The field of mRNA translation has witnessed an impressive expansion in the last decade. The once standard model of translation initiation has undergone, and is still undergoing, a major overhaul, partly due to more recent technical advancements detailing, for example, initiation at non-AUG codons. However, some of the pioneering works in this area have come from immunology and more precisely from the field of antigen presentation to the major histocompatibility class I (MHC-I) pathway. Despite early innovative studies from the lab of Nilabh Shastri demonstrating alternative mRNA translation initiation as a source for MHC-I peptide substrates, the mRNA translation field did not include these into their models. It was not until the introduction of the ribo-sequence technique that the extent of non-canonical translation initiation became widely acknowledged. The detection of peptides on MHC-I molecules by CD8 + T cells is extremely sensitive, making this a superior model system for studying alternative mRNA translation initiation from specific mRNAs. In view of this, we give a brief history on alternative initiation from an immunology perspective and its fundamental role in allowing the immune system to distinguish self from non-self and at the same time pay tribute to the works of Nilabh Shastri.
- MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- lidé MeSH
- messenger RNA genetika imunologie MeSH
- MHC antigeny I. třídy genetika imunologie MeSH
- peptidy genetika imunologie MeSH
- prezentace antigenu genetika imunologie MeSH
- proteosyntéza genetika imunologie MeSH
- receptory pro aktivovanou kinasu C genetika imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
V současné době existuje eminentní zájem států na proočkovanosti obyvatelstva proti COVID-19. V České republice k tomuto účelu slouží podmínečně registrované genové mRNA a vektorové DNA vakcíny, u kterých zatím absentují úplné a dlouhodobé údaje o bezpečnosti. Vakcíny vykazují řadu potenciálních rizik, jako je pronikání lipidických nanočástic do okolních tkání, zabudování DNA do hostitelského genomu, ADE syndrom, vznik rezistentních mutací, myokarditida, perikarditida a tromboembolické příhody. Vzhledem k tomu, že hladina protilátek po vakcinaci brzy klesá, imunita po prodělání nemoci je trvalejší a smrtnost nemoci je zejména u mladistvých velmi nízká, je z etického pohledu přijatelné jen dobrovolné očkování, a to bez případných přímých i nepřímých restrikcí pro neočkované. Tento závěr je v souladu s principy lékařské etiky nonmaleficence, beneficence, autonomie a spravedlnosti.
In the current context, there is an extraordinary interest of states in vaccinating the population to prevent Covid-19. In the Czech Republic, gene mRNA and vector DNA vaccines are approved only with conditional marketing authorization, for which a complete and long-term safety assessment is currently lacking. Vaccines show some potential risks, such as penetration of lipid nanoparticles into surrounding tissues, incorporation of DNA into the host genome, ADE syndrome, development of resistant mutations, myocarditis, pericarditis, and thromboembolic events. Since the level of antibodies after vaccination is soon decreasing, immunity after the disease persists longer, and the disease's fatality rate is very low, especially in adolescents, only voluntary vaccination is ethically acceptable, without any direct or indirect restrictions on the unvaccinated. The conclusion is in line with the principles of medical ethics of nonmaleficence, beneficence, autonomy, and justice.
- MeSH
- COVID-19 prevence a kontrola MeSH
- DNA vakcíny genetika imunologie škodlivé účinky MeSH
- hodnocení rizik MeSH
- lidé MeSH
- messenger RNA genetika imunologie škodlivé účinky MeSH
- nežádoucí účinky léčiv MeSH
- schvalování léčiv MeSH
- vakcinace * etika MeSH
- vakcíny proti COVID-19 * genetika imunologie škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Intra-amniotic infections (IAI) are one of the reasons for preterm birth. High mobility group box 1 (HMGB1) is a nuclear protein with various physiological functions, including tissue healing. Its excessive extracellular release potentiates inflammatory reaction and can revert its action from beneficial to detrimental. We infected the amniotic fluid of a pig on the 80th day of gestation with 1 × 104 colony forming units (CFUs) of E. coli O55 for 10 h, and evaluated the appearance of HMGB1, receptor for glycation endproducts (RAGE), and Toll-like receptor (TLR) 4 in the amniotic membrane and fluid. Sham-infected amniotic fluid served as a control. The expression and release of HMGB1 were evaluated by Real-Time PCR, immunofluorescence, immunohistochemistry, and ELISA. The infection downregulated HMGB1 mRNA expression in the amniotic membrane, changed the distribution of HMGB1 protein in the amniotic membrane, and increased its level in amniotic fluid. All RAGE mRNA, protein expression in the amniotic membrane, and soluble RAGE level in the amniotic fluid were downregulated. TLR4 mRNA and protein expression and soluble TLR4 were all upregulated. HMGB1 is a potential target for therapy to suppress the exaggerated inflammatory response. This controlled expression and release can, in some cases, prevent the preterm birth of vulnerable infants. Studies on suitable animal models can contribute to the development of appropriate therapy.
- MeSH
- amnion imunologie mikrobiologie patologie MeSH
- Escherichia coli růst a vývoj patogenita MeSH
- infekce vyvolané Escherichia coli genetika imunologie mikrobiologie veterinární MeSH
- infekční komplikace v těhotenství genetika imunologie mikrobiologie veterinární MeSH
- interakce hostitele a patogenu genetika imunologie MeSH
- lidé MeSH
- messenger RNA genetika imunologie MeSH
- modely nemocí na zvířatech MeSH
- plodová voda imunologie mikrobiologie MeSH
- prasata MeSH
- předčasný porod prevence a kontrola MeSH
- protein HMGB1 genetika imunologie MeSH
- receptor pro konečné produkty pokročilé glykace genetika imunologie MeSH
- regulace genové exprese MeSH
- signální transdukce MeSH
- těhotenství MeSH
- toll-like receptor 4 genetika imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The first outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred in Wuhan, Hubei Province, China, in late 2019. The subsequent COVID-19 pandemic rapidly affected the health and economy of the world. The global approach to the pandemic was to isolate populations to reduce the spread of this deadly virus while vaccines began to be developed. In March 2020, the first phase I clinical trial of a novel lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine, mRNA-1273, which encodes the spike protein (S protein) of SARS-CoV-2, began in the United States (US). The production of mRNA-based vaccines is a promising recent development in the production of vaccines. However, there remain significant challenges in the development and testing of vaccines as rapidly as possible to control COVID-19, which requires international collaboration. This review aims to describe the background to the rationale for the development of mRNA-based SARS-CoV-2 vaccines and the current status of the mRNA-1273 vaccine.
- MeSH
- Betacoronavirus * imunologie MeSH
- glykoprotein S, koronavirus genetika imunologie MeSH
- koronavirové infekce imunologie prevence a kontrola MeSH
- lidé MeSH
- messenger RNA imunologie MeSH
- pandemie prevence a kontrola MeSH
- RNA virová imunologie MeSH
- virová pneumonie imunologie prevence a kontrola MeSH
- virové vakcíny * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Geografické názvy
- Spojené státy americké MeSH
Earthworms are not endowed with adaptive immunity and they are rely on the tools of innate immunity. Cells of the innate immune system utilize pattern recognition receptors, such as Toll-like receptors, to detect the pathogen-associated molecular patterns (PAMPs). The first earthworm TLR was isolated from Eisenia andrei earthworms (EaTLR), which belongs to the single cysteine cluster TLR (sccTLR). Here, we identified a new multiple cysteine cluster TLR (mccTLR) in E. andrei earthworms. Phylogenetic DNA analysis revealed that it has no variability within one earthworm as well as in the population. By screening of the tissue expression profile, the TLR was expressed primarily in earthworm seminal vesicles and receptacles suggesting a connection to sperm cells. Seminal vesicles are often heavily infected by gregarine parasites. As a sign of immune response, a strong melanization reaction is visible around parasites. Stimulation experiments with profilin from related parasite Toxoplasma gondii, led to the upregulation of mccEaTLR in the earthworm seminal vesicles. Also, profilin activated prophenoloxidase cascade, the efficient mechanism of innate immunity. However, its involvement in the NF-κB signaling was not proven. Further, we provide evidence that the antibiotics metronidazole and griseofulvin destroyed the developing spermatocytes. The observed decrease in the mccEaTLR mRNA levels after the antibiotic treatment of parasites is caused by the decline of sperm cells numbers rather than by diminution of the parasites. Since earthworms with extensively reduced parasite load had a similar amount of mccEaTLR mRNA, presumably, earthworm sperm cells have a certain level of mccEaTLR expressed as a standard, which can be augmented by particular antigenic stimulation. Also, mccEaTLR was expressed mainly in the early stages of earthworm development and presumably is primarily involved in early embryonic development. Expression of mccEaTLR in seminal vesicles correlates with the expression of endothelial monocyte-activation polypeptide II. High-throughput sequencing of gregarine DNA from seminal vesicles of individual earthworms resulted in great diversity of the observed genotypes. Phylogenetically, all observed OTUs belong to the clade of earthworm gregarines suggesting host specificity. Overall, mccEaTLR is supposed to play a function role in early embryonic development and potentially it participates in immune response against parasites.
- MeSH
- cystein MeSH
- cytokiny imunologie MeSH
- embryonální vývoj imunologie MeSH
- fylogeneze MeSH
- messenger RNA imunologie MeSH
- nádorové proteiny imunologie MeSH
- NF-kappa B imunologie MeSH
- Oligochaeta imunologie MeSH
- přirozená imunita imunologie MeSH
- proteiny vázající RNA imunologie MeSH
- receptory rozpoznávající vzory imunologie MeSH
- signální transdukce imunologie MeSH
- toll-like receptory imunologie MeSH
- Toxoplasma imunologie MeSH
- upregulace imunologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Peptides presented on major histocompatibility (MHC) class I molecules form an essential part of the immune system's capacity to detect virus-infected or transformed cells. Earlier works have shown that pioneer translation peptides (PTPs) for the MHC class I pathway are as efficiently produced from introns as from exons, or from mRNAs targeted for the nonsense-mediated decay pathway. The production of PTPs is a target for viral immune evasion but the underlying molecular mechanisms that govern this non-canonical translation are unknown. Here, we have used different approaches to show how events taking place on the nascent transcript control the synthesis of PTPs and full-length proteins. By controlling the subcellular interaction between the G-quadruplex structure (G4) of a gly-ala encoding mRNA and nucleolin (NCL) and by interfering with mRNA maturation using multiple approaches, we demonstrate that antigenic peptides derive from a nuclear non-canonical translation event that is independently regulated from the synthesis of full-length proteins. Moreover, we show that G4 are exploited to control mRNA localization and translation by distinguishable mechanisms that are targets for viral immune evasion.
- MeSH
- antigeny genetika imunologie MeSH
- buněčné jádro genetika imunologie MeSH
- G-kvadruplexy MeSH
- imunitní únik genetika imunologie MeSH
- lidé MeSH
- messenger RNA genetika imunologie MeSH
- MHC antigeny I. třídy genetika imunologie MeSH
- nonsense mediated mRNA decay genetika imunologie MeSH
- peptidy genetika imunologie MeSH
- proteosyntéza genetika imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Nonsense-mediated mRNA decay (NMD) is a conserved eukaryotic RNA surveillance mechanism that degrades aberrant mRNAs. NMD impairment in Arabidopsis is linked to constitutive immune response activation and enhanced antibacterial resistance, but the underlying mechanisms are unknown. Here we show that NMD contributes to innate immunity in Arabidopsis by controlling the turnover of numerous TIR domain-containing, nucleotide-binding, leucine-rich repeat (TNL) immune receptor-encoding mRNAs. Autoimmunity resulting from NMD impairment depends on TNL signaling pathway components and can be triggered through deregulation of a single TNL gene, RPS6. Bacterial infection of plants causes host-programmed inhibition of NMD, leading to stabilization of NMD-regulated TNL transcripts. Conversely, constitutive NMD activity prevents TNL stabilization and impairs plant defense, demonstrating that host-regulated NMD contributes to disease resistance. Thus, NMD shapes plant innate immunity by controlling the threshold for activation of TNL resistance pathways.
- MeSH
- Arabidopsis genetika imunologie mikrobiologie MeSH
- interakce hostitele a patogenu MeSH
- messenger RNA genetika imunologie MeSH
- nemoci rostlin genetika imunologie mikrobiologie MeSH
- nesmyslný kodon MeSH
- nonsense mediated mRNA decay * MeSH
- proteiny huseníčku genetika imunologie MeSH
- Pseudomonas syringae genetika fyziologie MeSH
- receptory imunologické genetika imunologie MeSH
- RNA-helikasy genetika imunologie MeSH
- transportní proteiny genetika imunologie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Epithelial cells represent an important source of cytokines that may modulate the influx and functions of mononuclear phagocytes. The aim of our study was to characterize changes in the gene expression of selected cytokines in human macrophages co-cultured with respiratory epithelial cells. The A549 alveolar type II-like cell line was co-cultured with THP-1 cells (monocyte/macrophage cell line) in filter-separated mode to avoid their cell-cell contact. At different time-points (0, 4, 8, 12 and 24 h), the cells were harvested separately to evaluate their gene and protein expression (IL-1 beta, IL-6, IL-8, IL-10 and GM-CSF). Quantitative RT-PCR analysis showed prominent changes in the THP-1 cytokine gene expression induced by a co-culture with A549 cells. Fourfold upregulation of mRNA expression has been found in 12 genes and 4-fold downregulation in 5 genes as compared to the unstimulated control sample with a p value smaller than 0.05. The induction of inhibin beta A and IL-1 beta mRNA after 12 h and the expression of IL-1 alpha and GM-CSF mRNA after 24 h were the most prominent. When looking at the cytokine levels in culture supernatants, IL-1 beta and IL-8 were induced early (at 8 h) as compared to the release of IL-6 and GM-CSF (at 24 h). We conclude that respiratory epithelial cells constitutively regulate the cytokine gene expression of macrophages located in their environment and might further modulate the release of cytokines by posttranslational pathways.
- MeSH
- buněčné linie MeSH
- časové faktory MeSH
- cytokiny biosyntéza imunologie MeSH
- epitelové buňky cytologie imunologie metabolismus MeSH
- kokultivační techniky MeSH
- lidé MeSH
- messenger RNA biosyntéza imunologie MeSH
- monocyty cytologie imunologie metabolismus MeSH
- regulace genové exprese imunologie MeSH
- stanovení celkové genové exprese MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
MicroRNAs (miRNAs) represent the most abundant class of regulators of gene expression in humans: they regulate one-third of human protein-coding genes. These small noncoding ∼22-nucleotides (nt)-long RNAs originate by multistep process from miRNA genes localized in the genomic DNA. To date, more than 1420 miRNAs have been identified in humans (miRBase v17). The main mechanism of miRNA action is the posttranscriptional regulation via RNA interference with their target mRNAs. The majority of target mRNAs (more than 80%) undergo degradation after recognition by complementary miRNA; the translational inhibition with little or no influence on mRNA levels has been also reported. Each miRNA may suppress multiple mRNA targets (average ∼200), and at the same time, one mRNA can be targeted by many miRNAs enabling to control a spectrum wide range of cellular processes. Recently, the role of miRNAs in the development of immune cells and the maintenance of immune system homeostasis gained attention, and the involvement of miRNAs in the pathogenesis of several immune system diseases has emerged. This review focuses on the role of miRNAs in autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and psoriasis), inflammatory pathologies of distinct organ (atherosclerosis, osteoarthritis and atopic eczema) and/or systemic locations such as allergy. The role of miRNAs, their predicted and known mRNA targets and description of their actions in physiological immune reactions and in the pathological processes ongoing in immune-mediated human disorders will be discussed. Finally, miRNA-based diagnostics and therapeutic potentials will be highlighted.
- MeSH
- ateroskleróza genetika imunologie patologie MeSH
- atopická dermatitida genetika imunologie patologie MeSH
- epigeneze genetická imunologie MeSH
- idiopatické střevní záněty genetika imunologie patologie MeSH
- lidé MeSH
- messenger RNA genetika imunologie MeSH
- mikro RNA genetika imunologie MeSH
- osteoartróza genetika imunologie patologie MeSH
- přirozená imunita MeSH
- psoriáza genetika imunologie patologie MeSH
- revmatoidní artritida genetika imunologie patologie MeSH
- RNA interference imunologie MeSH
- roztroušená skleróza genetika imunologie patologie MeSH
- stabilita RNA MeSH
- systémový lupus erythematodes genetika imunologie patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
