innate recognition
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Začiatočné rozpoznanie mikróbov, ktoré vniknú do organizmu, sa zakladá na ich geneticky zakódovaných molekulových vzoroch patogénnosti (PAMPs), ktoré umožňujú odpovedať na mikróbnu inváziu ihneď, čiže ešte pred vznikom aktívnej špecifickej imunity. Táto odpoveď hostiteľa na infekciu a poranenie sa realizuje prostredníctvom neustále sa rozširujúcej skupiny receptorov patriacich do veľkorodiny receptorov pre interleukín-1 (IL-1Rs) a receptorov podobných Toll (TLRs). Členovia obidvoch týchto rodín obsahujú v cytoplamových častiach ich molekúl doménu TIR (Toll/IL-1R). Doteraz sa zistilo desať IL-1Rs (vrátane IL-1RI a IL-18R) a desať TLRs (TLR1 až TLR10). Exprimujú sa najmä na bunkách, ktoré sa nachádzajú na tkanivách prichádzajúcich do kontaktu s vonkajším prostredím. Aktivácia TLRs má za následok aktiváciu priamych antimikróbnych mechanizmov, ako súčasti prirodzenej imunity, expresiu kostimulačných molekúl a uvoľnenie cytokínov, ktoré regulujú adaptívnu imunitnú odpoveď. Prenos signálov cez tieto receptory môže zodpovedať aj za stimuláciu dozrievania imunitného systému a môže sa preto zúčastňovať na patogenéze alergických chorôb. Využitie poznatkov o TLRs sa pravdepodobne v budúcnosti bude dať preto využiť pri nových účinných postupoch liečby osobitne atopických chorôb. Genetické a vývojové variácie v expresii TLRs môžu ovplyvňovať individuálnu predispozíciu na infekcie v detskom veku a prispievať k zvýšenej citlivosti nielen na alergie, ale aj na zápalové a autoimunitné choroby.
Initial recognition of microbes, as they enter the body, is based on germ line-encoded pathogen-associated molecular patterns (PAMPs) to respond immediately to the microbial invasion before the development of active specific immunity. This host response to infection and injury is performed through an expanding group of receptors belonging to the superfamily of interleukin-1 receptors (IL-1Rs) and Toll-like receptors (TLRs). They both contain the Toll-IL-1 receptor (TIR) domain which occurs in the cytosolic region. So far, ten IL-1Rs (including IL-1RI and IL-18R) and ten TLRs (TLR1 to TLR10) have been revealed. They are predominatly expressed on cells at the interface of the body with the environment. The activation of TLRs leads to direct antimicrobial pathways, as a part of innate immunity, to the expression of co-stimulatory molecules and to the release of cytokines that instruct the adaptive immune response. Signalling via these receptors may be also responsible for driving the maturation of the adult immune system and therefore it may participate in the pathogenesis of allergic diseases. Exploitation of the TLR signalling will probably lead to novel effective therapies for these diseases. Genetic and developmental variations in the expression of TLRs may affect the individual predisposition to infections in childhood and may contribute to the increased susceptibility not only to allergies but to inflammatory and autoimmune diseases as well.
Neadaptivní imunitní systém je první obranou organismu při jeho napadení patogenem. Signalizační cesta cGAS -cGAMP -STING je součástí tohoto systému a je zcela klíčová při obraně proti DNA virům a retrovirům Zároveň je chronické vybuzení této kaskády pravděpodobnou příčinou některých autoimunitních onemocnění. Studium této signalizační cesty je klíčové pro vývoj terapeutik virových a autoimunitních onemocnění.
The innate immune system is the first line of defence of organism against pathogens. As a part of innate immune system, cGAS -cGAMP- -STING signaling pathway takes a crucial part in immune response to DNA viruses and retroviruses. In contrast, chronic activation of this pathway is probably cause of some autoimmune diseases. Studium of this signaling pathway is crucial for new antiviral and immunosupresive drugs development.
- Klíčová slova
- cGAS-cGAMP-STING,
- MeSH
- DNA viry * imunologie MeSH
- DNA genetika chemie imunologie MeSH
- fosforylace MeSH
- interferon typ I * metabolismus MeSH
- lidé MeSH
- přirozená imunita * MeSH
- receptor interferonu alfa-beta * MeSH
- receptory rozpoznávající vzory MeSH
- Retroviridae * imunologie MeSH
- signální transdukce * MeSH
- ubikvitiny metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
The existence of pattern recognition receptors (PRRs) on immune cells was discussed in 1989 by Charles Janeway, Jr., who proposed a general concept of the ability of PRRs to recognize and bind conserved molecular structures of microorganisms known as pathogen-associated molecular patterns (PAMPs). Upon PAMP engagement, PRRs trigger intracellular signaling cascades resulting in the expression of various proinflammatory molecules. These recognition molecules represent an important and efficient innate immunity tool of all organisms. As invertebrates lack the instruments of the adaptive immune system, based on "true" lymphocytes and functional antibodies, the importance of PRRs are even more fundamental. In the present review, the structure, specificity, and expression profiles of PRRs characterized in annelids are discussed, and their role in innate defense is suggested.
- MeSH
- kroužkovci imunologie MeSH
- membránové glykoproteiny chemie genetika metabolismus MeSH
- PAMP struktury imunologie metabolismus MeSH
- přirozená imunita * MeSH
- proteiny akutní fáze chemie genetika metabolismus MeSH
- receptory rozpoznávající vzory chemie genetika metabolismus MeSH
- regulace genové exprese MeSH
- signální transdukce imunologie MeSH
- tkáňová distribuce MeSH
- toll-like receptory chemie genetika metabolismus MeSH
- transportní proteiny chemie genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
The innate immunity is frequently accepted as a first line of relatively primitive defense interfering with the pathogen invasion until the mechanisms of 'privileged' adaptive immunity with the production of antibodies and activation of cytotoxic lymphocytes 'steal the show'. Recent advancements on the molecular and cellular levels have shaken the traditional view of adaptive and innate immunity. The innate immune memory or 'trained immunity' based on metabolic changes and epigenetic reprogramming is a complementary process insuring adaptation of host defense to previous infections.Innate immune cells are able to recognize large number of pathogen- or danger- associated molecular patterns (PAMPs and DAMPs) to behave in a highly specific manner and regulate adaptive immune responses. Innate lymphoid cells (ILC1, ILC2, ILC3) and NK cells express transcription factors and cytokines related to subsets of T helper cells (Th1, Th2, Th17). On the other hand, T and B lymphocytes exhibit functional properties traditionally attributed to innate immunity such as phagocytosis or production of tissue remodeling growth factors. They are also able to benefit from the information provided by pattern recognition receptors (PRRs), e.g. γδT lymphocytes use T-cell receptor (TCR) in a manner close to PRR recognition. Innate B cells represent another example of limited combinational diversity usage participating in various innate responses. In the view of current knowledge, the traditional black and white classification of immune mechanisms as either innate or an adaptive needs to be adjusted and many shades of gray need to be included.
- MeSH
- adaptivní imunita * MeSH
- B-lymfocyty imunologie MeSH
- buňky NK imunologie MeSH
- cytokiny genetika imunologie MeSH
- lidé MeSH
- přirozená imunita * MeSH
- T-lymfocyty imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Ticks are blood feeding parasites transmitting a wide variety of pathogens to their vertebrate hosts. The vector competence of ticks is tightly linked with their immune system. Despite its importance, our knowledge of tick innate immunity is still inadequate and the limited number of sufficiently characterized immune molecules and cellular reactions are dispersed across numerous tick species. The phagocytosis of microbes by tick hemocytes seems to be coupled with a primitive complement-like system, which possibly involves self/nonself recognition by fibrinogen-related lectins and the action of thioester-containing proteins. Ticks do not seem to possess a pro-phenoloxidase system leading to melanization and also coagulation of tick hemolymph has not been experimentally proven. They are capable of defending themselves against microbial infection with a variety of antimicrobial peptides comprising lysozymes, defensins and molecules not found in other invertebrates. Virtually nothing is known about the signaling cascades involved in the regulation of tick antimicrobial immune responses. Midgut immunity is apparently the decisive factor of tick vector competence. The gut content is a hostile environment for ingested microbes, which is mainly due to the antimicrobial activity of hemoglobin fragments generated by the digestion of the host blood as well as other antimicrobial peptides. Reactive oxygen species possibly also play an important role in the tick-pathogen interaction. The recent release of the Ixodes scapularis genome and the feasibility of RNA interference in ticks promise imminent and substantial progress in tick innate immunity research.
Primary interaction of an intracellular bacterium with its host cell is initiated by activation of multiple signaling pathways in response to bacterium recognition itself or as cellular responses to stress induced by the bacterium. The leading molecules in these processes are cell surface membrane receptors as well as cytosolic pattern recognition receptors recognizing pathogen-associated molecular patterns or damage-associated molecular patterns induced by the invading bacterium. In this review, we demonstrate possible sequences of events leading to recognition of Francisella tularensis, present findings on known mechanisms for manipulating cell responses to protect Francisella from being killed, and discuss newly published data from the perspective of early stages of host-pathogen interaction.
- MeSH
- alarminy genetika imunologie MeSH
- bakteriální proteiny genetika imunologie MeSH
- fagocytóza genetika MeSH
- Francisella tularensis genetika imunologie patogenita MeSH
- interakce hostitele a patogenu genetika imunologie MeSH
- lidé MeSH
- makrofágy imunologie mikrobiologie MeSH
- PAMP struktury imunologie metabolismus MeSH
- přirozená imunita * MeSH
- receptory buněčného povrchu genetika imunologie MeSH
- receptory rozpoznávající vzory genetika imunologie MeSH
- regulace genové exprese MeSH
- signální transdukce MeSH
- tularemie genetika imunologie mikrobiologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
The success of pathogens depends on their ability to circumvent immune defences. Francisella tularensis is one of the most infectious bacteria known. The remarkable virulence of Francisella is believed to be due to its capacity to evade or subvert the immune system, but how remains obscure. Here, we show that Francisella triggers but concomitantly inhibits the Toll-like receptor, RIG-I-like receptor, and cytoplasmic DNA pathways. Francisella subverts these pathways at least in part by inhibiting K63-linked polyubiquitination and assembly of TRAF6 and TRAF3 complexes that control the transcriptional responses of pattern recognition receptors. We show that this mode of inhibition requires a functional type VI secretion system and/or the presence of live bacteria in the cytoplasm. The ability of Francisella to enter the cytosol while simultaneously inhibiting multiple pattern recognition receptor pathways may account for the notable capacity of this bacterium to invade and proliferate in the host without evoking a self-limiting innate immune response.
- MeSH
- adaptorové proteiny signální transdukční genetika MeSH
- adaptorové proteiny vezikulární transportní genetika MeSH
- faktor 3 asociovaný s receptory TNF metabolismus MeSH
- faktor 6 asociovaný s receptory TNF metabolismus MeSH
- Francisella tularensis imunologie patogenita MeSH
- imunitní únik imunologie MeSH
- myeloidní diferenciační faktor 88 genetika MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- přirozená imunita imunologie MeSH
- receptory rozpoznávající vzory antagonisté a inhibitory MeSH
- sekreční systém typu VI metabolismus MeSH
- tularemie imunologie mikrobiologie patologie MeSH
- ubikvitinace imunologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Pattern-recognition receptors (PRRs) recognize pathogen-associated molecular patterns and play an important role in triggering innate immune responses. PRRs distribution and function is well documented in mice and humans, but studies in pigs are scarce. Salmonella enterica serovar Typhimurium is common pathogen found in pigs and was used as a model for interaction with PRRs. This study investigated expression of PRRs in porcine leukocyte subpopulations at the mRNA level. Eight subpopulations of leukocytes comprising NK cells, Th, Tc, double positive T cells and γδ T cells, B cells, monocytes and neutrophils were sorted, and the expression of 12 PRRs was measured, including selected Toll-like receptors and their co-receptors, NOD-like receptor NOD2, RP-105, CD14, and dectin. The highest expression rates of most PRRs were observed in monocytes and neutrophils. The B cells expressed high levels of TLR1, TLR6, TLR9, TLR10, and RP-105. Only monocytes and γδ T cells were found to respond to Salmonella enterica serovar Typhimurium infection by intensification of PRRs expression. In Th and B cells, PRRs mRNA down-regulation was detected after infection.
- MeSH
- down regulace MeSH
- leukocyty metabolismus mikrobiologie MeSH
- messenger RNA genetika MeSH
- neutrofily metabolismus MeSH
- prasata MeSH
- přirozená imunita MeSH
- receptory rozpoznávající vzory genetika metabolismus MeSH
- regulace genové exprese imunologie MeSH
- Salmonella typhimurium fyziologie MeSH
- salmonelová infekce u zvířat imunologie MeSH
- séroskupina MeSH
- T-lymfocyty metabolismus MeSH
- toll-like receptory genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The intracellular bacterial pathogen Francisella tularensis causes serious infectious disease in humans and animals. Moreover, F. tularensis, a highly infectious pathogen, poses a major concern for the public as a bacterium classified under Category A of bioterrorism agents. Unfortunately, research has so far failed to develop effective vaccines, due in part to the fact that the pathogenesis of intracellular bacteria is not fully understood and in part to gaps in our understanding of innate immune recognition processes leading to the induction of adaptive immune response. Recent evidence supports the concept that immune response to external stimuli in the form of bacteria is guided by the primary interaction of the bacterium with the host cell. Based on data from different Francisella models, we present here the basic paradigms of the emerging innate immune recognition concept. According to this concept, the type of cell and its receptor(s) that initially interact with the target constitute the first signaling window; the signals produced in the course of primary interaction of the target with a reacting cell act in a paracrine manner; and the innate immune recognition process as a whole consists in a series of signaling windows modulating adaptive immune response. Finally, the host, in the strict sense, is the interacting cell.
- MeSH
- adaptivní imunita MeSH
- Francisella tularensis imunologie MeSH
- imunitní systém MeSH
- interakce hostitele a patogenu imunologie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- parakrinní signalizace imunologie MeSH
- přirozená imunita * MeSH
- tularemie imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Aging is generally regarded as an irreversible process, and its intricate relationship with the immune system has garnered significant attention due to its profound implications for the health and well-being of the aging population. As people age, a multitude of alterations occur within the immune system, affecting both innate and adaptive immunity. In the realm of innate immunity, aging brings about changes in the number and function of various immune cells, including neutrophils, monocytes, and macrophages. Additionally, certain immune pathways, like the cGAS-STING, become activated. These alterations can potentially result in telomere damage, the disruption of cytokine signaling, and impaired recognition of pathogens. The adaptive immune system, too, undergoes a myriad of changes as age advances. These include shifts in the number, frequency, subtype, and function of T cells and B cells. Furthermore, the human gut microbiota undergoes dynamic changes as a part of the aging process. Notably, the interplay between immune changes and gut microbiota highlights the gut's role in modulating immune responses and maintaining immune homeostasis. The gut microbiota of centenarians exhibits characteristics akin to those found in young individuals, setting it apart from the microbiota observed in typical elderly individuals. This review delves into the current understanding of how aging impacts the immune system and suggests potential strategies for reversing aging through interventions in immune factors.
- MeSH
- adaptivní imunita * MeSH
- lidé MeSH
- přirozená imunita * MeSH
- stárnutí * imunologie MeSH
- střevní mikroflóra * imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
