Antimicrobial Immunity Research Articles

Tofacitinib downregulates antiviral immune defence in keratinocytes and reduces T cell activation

BackgroundTofacitinib is a novel Janus kinase (JAK) inhibitor approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. In clinical trials, the most common adverse events observed were nasopharyngitis, upper respiratory tract infections, and zoster. JAKs are found downstream of the type II cytokine receptor family used by a number of TH17 cell-associated cytokines for signal transduction. These cytokines lead to the secretion of antiviral and antimicrobial peptides (AMPs) by keratinocytes or synoviocytes. Blocking the JAK pathway might result in a diminished secretion of antimicrobial and antiviral peptides causing higher susceptibility to infections in patients treated with JAK inhibitors.MethodsWe treated primary human keratinocytes and synoviocytes with tofacitinib and subsequently added various cytokines and bacterial surface proteins before evaluation of the response via RT-qPCR. CD69 expression on tofacitinib-treated PBMCs was investigated via flow cytometry.ResultsWe found a markedly reduced gene expression of all tested antiviral peptides such as MX1 or ISG15 in keratinocytes and synoviocytes in the presence of tofacitinib in vitro. Additionally, we found that JAK inhibition reduced activation of T cells after stimulation with bacterial LPS or viral VZV gE.ConclusionsThe antiviral immunity is strongly inhibited in the presence of tofacitinib in vitro, while the antimicrobial immunity does not seem to be affected. In T cells, the overall activation process seems to be influenced by tofacitinib. These findings suggest that tofacitinib has an impact on antiviral immunity such as patients treated with tofacitinib often show adverse events like herpes zoster.Graphical abstract

Characteristics of local inflammation in patients with uterine fibroids and endometrial cancer.

e17561 Background: Contribution of local inflammation to the course of endometrial cancer (EC) is of interest since it may aggravate the disease. Methods: The study included 25 women aged 62+1.6 years with histologically verified EC (group 1a), 29 women aged 48+8.4 years with uterine fibroids (UF) (group 1b) and 13 non-cancer women aged 42+2.3 years (group 2, controls). Vaginal swabs were taken prior to antitumor treatment. Relative expression of genes encoding the synthesis of IL1B, IL10, IL18, TNFA, TLR4, GATA3, and CD68 in comparison with the reference gene B2M was determined by Real-time PCR using the ImmunoQuantex kit (Russia). An integral parameter of an inflammation index was calculated using binary logistics, and the ratios of the listed indicators were also calculated. 12 parameters were analyzed in total. Groups Ia and Ib were compared with healthy people (p1) and with each other (p2). Results: 4 of 12 studied parameters in EC patients differed from control; no differences were found in UF patients. 7 statistically significant differences were registered between EC and UF. Relative expression of the gene encoding the synthesis of IL10 was maximal in EC (2.8+0.2 vs. 1.8+0.3 in healthy women (p1= 0.006) and 1.8+0.2 in UF (p2= 0.002)). The IL10/IL18 ratio in EC statistically significantly exceeded the ratios in UF patients and in healthy women (61.4+21.7 (p1= 0.003), 46.3+32.2 (p2< 0.001) and 53.7+47.1 respectively). The TNFA/IL18 ratio in EC patients was also higher than in UF patients (1.1+0.7 vs. 0.5+0.2 (p2= 0.035)) due to higher TNFA levels (3.7+0.1 vs. 3.3+0.1 (p2= 0.006)), one of which effects includes stimulation of neoangiogenesis. The ratio of TLR4/GATA3, on the contrary, was lower in EC than in UF (0.7+0.3 and 1.5+0.9 respectively (p2= 0.001). Apparently, it characterized antimicrobial immunity because both of these genes are involved in the response to PAMP (TLR4) and in the genesis of intraepithelial lymphocytes related to innate immunity, as well as in the development of a humoral response via stimulation of Th2 (GATA3). The latter, in addition, is involved in the ontogenesis some organs, including the vagina and uterus. The highest TLR4/GATA3 ratio was found in UF, which, in our opinion, indicated the predominance of the inflammatory process in UF and local immunosuppression in EC. The inflammation index determined with the ImmunoQuantex test system did not differ between the studied groups of women. Conclusions: Some differences were observed in local reactions of immunity and inflammation in benign and malignant uterine tumors, involving the prevalence of immunosuppressive and angiogenic factors in EC and inflammatory factors in UF.

Multiplexed proteomics of autophagy deficient macrophages reveals enhanced anti-microbial immunity via the oxidative stress response

Abstract Macrophages play a critical role in clearance of cytosolic pathogens. Autophagy functions at the intersection of antimicrobial innate immunity, metabolism and protein quality control; however, the impacts of infection and autophagy on shaping the macrophage proteome are poorly understood. Here, we describe a deep multi-dimensional proteomic analysis of primary murine macrophages infected with Shigella flexneri (S. flexneri). Tandem mass tagging (TMT) revealed dynamic genotype- and infection-dependent differences in host and pathogen proteins, phosphorylation and ubiquitination. These data catalogue the complex circuitry connecting autophagy, inflammatory signaling and the oxidative stress response. Loss of the autophagy gene Atg16l1 induced basal oxidative stress, activated the compensatory glutathione biosynthetic machinery, and surprisingly, enhanced clearance of S. flexneri. Pathogen clearance was similarly enhanced in wild type macrophages upon pharmacological inhibition of cysteine import. Our study provides a resource for innate immunity research and unexpectedly reveals that ATG16L1 dampens antimicrobial immunity by regulating oxidative stress.

Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer's Disease.

Alzheimer’s disease (AD) is the most common form of dementia and aging is the most common risk factor for developing the disease. The etiology of AD is not known but AD may be considered as a clinical syndrome with multiple causal pathways contributing to it. The amyloid cascade hypothesis, claiming that excess production or reduced clearance of amyloid-beta (Aβ) and its aggregation into amyloid plaques, was accepted for a long time as the main cause of AD. However, many studies showed that Aβ is a frequent consequence of many challenges/pathologic processes occurring in the brain for decades. A key factor, sustained by experimental data, is that low-grade infection leading to production and deposition of Aβ, which has antimicrobial activity, precedes the development of clinically apparent AD. This infection is chronic, low grade, largely clinically silent for decades because of a nearly efficient antimicrobial immune response in the brain. A chronic inflammatory state is induced that results in neurodegeneration. Interventions that appear to prevent, retard or mitigate the development of AD also appear to modify the disease. In this review, we conceptualize further that the changes in the brain antimicrobial immune response during aging and especially in AD sufferers serve as a foundation that could lead to improved treatment strategies for preventing or decreasing the progression of AD in a disease-modifying treatment.

Mitochondrial DNA and cGAS-STING Innate Immune Signaling Pathway: Latest Research Progress

Mitochondria are important organelles that present extensively in cells, serving diverse functions. In addition to controlling cell energy production and metabolism, mitochondria are also involved in various biological processes, including anti-infection, apoptosis, and autophagy. Harmful stimuli from external environment or those generated by the cells themselves can damage mitochondria and cause mitochondrial stress response, during which the mitochondrial matrix containing mitochondrial DNA (mtDNA) can leak into the cytoplasm. Cytoplasmic mtDNA, acting as a damage-associated molecular pattern (DAMP), can activate a panel of DNA sensors and elicit innate immune response in organisms. Cyclic GMP-AMP synthase (cGAS), a key intracellular DNA sensor, can catalyze the conversion of GTP and ATP to cyclic GMP-AMP (2'3'-cGAMP), which serves as second messenger to bind and activate stimulator of interferon gene (STING), an endoplasmic adaptor protein. Beyond its critical roles in anti-microbial immunity, cGAS-STING pathway also serves important functions in many pathological and physiological processes such as autoimmunity, tumor and senescence. In this review, we focus on how the mtDNA released during mitochonrial stress response activates the cGAS-STING innate immune signaling pathway and the associated diseases, in order to help promote basic research about the role of mitochondria in innate immunity and provide new strategies for developing mitochondria-targeting drugs.

CpG-ODN induced antimicrobial immunity in neonatal chicks involves a substantial shift in serum metabolic profiles

Synthetic CpG-ODNs can promote antimicrobial immunity in neonatal chicks by enriching immune compartments and activating immune cells. Activated immune cells undergo profound metabolic changes to meet cellular biosynthesis and energy demands and facilitate the signaling processes. We hypothesize that CpG-ODNs induced immune activation can change the host’s metabolic demands in neonatal chicks. Here, we used NMR-based metabolomics to explore the potential of immuno-metabolic interactions in the orchestration of CpG-ODN-induced antimicrobial immunity. We administered CpG-ODNs to day-old broiler chicks via intrapulmonary (IPL) and intramuscular (IM) routes. A negative control group was administered IPL distilled water (DW). In each group (n = 60), chicks (n = 40) were challenged with a lethal dose of Escherichia coli, two days post-CpG-ODN administration. CpG-ODN administered chicks had significantly higher survival (P < 0.05), significantly lower cumulative clinical scores (P < 0.05), and lower bacterial loads (P < 0.05) compared to the DW control group. In parallel experiments, we compared NMR-based serum metabolomic profiles in neonatal chicks (n = 20/group, 24 h post-treatment) treated with IM versus IPL CpG-ODNs or distilled water (DW) control. Serum metabolomics revealed that IM administration of CpG-ODN resulted in a highly significant and consistent decrease in amino acids, purines, betaine, choline, acetate, and a slight decrease in glucose. IPL CpG-ODN treatment resulted in a similar decrease in purines and choline but less extensive decrease in amino acids, a stronger decrease in acetate, and a considerable increase in 2-hydroxybutyrate, 3-hydroxybutyrate, formic acid and a mild increase in TCA cycle intermediates (all P < 0.05 after FDR adjustment). These perturbations in pathways associated with energy production, amino acid metabolism and nucleotide synthesis, most probably reflect increased uptake of nutrients to the cells, to support cell proliferation triggered by the innate immune response. Our study revealed for the first time that CpG-ODNs change the metabolomic landscape to establish antimicrobial immunity in neonatal chicks. The metabolites highlighted in the present study can help future targeted studies to better understand immunometabolic interactions and pinpoint the key molecules or pathways contributing to immunity.

Perillaldehyde Inhibition of cGAS Reduces dsDNA-Induced Interferon Response.

Cyclic GMP-AMP synthase (cGAS), serving as a primary sensor of intracellular DNA, is essential to initiate anti-microbial innate immunity. Inappropriate activation of cGAS by self-DNA promotes severe autoinflammatory diseases such as Aicardi–Goutières syndrome (AGS); thus, inhibition of cGAS may provide therapeutic benefit in anti-autoimmunity. Here we report that perillaldehyde (PAH), a natural monoterpenoid compound derived from Perilla frutescens, suppresses cytosolic-DNA-induced innate immune responses by inhibiting cGAS activity. Mice treated with PAH are more susceptible to herpes simplex virus type 1 (HSV-1) infection. Moreover, administration with PAH markedly ameliorates self-DNA-induced autoinflammatory responses in a mouse model of AGS. Collectively, our study reveals that PAH can effectively inhibit cGAS-STING signaling and could be developed toward the treatment of cGAS-mediated autoimmune diseases.

β-Thymosin is an essential regulator of stem cell proliferation and neuron regeneration in planarian (Dugesia japonica)

β-Thymosin is a multifunctional peptide ubiquitously expressed in vertebrates and invertebrates. Many studies have found β-thymosin is critical for wound healing, angiogenesis, cardiac repair, hair regrowth, and anti-fibrosis in vertebrates, and plays an important role in antimicrobial immunity in invertebrates. However, whether β-thymosin participates in the regeneration of organisms is still poorly understood. In this study, we identified a β-thymosin gene in Dugesia japonica which played an important role in stem cell proliferation and neuron regeneration during the tissue repair process in D. japonica. Sequencing analysis showed that β-thymosin contained two conserved β-thymosin domains and two actin-binding motifs, and had a high similarity with other β-thymosins of invertebrates. In situ or fluorescence in situ hybridization analysis revealed that Djβ-thymosin was co-localized with DjPiWi in the neoblast cells of intact adult planarians and the blastema of regenerating planarians, suggesting Djβ-thymosin has a potential function of regeneration. Disruption Djβ-thymosin by RNA interference results in a slightly curled up head of planarian and stem cell proliferation defects. Additionally, we found that, upon amputation, Djβ-thymosin RNAi-treated animals had impaired regeneration ability, including impaired blastema formation, delayed eyespot formation, decreased brain area, and disrupted central CNS formation, implying Djβ-thymosin is an essential regulator of stem cell proliferation and neuron regeneration.

Interplay between SMAD2 and STAT5A is a critical determinant of IL-17A/IL-17F differential expression

Interleukins (IL)-17A and F are critical cytokines in anti-microbial immunity but also contribute to auto-immune pathologies. Recent evidence suggests that they may be differentially produced by T-helper (Th) cells, but the underlying mechanisms remain unknown. To address this question, we built a regulatory graph integrating all reported upstream regulators of IL-17A and F, completed by ChIP-seq data analyses. The resulting regulatory graph encompasses 82 components and 136 regulatory links. The graph was then supplemented by logical rules calibrated with original flow cytometry data using naive CD4+ T cells, in conditions inducing IL-17A or IL-17F. The model displays specific stable states corresponding to virtual phenotypes explaining IL-17A and IL-17F differential regulation across eight cytokine stimulatory conditions. Our model analysis points to the transcription factors NFAT2A, STAT5A and SMAD2 as key regulators of the differential expression of IL-17A and IL-17F, with STAT5A controlling IL-17F expression, and an interplay of NFAT2A, STAT5A and SMAD2 controlling IL-17A expression. We experimentally observed that the production of IL-17A was correlated with an increase of SMAD2 transcription, and the expression of IL-17F correlated with an increase of BLIMP-1 transcription, together with an increase of STAT5A expression (mRNA), as predicted by our model. Interestingly, RORγt presumably plays a more determinant role in IL-17A expression as compared to IL-17F expression. In conclusion, we propose the first mechanistic model accounting for the differential expression of IL-17A and F in Th cells, providing a basis to design novel therapeutic interventions in auto-immune and inflammatory diseases.

MicroRNA-210 and microRNA-3570 Negatively Regulate NF-κB-Mediated Inflammatory Responses by Targeting RIPK2 in Teleost Fish.

Pathogen infection can cause the production of inflammatory cytokines, which are key mediators that cause the host’s innate immune response. Therefore, proper regulation of immune genes associated with inflammation is essential for immune response. Among them, microRNAs (miRNAs) as gene regulator have been widely reported to be involved in the innate immune response of mammals. However, the regulatory network in which miRNAs are involved in the development of inflammation is largely unknown in lower vertebrates. Here, we identified two miRNAs from miiuy croaker (Miichthys miiuy), miR-210 and miR-3570, which play a negative regulatory role in host antibacterial immunity. We found that the expressions of miR-210 and miR-3570 were significantly upregulated under the stimulation of Gram-negative bacterium vibrio harveyi and LPS (lipopolysaccharide). Induced miR-210 and miR-3570 inhibit inflammatory cytokine production by targeting RIPK2, thereby avoiding excessive inflammation. In particular, we found that miR-210 and miR-3570 negatively regulate antimicrobial immunity by regulating the RIPK2-mediated NF-κB signaling pathway. The collective results indicated that both miRNAs are used as negative feedback regulators to regulate RIPK2-mediated NF-κB signaling pathway and thus play a regulatory role in bacteria-induced inflammatory response.

Mitochondrial Reactive Oxygen Species Regulate Immune Responses of Macrophages to Aspergillus fumigatus.

Reactive Oxygen Species (ROS) are highly reactive molecules that can induce oxidative stress. For instance, the oxidative burst of immune cells is well known for its ability to inhibit the growth of invading pathogens. However, ROS also mediate redox signalling, which is important for the regulation of antimicrobial immunity. Here, we report a crucial role of mitochondrial ROS (mitoROS) in antifungal responses of macrophages. We show that mitoROS production rises in murine macrophages exposed to swollen conidia of the fungal pathogen Aspergillus fumigatus compared to untreated macrophages, or those treated with resting conidia. Furthermore, the exposure of macrophages to swollen conidia increases the activity of complex II of the respiratory chain and raises mitochondrial membrane potential. These alterations in mitochondria of infected macrophages suggest that mitoROS are produced via reverse electron transport (RET). Significantly, preventing mitoROS generation via RET by treatment with rotenone, or a suppressor of site IQ electron leak, S1QEL1.1, lowers the production of pro-inflammatory cytokines TNF-α and IL-1β in macrophages exposed to swollen conidia of A. fumigatus. Rotenone and S1QEL1.1 also reduces the fungicidal activity of macrophages against swollen conidia. Moreover, we have established that elevated recruitment of NADPH oxidase 2 (NOX2, also called gp91phox) to the phagosomal membrane occurs prior to the increase in mitoROS generation. Using macrophages from gp91phox-/- mice, we have further demonstrated that NOX2 is required to regulate cytokine secretion by RET-associated mitoROS in response to infection with swollen conidia. Taken together, these observations demonstrate the importance of RET-mediated mitoROS production in macrophages infected with A. fumigatus.

The Role of Nucleases and Nucleic Acid Editing Enzymes in the Regulation of Self-Nucleic Acid Sensing.

Detection of microbial nucleic acids by the innate immune system is mediated by numerous intracellular nucleic acids sensors. Upon the detection of nucleic acids these sensors induce the production of inflammatory cytokines, and thus play a crucial role in the activation of anti-microbial immunity. In addition to microbial genetic material, nucleic acid sensors can also recognize self-nucleic acids exposed extracellularly during turn-over of cells, inefficient efferocytosis, or intracellularly upon mislocalization. Safeguard mechanisms have evolved to dispose of such self-nucleic acids to impede the development of autoinflammatory and autoimmune responses. These safeguard mechanisms involve nucleases that are either specific to DNA (DNases) or RNA (RNases) as well as nucleic acid editing enzymes, whose biochemical properties, expression profiles, functions and mechanisms of action will be detailed in this review. Fully elucidating the role of these enzymes in degrading and/or processing of self-nucleic acids to thwart their immunostimulatory potential is of utmost importance to develop novel therapeutic strategies for patients affected by inflammatory and autoimmune diseases.

Functions of ROS in Macrophages and Antimicrobial Immunity.

Reactive oxygen species (ROS) are a chemically defined group of reactive molecules derived from molecular oxygen. ROS are involved in a plethora of processes in cells in all domains of life, ranging from bacteria, plants and animals, including humans. The importance of ROS for macrophage-mediated immunity is unquestioned. Their functions comprise direct antimicrobial activity against bacteria and parasites as well as redox-regulation of immune signaling and induction of inflammasome activation. However, only a few studies have performed in-depth ROS analyses and even fewer have identified the precise redox-regulated target molecules. In this review, we will give a brief introduction to ROS and their sources in macrophages, summarize the versatile roles of ROS in direct and indirect antimicrobial immune defense, and provide an overview of commonly used ROS probes, scavengers and inhibitors.

Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development.

Simple SummaryTumor immune evasion is one of the hallmarks of tumor progression that enables tumor growth despite the activity of the host immune system. It is mediated by various types of cells. Recently, immature red blood cells called erythroid progenitor cells (EPCs) were identified as regulators of the immune response in cancer. EPCs expand in cancer as a result of dysregulated erythropoiesis and potently suppress the immune response. Thus, targeting dysregulated EPC differentiation appears to be a promising therapeutic strategy.Cancer cells harness normal cells to facilitate tumor growth and metastasis. Within this complex network of interactions, the establishment and maintenance of immune evasion mechanisms are crucial for cancer progression. The escape from the immune surveillance results from multiple independent mechanisms. Recent studies revealed that besides well-described myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) or regulatory T-cells (Tregs), erythroid progenitor cells (EPCs) play an important role in the regulation of immune response and tumor progression. EPCs are immature erythroid cells that differentiate into oxygen-transporting red blood cells. They expand in the extramedullary sites, including the spleen, as well as infiltrate tumors. EPCs in cancer produce reactive oxygen species (ROS), transforming growth factor β (TGF-β), interleukin-10 (IL-10) and express programmed death-ligand 1 (PD-L1) and potently suppress T-cells. Thus, EPCs regulate antitumor, antiviral, and antimicrobial immunity, leading to immune suppression. Moreover, EPCs promote tumor growth by the secretion of growth factors, including artemin. The expansion of EPCs in cancer is an effect of the dysregulation of erythropoiesis, leading to the differentiation arrest and enrichment of early-stage EPCs. Therefore, anemia treatment, targeting ineffective erythropoiesis, and the promotion of EPC differentiation are promising strategies to reduce cancer-induced immunosuppression and the tumor-promoting effects of EPCs.

Pol-miR-150 regulates anti-bacterial and viral infection in Japanese flounder (Paralichthys olivaceus) via the lysosomal protein LMP2L.

MiR-150 is a microRNA (miRNA) present in a number of teleost species, but its target and regulation mechanism are unknown. Similarly, lysosome membrane protein 2-like (LMP2L) is a gene identified in fish but with unknown function. In this study, we examined the regulation mechanism and function of flounder miR-150 (named pol-miR-150) and its target gene LMP2L (named PoLMP2L) in association with bacterial and viral infection. We found that pol-miR-150 expression was not only modulated by the bacterial pathogen Streptococcus iniae but also by the viral pathogen megalocytivirus. Pol-miR-150 targeted PoLMP2L by binding to the 3'-untranslated region (3'-UTR) of PoLMP2L and inhibited PoLMP2L expression in vitro and in vivo. PoLMP2L is a member of the CD36 superfamily of scavenger receptors and homologous to but phylogenetically distinct from lysosomal integral membrane protein type 2 (LIMP2). PoLMP2L was localized mainly in the lysosomes and expressed in multiple organs of flounder. In vivo knockdown and overexpression of PoLMP2L enhanced and suppressed, respectively, S. iniae dissemination in flounder tissues, whereas in vivo knockdown and overexpression of pol-miR-150 produced the opposite effects on S. iniae dissemination. In addition, pol-miR-150 knockdown also significantly inhibited the replication of megalocytivirus. The results of this study revealed the regulation mechanism and immune functions of fish miR-150 and LMP2L, and indicated that LMP2L and miR-150 play an important role in the antimicrobial immunity of fish.

Immunosensation: Neuroimmune Cross Talk in the Skin.

Classically, skin was considered a mere structural barrier protecting organisms from a diversity of environmental insults. In recent decades, the cutaneous immune system has become recognized as a complex immunologic barrier involved in both antimicrobial immunity and homeostatic processes like wound healing. To sense a variety of chemical, mechanical, and thermal stimuli, the skin harbors one of the most sophisticated sensory networks in the body. However, recent studies suggest that the cutaneous nervous system is highly integrated with the immune system to encode specific sensations into evolutionarily conserved protective behaviors. In addition to directly sensing pathogens, neurons employ novel neuroimmune mechanisms to provide host immunity. Therefore, given that sensation underlies various physiologies through increasingly complex reflex arcs, a much more dynamic picture is emerging of the skin as a truly systemic organ with highly coordinated physical, immunologic, and neural functions in barrier immunology.

Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity.

Infection triggers expansion and effector differentiation of T cells specific for microbial antigens in association with metabolic reprograming. We found that the glycolytic enzyme lactate dehydrogenase A (LDHA) is induced in CD8+ T effector cells through phosphoinositide 3-kinase (PI3K) signaling. In turn, ablation of LDHA inhibits PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1, causing defective antimicrobial immunity. LDHA deficiency cripples cellular redox control and diminishes adenosine triphosphate (ATP) production in effector T cells, resulting in attenuated PI3K signaling. Thus, nutrient metabolism and growth factor signaling are highly integrated processes, with glycolytic ATP serving as a rheostat to gauge PI3K-Akt-Foxo1 signaling in the control of T cell immunity. Such a bioenergetic mechanism for the regulation of signaling may explain the Warburg effect.

Viral Impacts on MR1 Antigen Presentation to MAIT Cells.

Mucosal-associated invariant T (MAIT) cells are abundant innate-like T cells important in antimicrobial immunity. These cells express a semi-invariant T cell receptor that recognizes the Major Histocompatibility Complex (MHC) class I-related protein 1 (MR1) in complex with small metabolite antigens derived from a range of commensal and pathogenic bacteria and yeasts, but not other pathogens such as viruses. Thus, MR1 stimulation of MAIT cells was thought to act as a sensor of bacterial infection and was not directly involved in anti-viral immunity. Surprisingly, viruses have recently been shown to directly impair MR1 antigen presentation by targeting the intracellular pool of MR1 for degradation. In this review, we summarize our current understanding of viral evasion of MR1 presentation pathway, and contrast this to evasion of other related MHC molecules. We examine MAIT cell activity in viral infection with a focus on the role of TCR-mediated activation of these innate-like cells and speculate on the selective pressure for viral evasion of MR1 antigen presentation. Overall, viral evasion of MR1 presentation uncovers a new avenue of research and implies that the MR1-MAIT cell axis is more important in viral immunity than was previously appreciated.

Circular RNA TRAPPC6B inhibits intracellular Mycobacterium tuberculosis growth while inducing autophagy in macrophages by targeting microRNA-874-3p.

ObjectivesGenetic and epigenetic mechanisms regulate antimicrobial immunity against Mycobacterium tuberculosis (Mtb) infection.MethodsThe present study assessed circular RNA TRAPPC6B (circTRAPPC6B) for antimicrobial immune functions and defined mechanisms wherein circTRAPPC6B regulates Mtb growth, autophagy and microRNA in macrophages.ResultsThe Mtb infection of monocytes/macrophages resulted in a significantly decreased level of circTRAPPC6B that inhibited intracellular Mtb growth in macrophages. Conversely, circTRAPPC6B expression enhanced autophagy or autophagy‐associated protein LC3‐II production in Mtb‐infected macrophages. circTRAPPC6B‐enhanced autophagy aggregation or sequestration was also observed in fluorescence in situ hybridisation (FISH) analysis and confocal imaging. Mechanistically, circTRAPPC6B targets an inhibiting element miR‐874‐3p, as shown by bioinformatics, dual‐luciferase reporter gene analysis and pull‐down assay, respectively. Notably, miR‐874‐3p prohibited autophagy via suppressing autophagy protein ATG16L1 by binding to its 3′‐untranslated region (UTR) in Mtb‐infected macrophages and thus promoting intracellular Mtb growth. Concurrently, circTRAPPC6B enhanced autophagy in Mtb‐infected macrophages by blocking the ability of miR‐874‐3p to inhibit ATG16L1. Thus, circTRAPPC6B antagonises the ability of miR‐874‐3p to suppress ATG16L1 expression and activate and enhance autophagy sequestration to restrict Mtb growth in macrophages.ConclusionThe current findings suggested that both circTRAPPC6B and miR‐874‐3p mechanisms can be explored as potential therapeutics against Mtb infection.

Predicting candidate therapeutic drugs for sepsis-induced acute respiratory distress syndrome based on transcriptome profiling

ABSTRACT Sepsis-induced acute respiratory distress syndrome (ARDS) remains a major threat to human health without effective therapeutic drugs. Previous studies demonstrated the power of gene expression profiling to reveal pathological changes associated with sepsis-induced ARDS. However, there is still a lack of systematic data mining framework for identifying potential targets for treatment. In this study, we demonstrated the feasibility of druggable targets prediction based on gene expression data. Through the functional enrichment analysis of microarray-based expression profiles between sepsis-induced ARDS and non-sepsis ARDS samples, we revealed genes involved in anti-microbial infection immunity were significantly altered in sepsis-induced ARDS. Protein–protein interaction (PPI) network analysis highlighted TOP2A gene as the key regulator in the dysregulated gene network of sepsis-induced ARDS. We were also able to predict several therapeutic drug candidates for sepsis-induced ARDS using Connectivity Map (Cmap) database, among which doxorubicin was identified to interact with TOP2A with a high affinity similar to its endogenous ligand. Overall, our findings suggest that doxorubicin could be a potential therapeutic for sepsis-induced ARDS by targeting TOP2A, which requires further investigation and validation. The whole study relies on publicly available dataset and publicly accessible database or bioinformatic tools for data mining. Therefore, our study benchmarks a workflow for druggable target prediction which can be widely applicable in the search of targets in other pathological conditions.