Cytokine Receptors-Regulators of Antimycobacterial Immune Response

Cytokine receptors are critical regulators of the antimycobacterial immune response, playing a key role in initiating and coordinating the recruitment and activation of immune cells during infection. They recognize and bind specific cytokines and are involved in inducing intracellular signal transduction pathways that regulate a diverse range of biological functions, including proliferation, differentiation, metabolism and cell growth. Due to mutations in cytokine receptor genes, defective signaling may contribute to increased susceptibility to mycobacteria, allowing the pathogens to avoid killing and immune surveillance. This paper provides an overview of cytokine receptors important for the innate and adaptive immune responses against mycobacteria and discusses the implications of receptor gene defects for the course of mycobacterial infection. Keywords: cytokine; cytokine receptors; immune response; mycobacteri

Monocyte response receptors in BCG driven delayed type hypersensitivity to tuberculin.

Tuberculosis (TB) still remains the leading cause of mortality due to bacterial pathogen. The only currently available vaccine against TB, Bacille Calmette-GuĂŠrin (BCG) is at best credited with a 50% overall protective efficacy. Skin testing with purified protein derivative (PPD) from Mycobacterium tuberculosis is the method of detecting BCG-induced cell mediated immunity, in vivo. In the previous study we found that approximately 60% young volunteers with no history of TB, who had been subjected to neonatal BCG vaccination and revaccination(s) at school age, developed delayed type hypersensitivity (DTH) to tuberculin. The remaining volunteers were persistently tuberculin negative. Moreover, we found a significant association between BCG driven development of DTH to PPD and the polymorphism within the CD14 C/T(-159) gene for macrophage receptor recognising mycobacterial compounds. It has suggested that the CD14 gene variants may play a role in the appearance and persistence of DTH to PPD in BCG vaccinated subjects. In order to extend our study on a possible role of CD14 in BCG driven DTH response to PPD, we measured the expression of mCD14 on macrophages, stimulated or not stimulated with mycobacterial antigens, and the serum levels of sCD14. Considering the importance of CD14 - TLR2/TLR4 interactions in macrophage signalling, we determined the polymorphism of TLR2 and TLR4 genes as well as macrophage expression of TLR2 for the volunteers with and without skin reactivity to PPD. We observed a subtle but significant decrease in CD14 density on adherent monocytes from tuberculin positive versus tuberculin negative volunteers. However, we found no difference in CD14 density on monocytes enriched in CD14+ cells using anti-CD14 mAb coupled to magnetic beads. A significant increase in CD14 density was observed on macrophages stimulated with PPD and LPS but not with live BCG bacilli. However, this increase as well as serum levels of soluble sCD14 were similar in the volunteers with and without skin reactions to PPD. Thus, our suggestion on the role of CD14 in the generation of DTH to tuberculin in BCG vaccinated subjects should be further explored. The most important CD14 co-receptors are Toll-like receptors (TLRs) which activate nuclear factors for the production of inflammatory cytokines. However, we could see no association between the polymorphisms of TLR4 (Asp299Gly and Thr399Ile) and TLR2 genes (Arg753Gln and Arg677Trp) and skin responses to PPD. Also, the TLR2 density was similar on monocytes from tuberculin negative and tuberculin positive volunteers

Interaction of Helicobacter pylori with C-Type Lectin Dendritic Cell-Specific ICAM Grabbing Nonintegrin

In this study we asked whether Helicobacter pylori whole cells and lipopolysaccharide (LPS) utilize sugar moieties of Lewis (Le) antigenic determinants to interact with DC-SIGN (dendritic cell specific ICAM grabbing nonintegrin) receptor on dendritic cells (DCs). For this purpose the soluble DC-SIGN/Fc adhesion assay and the THP-1 leukemia cells with induced expression of DC-SIGN were used. We showed that the binding specificity of DC-SIGN with H. pylori LeX/Y positive whole cells and H. pylori LPS of LeX/Y type was fucose dependent, whereas in LeXY negative H. pylori strains and LPS preparations without Lewis determinants, this binding was galactose dependent. The binding of soluble synthetic LeX and LeY to the DC-SIGN-like receptor on THP-1 cells was also observed. In conclusion, the LeXY dependent as well as independent binding of H. pylori whole cells and H. pylori LPS to DC-SIGN was described. Moreover, we demonstrated that THP-1 cells may serve as an in vitro model for the assessment of H. pylori-DC-SIGN interactions mediated by LeX and LeY determinants

Rapid method for Mycobacterium tuberculosis identification using electrospray ionization tandem mass spectrometry analysis of mycolic acids

Mycolic acids (MAs), which play a crucial role in the architecture of mycobacterial cell walls, were analyzed using electrospray ionization tandem mass spectrometry. A targeted analysis based on the 10 most abundant and characteristic multiple reaction monitoring pairs was used to profile the crude fatty acid mixtures from Mtb and several nontuberculous mycobacterial strains. Comparative analysis yielded unique profiles for MAs, enabling the reliable identification of mycobacterial species. In a case-control study of tuberculosis (TB) and non-TB Polish patients, we demonstrated the potential diagnostic utility of our approach for the rapid diagnosis of active TB with sensitivity and specificity surpassing those of existing methods. This robust method allows the identification of TB-positive patients after 2 h of sample preparation in the case of direct sputum analysis or 10 days of culturing, both of which are followed by 1 min of liquid chromatography– tandem mass spectrometry analysis

Cytokine Receptors—Regulators of Antimycobacterial Immune Response

Cytokine receptors are critical regulators of the antimycobacterial immune response, playing a key role in initiating and coordinating the recruitment and activation of immune cells during infection. They recognize and bind specific cytokines and are involved in inducing intracellular signal transduction pathways that regulate a diverse range of biological functions, including proliferation, differentiation, metabolism and cell growth. Due to mutations in cytokine receptor genes, defective signaling may contribute to increased susceptibility to mycobacteria, allowing the pathogens to avoid killing and immune surveillance. This paper provides an overview of cytokine receptors important for the innate and adaptive immune responses against mycobacteria and discusses the implications of receptor gene defects for the course of mycobacterial infection

NOD1, NOD2, and NLRC5 Receptors in Antiviral and Antimycobacterial Immunity

The innate immune system recognizes pathogen-associated molecular motifs through pattern recognition receptors (PRRs) that induce inflammasome assembly in macrophages and trigger signal transduction pathways, thereby leading to the transcription of inflammatory cytokine genes. Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) represent a family of cytosolic PRRs involved in the detection of intracellular pathogens such as mycobacteria or viruses. In this review, we discuss the role of NOD1, NOD2, and NLRC5 receptors in regulating antiviral and antimycobacterial immune responses by providing insight into molecular mechanisms as well as their potential health and disease implications

Tlr11 as a receptor for profilin and flagellin

Rodzina receptorów Toll-podobnych jest grupą transbłonowych białek rozpoznających konserwatywne wzorce molekularne patogenów (ang. pathogen associated molecular patterns, PAMPs). Ich cechą charakterystyczną jest występowanie wielu powtórzeń bogatych w leucynę w domenie zewnątrzkomórkowej i obecność domeny TIR w ich części cytoplazmatycznej. Kluczowa rola receptorów Toll-podobnych, będących swoistymi łącznikami odporności wrodzonej i nabytej, polega na inicjacji i regulacji odpowiedzi odpornościowej indukowanej przez wnikające do organizmu patogeny. Dotychczas odkryto 13 receptorów Toll-podobnych, z których dziesięć wykryto u ludzi (TLR1-10), a dwanaście u myszy (TLR1-9 i TLR11-13). Każdy z receptorów rozpoznaje zachowane w ewolucji związki, a wiążąc je prowadzi do aktywacji szeregu białek i wzbudzenia ekspresji wielu różnych genów. Cząsteczka TLR11 należy wraz z TLR12 i TLR13 do rodziny receptorów TLR11 występujących w błonie endosomów mysich komórek dendrytycznych, makrofagów oraz komórek nabłonkowych. Głównymi ligandami rozpoznawanymi przez ten receptor są flagelina wici bakteryjnych oraz profilina T. gondii. Mimo obecności homologicznego genu w komórkach ludzkich, ze względu na liczne kodony stop, nie ulega on transkrypcji. Wyniki wielu badań sugerują, że brak ekspresji cząsteczek TLR11 u ludzi może być jednym z ważnych elementów determinujących podatność na zakażenia wywoływane przez niektóre patogeny, których struktury PAMP rozpoznawane są przez ten receptor.Family of Toll-like receptors (TLR) is a group of transmembrane proteins, which recognize pathogen associated molecular patterns (PAMPs). Unique feature of these molecules is the presence of multiple leucine-rich repeats in the extracellular domain and a TIR domain located in the cytoplasmic part of the receptor. The key role of TLR receptors stems from their ability to connect innate and acquired immunity by regulating the immune responses against invading pathogens. Until now, thirteen TLRs have been discovered, out of which ten have been found in humans (TLR1-TLR10), and twelve (TLR1-9 and TLR11-13) in mice. Each TLR receptor recognizes and binds evolutionarily conserved molecules; in consequence a cascade of proteins is activated which leads to the expression of many different genes. TLR11 molecule belongs, along with TLR12 and TLR13, to Toll-like 11 receptor family found in the endosomal membrane of murine dendritic cells, macrophages and epithelial cells. Flagellin which builds bacterial flagella and T. gondi profilin are main ligands for that receptor. Although humans have an orthologue of TLR11 gene, it is nonfunctional due to the presence of many stop codons. Plentiful publications suggest that the lack of expression of TLR11 in humans can be one of the causes for increased susceptibility to some of the pathogens whose PAMPs are recognized by that receptor.

Tuberculosis - the forgotten disease worth to remember

Gruźlica wciąż stanowi poważny problem epidemiologiczny na całym świecie. Ponad 130 lat wytężonej pracy naukowców na całym świecie nie przyniosło zapewniającej protekcję szczepionki przeciwgruźliczej, szybkich i pewnych metod diagnozowania tej choroby oraz skutecznych sposobów leczenia gruźlicy wywoływanej przez izolowane ze wzrastającą częstością wielolekooporne prątki gruźlicy. Wywołujące gruźlicę prątki Mycobacterium tuberculosis są Gram-dodatnimi pałeczkami tlenowymi o unikatowej w świecie bakterii ścianie komórkowej, która zbudowana jest, poza peptydoglikanem i polisacharydami, z nietypowych glikolipidów i lipidów, w tym długołańcuchowych kwasów mykolowych, będących silnymi modulatorami układu odpornościowego człowieka. Diagnozowanie gruźlicy oparte jest na hodowli prątków na podłożach bakteriologicznych, obok której wykonywane jest badanie bakterioskopowe plwociny, radiologiczna ocena zmian w klatce piersiowej, tuberkulinowy test skórny, czy też testy molekularne (AMPLICOR Mycobacterium tuberculosisis Xpert MTB/RIF) lub metody wykorzystujące mykobakteriofagi (FastPlaque oraz ReporterPhage). Istotnym problem epidemiologicznym są uśpione (latente) zakażenia prątkami gruźlicy, które wykrywa się testami interferonowymi (QuantiFERON®-TB Gold Plus oraz T-SPOT.TB). Mimo znacznego postępu wciąż brakuje szybkich, wiarygodnych i tanich testów diagnostycznych gruźlicy.Tuberculosis (TB) remains a serious epidemiological problem throughout the world. More than 130 years of hard work of scientists around the world has not delivered fully protective vaccine for TB, fast and reliable methods for diagnosing and effective treatment of tuberculosis caused by multi-drug resistant Mycobacterium tuberculosis (MDR-TB), isolated recently with an increasing incidence. MDR- TB are Gram-positive, aerobic bacilli with the unique bacterial cell wall, which is built not only of peptidoglycan and polysaccharides, but also of unusual glycolipids and lipids, including long-chain mycolic acids, which are potential modulators of the human immune system. Diagnosis of tuberculosis is based on the culture of mycobacteria on bacteriological media, alongside which are carried out: bacterioscopy of sputum, radiographic assessment of changes in the chest, tuberculin skin test, or molecular test (AMPLICOR Mycobacterium tuberculosisis Xpert MTB/RIF), and tests with mycobacteriohages (FastPlaque and ReporterPhage). The important epidemiological issue are dormant (latent) mycobacterial infections, which can be detected by interferon-γ release assays (QuantiFERON®-TB Gold Plus and T-SPOT.TB). Despite considerable progress we are still lacking high-speed, reliable and low-cost diagnostic tests for tuberculosis

Trained Innate Immunity Not Always Amicable

The concept of “trained innate immunity” is understood as the ability of innate immune cells to remember invading agents and to respond nonspecifically to reinfection with increased strength. Trained immunity is orchestrated by epigenetic modifications leading to changes in gene expression and cell physiology. Although this phenomenon was originally seen mainly as a beneficial effect, since it confers broad immunological protection, enhanced immune response of reprogrammed innate immune cells might result in the development or persistence of chronic metabolic, autoimmune or neuroinfalmmatory disorders. This paper overviews several examples where the induction of trained immunity may be essential in the development of diseases characterized by flawed innate immune response