3, and more surprisingly, -9. Finally, both mDC subsets are potent inducers of Th1 response, particularly after TLR3 triggering. Taken together, these data confirmed functional differences between blood mDC subsets. The major response of CD141(+) mDCs to TLR3 ligand and their cytokine production pattern suggest a role for these cells in antiviral immunity.
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Antígenos CD/inmunología , Citocinas/inmunología , Células Dendríticas/inmunología , Receptores Toll-Like/inmunología , Presentación de Antígeno , Antígenos CD/genética , Antígenos CD1/genética , Antígenos CD1/inmunología , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas/clasificación , Células Dendríticas/citología , Citometría de Flujo , Glicoproteínas/genética , Glicoproteínas/inmunología , Humanos , Separación Inmunomagnética , Inmunofenotipificación , Isoformas de Proteínas/clasificación , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Receptores Toll-Like/clasificación , Receptores Toll-Like/genéticaRESUMEN
Toll-like receptors (TLRs) play a crucial role in host defence, since they trigger immune response following recognition of pathogen-associated molecular patterns (PAMPs) in potential infectious agents. TLRs have been found in numerous organisms, including mammals, birds and teleosts. Some TLR members are commonly retained across all species, whilst others were lost, gained or diverged independently during evolution. Our knowledge about the evolution and specific functions of tlr21, tlr22 and tlr23 in teleosts are still scarce. Phylogenetic analysis of 18 tlr13, tlr21, tlr22 and tlr23 genes from 9 different fish species divided them in two groups. All tlr21 genes were under the first clade, while the second comprised tlr22, tlr23 and tlr13 from Atlantic salmon. Evidence of positive selection was detected at three sites within the leucine-rich repeat regions of Tlr22, which may influence PAMP recognition. Immunostimulation experiments revealed that expression of zebrafish tlr22 is modulated by several unrelated PAMPs. Up to a 3-fold increase in tlr21 and tlr22 expression was detected in larvae exposed to immunostimulants such as lipopolysaccharide, peptidoglycan or poly I:C. We found that zebrafish tlrs are expressed mainly in immune-related organs, such as spleen and kidney as well as in testis and temperature stress did not have an effect on the expression of tlr21 and tlr22 in the early stages of development in zebrafish larvae. Our data indicates that these teleost tlrs may play a role in innate host defence. In particular, tlr22 is evolving under positive selection, which indicates functional diversification and adaptation of the response to different PAMPs.