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Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation with no exact known cause. Intestinal innate immunity is enacted by neutrophils, monocytes, macrophages, and dendritic cells (DCs), and innate lymphoid cells and NK cells, characterized by their capacity to produce a rapid and nonspecific reaction as a first-line response. Innate immune cells (IIC) defend against pathogens and excessive entry of intestinal microorganisms, while preserving immune tolerance to resident intestinal microbiota. Changes to this equilibrium are linked to intestinal inflammation in the gut and IBD. IICs mediate host defense responses, inflammation, and tissue healing by producing cytokines and chemokines, activating the complement cascade and phagocytosis, or presenting antigens to activate the adaptive immune response. IICs exert important functions that promote or ameliorate the cellular and molecular mechanisms that underlie and sustain IBD. A comprehensive understanding of the mechanisms underlying these clinical manifestations will be important for developing therapies targeting the innate immune system in IBD patients. This review examines the complex roles of and interactions among IICs, and their interactions with other immune and non-immune cells in homeostasis and pathological conditions., Instituto de Salud Carlos III, European Regional Development Fund, Depto. de Inmunología, Oftalmología y ORL, Fac. de Medicina, TRUE, pub

BackgroundEarly-life adversity (ELA) has been linked to higher depression risk across the life span and chronic inflammatory conditions that contribute to earlier mortality. In this study, we characterized innate immune responses to acute social stress in a community sample of adolescents (mean age = 13.9 ± 1.6 years; 46.4% female) as a potential pathway linking ELA and depression pathogenesis.MethodsParents reported their child's exposure to 9 ELAs, and adolescents participated in the Trier Social Stress Test for Children, with blood collected immediately before and then at 60 and 90 minutes thereafter. Overall, 65 adolescents had complete data for analysis of stress-induced changes in gene expression and 84 adolescents had complete data for circulating inflammatory markers.ResultsRelative to adolescents exposed to no ELA (11.9%) or low ELA (ELA = 1-3; 67.9%), those exposed to high ELA (ELA = 4+; 20.2%) showed larger stress-associated increases in expression of both proinflammatory and innate antiviral gene transcripts in circulating blood. Consistent with a potential mediating role of sympathetic nervous system activity, promoter-based bioinformatics analyses implicated CREB transcription factor activity in structuring observed gene expression differences. These effects were accompanied by a smaller initial but protracted increase in circulating interleukin 6 in adolescents with high ELA.ConclusionsResults are consistent with the hypothesis that ELA may enhance cellular and gene regulatory reactivity to stress, which may, in turn, increase vulnerability to depression and other inflammation-related disease processes.

European Research Council Starting grant, Mucous membranes are the largest contact site between the external environment and the internal milieu. They protect the body, allow the exchange of nutrients or respiratory gases and are the barrier that ensures the integrity of the internal environment. These barriers are also subject to aggression from infectious agents, toxins, and physical trauma. They are also sites colonized by an abundant microbiota. Mucous membranes are defensive barriers in which three layers can be defined. The epithelium ensures selective integrity and impermeability by the presence of adhesive junctions between their cells. On the outside of this layer there is a layer of mucus and other secretions that serves as a barrier to a commensal symbiont microbiota, which provides micronutrients vitamins and regulatory molecules. The microbiota lives in symbiosis with the organism but occasionally this microenvironment can be colonized by pathogenic species. To deal with these aggressions, a third layer of this defense barrier is the immunological barrier associated with the mucous membranes. Mucous membranes house the largest population of immune cells in the entire body. The immune system associated with the mucous membranes recognizes pathogens and toxins from outside the barrier but must react to pathogens and tolerate the commensal microbiota. Their different components also receive signals from the other components of the mucosal barrier. All the components of the barrier weave a network of mutual interactions that ensure homeostasis, not only of the mucous membranes but also of the whole organism. Imbalances in the response of the different components of these circuits are the basis of a large number of diseases, not only of the systems in which they are located, but also on the whole-body systems. This Research Topic addresses different aspects of their components and their mutual interrelationships., European Commision. European Research Council, German Research Foundation, Depto. de Biología Celular, Fac. de Ciencias Biológicas, TRUE, pub

The freshwater snail Biomphalaria glabrata is an intermediate host of Schistosoma mansoni, the agent of human intestinal schistosomiasis. However, much is to be discovered about its innate immune system that appears as a complex black box, in which the immune cells (called hemocytes) play a major role in both cellular and humoral response towards pathogens. Until now, hemocyte classification has been based exclusively on cell morphology and ultrastructural description and depending on the authors considered from 2 to 5 hemocyte populations have been described. In this study, we proposed to evaluate the hemocyte heterogeneity at the transcriptomic level. To accomplish this objective, we used single cell RNA sequencing (scRNAseq) technology coupled to a droplet-based system to separate hemocytes and analyze their transcriptome at a unique cell level in naive Biomphalaria glabrata snails. We were able to demonstrate the presence of 7 hemocyte transcriptomic populations defined by the expression of specific marker genes. As a result, scRNAseq approach showed a high heterogeneity within hemocytes, but provides a detailed description of the different hemocyte transcriptomic populations in B. glabrata supported by distinct cellular functions and lineage trajectory. As a main result, scRNAseq revealed the 3 main population as a super-group of hemocyte diversity but, on the contrary, a great hemocytes plasticity with a probable capacity of hemocytes to engage to different activation pathways. This work opens a new field of research to understand the role of hemocytes particularly in response to pathogens, and towards S. mansoni parasites.

It is estimated that 257 million people have chronic hepatitis B (CHB). HBV infection is endemic throughout Asia, sub-Saharan Africa, Polynesia, as well as in indigenous populations in North America, New Zealand and Australia. Nucleot(s)ide analogues (NA) are standard treatment for HBeAg-negative chronic hepatitis B (CHB). The two first-line NA, entecavir (ETV) and tenofovir disoproxil (TDF), are both potent antiviral agents which effect durable viral suppression, reduce hepatic necro-inflammation, fibrosis progression and reduce risk of cirrhosis, liver failure and hepatocellular carcinoma (HCC). However, HBsAg clearance, or functional cure, is rare, and long-term treatment is recommended. Finite therapy for individuals with HBeAg-negative CHB has been identified as an area of unmet need by expert organisations because of concerns regarding cost, long-term side effects and the risk of the development of drug resistance with indefinite treatment. In the past decade, there has been increasing interest in whether NA therapy can be safely stopped in a subset of patients. In 2012, Hadziyannis and colleagues published a landmark study evaluating clinical outcomes after stopping NA treatment in a small cohort of non-cirrhotic patients with HBeAg-negative CHB who were long-term responders to adefovir monotherapy. All patients experienced early virological relapse. Virological relapse was associated with biochemical relapse in 76% of patients, with antiviral therapy resumed in 15/33 patients. Eighteen patients remained off-treatment through five years of follow-up and all achieved a sustained response, defined by serum HBV DNA level < 2,000 IU/mL and normal serum ALT level. HBsAg loss was observed in 72% (13/18) of patients who maintained a sustained response off treatment by the end of 5 years of follow-up. HBsAg loss was associated with lower HBsAg level at the time adefovir was stopped, and was more common among participants who did not restart treatment. Among those pat

Background: The disruption of immune homeostasis after trauma is a major cause of post-traumatic organ dysfunction and/or sepsis. Recently, a variety of neutrophil phenotypes with distinct functions have been identified and suggested as involved in various clinical conditions. The association between neutrophil phenotypes and post-traumatic immunodeficiency has also been reported, yet the specific neutrophil phenotypes and their functional significance in post-traumatic sepsis have not been fully clarified. Therefore, we sought to investigate neutrophil phenotypic changes in a murine model, as these may hold prognostic value in post-traumatic sepsis. Materials and methods: Third-degree burns affecting 25% of the body surface area were used to establish trauma model, and sepsis was induced 24 h later through cecal ligation and puncture (CLP). The Burn/CLP post-traumatic sepsis model and the Sham/CLP control model were established to assess the immunological status after trauma. Histopathological evaluation was performed on the spleen, liver, kidneys, and lung tissues. Immunological evaluation included the assessment of neutrophil markers using mass cytometry as well as cytokine measurements in serum and ascitic fluid through multiplex analysis using LUMINEX (R). Results: The Burn/CLP group had a lower survival rate than the Sham/CLP group. Histopathological examination revealed an impaired immune response and more advanced organ damage in the Burn/CLP group. Furthermore, the Burn/CLP group exhibited higher levels of transforming growth factor-beta 1 in the blood and generally lower levels of cytokines than the Sham/CLP group. CD11b, which is involved in neutrophil adhesion and migration, was highly expressed on neutrophils in the Burn/CLP group. The expression of CD172a, which is related to the inhibition of phagocytosis, was also upregulated on neutrophils in the Burn/CLP group. The expression of sialic acid-binding lg - like lectin F and CD68 also differed between

Biliary atresia (BA) is a rapidly progressive perinatal inflammatory disease, resulting in liver failure. Hepatic Ly6CLo non-classical monocytes promote the resolution of perinatal liver inflammation during rhesus rotavirus-mediated (RRV) BA in mice. In this study, we aim to investigate the effects of inflammation on the transcription factor Nr4a1, a known regulator of non-classical monocytes. Nr4a1-GFP reporter mice were injected with PBS for control or RRV within 24 h of delivery to induce perinatal liver inflammation. GFP expression on myeloid immune populations in the liver and bone marrow (BM) was quantified 3 and 14 days after injection using flow cytometry. Statistical significance was determined using a student’s t-test and ANOVA, with a p-value < 0.05 for significance. Our results demonstrate that non-classical monocytes in the neonatal liver exhibit the highest mean fluorescence intensity (MFI) of Nr4a1 (Ly6CLo MFI 6344 vs. neutrophils 3611 p < 0.001; macrophages 2782; p < 0.001; and Ly6CHi classical monocytes 4485; p < 0.0002). During inflammation, hepatic Ly6CLo non-classical monocytes showed a significant increase in Nr4a1 expression intensity from 6344 to 7600 (p = 0.012), while Nr4a1 expression remained unchanged on the other myeloid populations. These findings highlight the potential of using Nr4a1 as a regulator of neonatal hepatic Ly6CLo non-classical monocytes to mitigate perinatal liver inflammation.

IntroductionVaccines have demonstrated protection against the morbidity and mortality of COVID-19, but concerns regarding the rare side effect of acute myocarditis have stymied immunization efforts. This review aims to describe the incidence and theorized mechanisms of COVID vaccine-associated myocarditis and review relevant principles for management of vaccine-associated myocarditis.Areas coveredEpidemiologic studies of myocarditis after COVID vaccination are reviewed, which show an incidence of approximately 20-30 per million patients. The vast majority of these cases are seen with mRNA vaccines especially in male patients under 30 years of age. Mechanisms are largely theoretical, but molecular mimicry and dysregulated innate immune reactions have been proposed. While studies suggest that this subtype of myocarditis is mild and self-limited, long-term evidence is lacking. Principles of myocarditis treatment and surveillance are outlined as they apply to COVID vaccine-associated myocarditis.Expert opinionCOVID vaccine-associated myocarditis is rare but well described in certain at-risk groups. Better understanding of its pathogenesis is key to mitigating this complication and advancing vaccination efforts. Risk-benefit analyses demonstrate that individual- and population-level benefits of vaccination exceed the risks of this rare and mild form of myocarditis.

Background: The disruption of immune homeostasis after trauma is a major cause of post-traumatic organ dysfunction and/or sepsis. Recently, a variety of neutrophil phenotypes with distinct functions have been identified and suggested as involved in various clinical conditions. The association between neutrophil phenotypes and post-traumatic immunodeficiency has also been reported, yet the specific neutrophil phenotypes and their functional significance in post-traumatic sepsis have not been fully clarified. Therefore, we sought to investigate neutrophil phenotypic changes in a murine model, as these may hold prognostic value in post-traumatic sepsis. Materials and methods: Third-degree burns affecting 25% of the body surface area were used to establish trauma model, and sepsis was induced 24 h later through cecal ligation and puncture (CLP). The Burn/CLP post-traumatic sepsis model and the Sham/CLP control model were established to assess the immunological status after trauma. Histopathological evaluation was performed on the spleen, liver, kidneys, and lung tissues. Immunological evaluation included the assessment of neutrophil markers using mass cytometry as well as cytokine measurements in serum and ascitic fluid through multiplex analysis using LUMINEX (R). Results: The Burn/CLP group had a lower survival rate than the Sham/CLP group. Histopathological examination revealed an impaired immune response and more advanced organ damage in the Burn/CLP group. Furthermore, the Burn/CLP group exhibited higher levels of transforming growth factor-beta 1 in the blood and generally lower levels of cytokines than the Sham/CLP group. CD11b, which is involved in neutrophil adhesion and migration, was highly expressed on neutrophils in the Burn/CLP group. The expression of CD172a, which is related to the inhibition of phagocytosis, was also upregulated on neutrophils in the Burn/CLP group. The expression of sialic acid-binding lg - like lectin F and CD68 also differed between

The high proliferation of microorganisms in aquatic environments has allowed their coevolution for billions of years with other living beings that also inhabit these niches. Among the different existing types of interaction, the eternal competition for supremacy between the susceptible species and their pathogens has selected, as part of the effector division of the immune system of the former ones, a vast and varied arsenal of efficient antimicrobial molecules, which is highly amplified by the broad biodiversity radiated, above any others, at the marine habitats. At present, the great recent scientific and technological advances already allow the massive discovery and exploitation of these defense compounds for therapeutic purposes against infectious diseases of our interest. Among them, antimicrobial peptides and antimicrobial metabolites stand out because of the wide dimensions of their structural diversities, mechanisms of action, and target pathogen ranges. This revision work contextualizes the research in this field and serves as a presentation and scope identification of the Special Issue from Marine Drugs journal “The Immune System of Marine Organisms as Source for Drugs against Infectious Diseases"

Longitudinal studies of various vertebrate populations have demonstrated senescent declines in reproductive performance and survival probability to be almost ubiquitous. Longitudinal studies of potential underlying proximate mechanisms, however, are still scarce. Due to its critical function in the maintenance of health and viability, the immune system is among the potential (mediators of) proximate mechanisms that could underlie senescence. Here, we studied three innate immune parameters—haemagglutination titre, haemolysis titre and haptoglobin concentration—in a population of common terns (Sterna hirundo) known to undergo actuarial senescence. We repeatedly sampled birds of known sex and age across 11 years and used random regression models to (a) quantify how immune parameters vary among individuals and (b) describe within-individual age-specific changes in, and potential trade-offs between, immune parameters. Our models revealed no differences between males and females in haemagglutination titre and haptoglobin concentration, and very low among-individual variation in these parameters in general. Within individuals, haemagglutination titre increased with age, while haptoglobin concentration did not change. We found no indication for selective (dis)appearance in relation to haemagglutination titre or haptoglobin concentration, nor for the existence of a trade-off between them. Haemolysis was absent in the majority (76%) of samples. Common terns do not exhibit clear senescence in haemagglutination titre and haptoglobin concentration and show very little among-individual variation in these parameters in general. This may be explained by canalisation of the immune parameters or by the colonial breeding behaviour of our study species, but more longitudinal studies are needed to facilitate investigation of links between species’ characteristics and immunosenescence in wild animals.

The surface of bacteria displays diverse carbohydrate structures that may significantly differ among bacteria with the same cell wall architecture and even among strains of a given bacterial species. These structures are often recognized by lectins of the innate immune system for triggering defense responses, although some bacterial pathogens exploit recognition by host lectins for favoring infection. Bacterial microarrays are a useful tool for profiling accessible bacterial surface glycans and for exploring their recognition by innate immune lectins. The use of array-printed bacterial cells enables evaluation of the recognition of the glycan epitopes in their natural presentation, i.e., preserving their real density and accessibility. Glycosylation patterns of bacterial surfaces can be examined by testing the binding to the bacterial arrays of a panel of lectins with known carbohydrate-binding preferences, and the recognition of surface glycans by innate immune lectins can easily be assessed using similar binding assays.

More than a million animals are used annually in the European Union for regulatory batch testing of medicinal products, predominantly for potency assessment. With respect to inactivated poultry vaccines, most potency tests are still performed in vivo due to the lack of in vitro alternatives. It is important to move away from in vivo testing because of ethical concerns, variability, long duration and high costs of these tests, risks for personnel working with infected animals, and legal requirements to use in vitro methods instead of in vivo methods whenever possible. The primary aim of this thesis was to set up in vitro cell-based assays to assess the immunostimulatory capacity of inactivated poultry vaccines and to determine their applicability for routine potency testing. The studies presented in Chapters 2 and 3 of this thesis focus on the immunostimulatory properties of inactivated poultry vaccines by investigating their effect on chicken macrophages. The cell-based assays described involve the use of the macrophage-like cell line HD11. A phagocytosis assay with IgY-opsonized beads was used to investigate whether inactivated poultry vaccines against infectious bronchitis virus (IBV), Newcastle disease virus (NDV) and egg-drop syndrome virus (EDSV) affect phagocytosis by macrophages. In addition, the use of nitric oxide production and cytokine gene expression are described to determine the immunostimulatory properties of an inactivated octavalent vaccine against IBV, NDV, EDSV and five strains of Avibacterium paragallinarum, the causative agents of infectious coryza characterized by an acute respiratory disease in chickens. The study presented in Chapter 4 describes a thorough morphological, phenotypical and functional characterization of chicken bone marrow-derived dendritic cell cultures. In Chapter 5, bone marrow-derived dendritic cells were exposed to an inactivated poultry vaccine against IBV and NDV to identify biomarkers of vaccine-induced immune responses

Epidemiological and experimental studies have shown that di-(2-ethylhexyl) phthalate (DEHP), a plasticizer, can aggravate allergic diseases. DEHP promotes adaptive immune responses, although its effect on the innate immune system remains largely unknown. The present study investigated the effects of DEHP on group 2 innate lymphoid cells (ILC2) that produce Th2 cytokines in response to epithelial cell-derived cytokines, such as interleukin (IL)-33. ILC2 (lineage-negative, CD45.2⁺, Sca1⁺, KLRG1⁺) were isolated from the lungs of C57BL/6 J mice. Co-exposure to DEHP and IL-33 significantly increased IL-5 release from ILC2, whose level was higher than that of the vehicle and IL-33 alone. The effects of DEHP in the presence of IL-33 showed an inverted-U dose-response. The present is the first report showing that DEHP exacerbates allergy through the innate immune system.

Introduction: Borrelia burgdorferi sensu lato complex (B. burgdorferi) can cause a variety of clinical manifestations including Lyme neuroborreliosis. Following the tick-borne transmission, B. burgdorferi initially evade immune responses, later symptomatic infection is associated with occurrence of specific antibody responses. We hypothesized that B. burgdorferi induce immune hyporesponsiveness or immune suppression and aimed to investigate patients with Lyme neuroborreliosis ability to respond to immune stimulation. Methods: An observational cohort study investigating the stimulated immune response by standardized whole blood assay (TruCulture®) in adult patients with Lyme neuroborreliosis included at time of diagnosis from 01.09.2018-31.07.2020. Reference intervals were based on a 5-95% range of cytokine concentrations from healthy individuals (n = 32). Patients with Lyme neuroborreliosis and references were compared using Mann-Whitney U test. Heatmaps of cytokine responses were generated using the webtool Clustvis. Results: In total, 22 patients with Lyme neuroborreliosis (19 definite, 3 probable) were included. In the unstimulated samples, the concentrations of cytokines in patients with Lyme neuroborreliosis were comparable with references, except interferon (IFN)-α, interleukin (IL)-17A, IL-1β and IL-8, which were all significantly below the references. Patients with Lyme neuroborreliosis had similar concentrations of most cytokines in all stimulations compared with references. IFN-α, IFN-γ, IL-12 and IL-17A were lower than references in multiple stimulations. Conclusion: In this exploratory cohort study, we found lower or similar concentrations of circulating cytokines in blood from patients with Lyme neuroborreliosis at time of diagnosis compared with references. The stimulated cytokine release in blood from patients with Lyme neuroborreliosis was in general slightly lower than in the references. Specific patterns of low IL-12 and IFN-γ indicat

Unlike animals, plants do not have specialized immune cells and lack an adaptive immune system. Instead, plant cells rely on their unique innate immune system to defend against pathogens and coordinate beneficial interactions with commensal and symbiotic microbes. One of the major convergent points for plant immune signaling is the nucleus, where transcriptome reprogramming is initiated to orchestrate defense responses. Mechanisms that regulate selective transport of nuclear signaling cargo and chromatin activity at the nuclear boundary play a pivotal role in immune activation. This review summarizes the current knowledge of how nuclear membrane-associated core protein and protein complexes, including the nuclear pore complex, nuclear transport receptors, and the nucleoskeleton participate in plant innate immune activation and pathogen resistance. We also discuss the role of their functional counterparts in regulating innate immunity in animals and highlight potential common mechanisms that contribute to nuclear membrane-centered immune regulation in higher eukaryotes.

Sea anemones vary immensely in life history strategies, environmental niches and their ability to regenerate. While the sea anemone Nematostella vectensis is the starlet of many key regeneration studies, recent work is emerging on the diverse regeneration strategies employed by other sea anemones. This manuscript will explore current molecular mechanisms of regeneration employed by non‐model sea anemones Exaiptasia diaphana (an emerging model species for coral symbiosis studies) and Calliactis polypus (a less well‐studied species) and examine how these species compare to the model sea anemone N. vectensis. We summarize the field of regeneration within sea anemones, within the greater context of phylum Cnidaria and in other invertebrate models of regeneration. We also address the current knowledge on two key systems that may be implemented in regeneration: the innate immune system and developmental pathways, including future aspects of work and current limitations.

Background: Potato cyst nematodes belong to the most harmful pathogens in potato, and durable management of these parasites largely depends on host-plant resistances. These resistances are pathotype specific. The current Globodera rostochiensis pathotype scheme that defines five pathotypes (Ro1 - Ro5) is both fundamentally and practically of limited value. Hence, resistant potato varieties are used worldwide in a poorly informed manner. Results: We generated two novel reference genomes of G. rostochiensis inbred lines derived from a Ro1 and a Ro5 population. These genome sequences comprise 173 and 189 scaffolds respectively, marking a ≈ 24-fold reduction in fragmentation as compared to the current reference genome. We provide copy number variations for 19 effector families. Four dorsal gland effector families were investigated in more detail. SPRYSECs, known to be implicated in plant defence suppression, constitute by far the most diversified family studied herein with 60 and 99 variants in Ro1 and Ro5 distributed over 18 and 26 scaffolds. In contrast, CLEs, effectors involved in feeding site induction, show strong physical clustering. The 10 and 16 variants cluster on respectively 2 and 1 scaffolds. Given that pathotypes are defined by their effectoromes, we pinpoint the disparate nature of the contributing effector families in terms of sequence diversification and loss and gain of variants. Conclusions: Two novel reference genomes allow for nearly complete inventories of effector diversification and physical organisation within and between pathotypes. Combined with insights we provide on effector family-specific diversification patterns, this constitutes a basis for an effectorome-based virulence scheme for this notorious pathogen.

Lyme borreliosis (LB) is caused by Borrelia burgdorferi and infection may lead to not only a large variety of clinical manifestations but also a subclinical outcome. The aim of the present study was to investigate if there is a constitutional difference in complement activation between individuals with previous subclinical Lyme borreliosis (SB) and patients previously diagnosed with Lyme neuroborreliosis (LNB). Lepirudin plasma for activation studies was collected from 60 SB individuals and from 22 patients pre-diagnosed with LNB. The plasma was incubated with live Borrelia spirochetes of two strains (complement sensitive B. garinii Lu59 and complement resistant B. afzelii ACA1). Complement factor C3 was measured in non-activated lepirudin plasma with immune-nephelometry and C3a and sC5b-9 generated during complement activation were measured by enzyme-linked immunosorbent assay. We found that the complement sensitive Lu59 induced higher complement activation than the complement resistant ACA1 when measuring activation products C3a and sC5b-9 in SB and LNB patients, p < 0.0001. No significant difference was found between SB and LNB patients in systemic levels of C3. Furthermore, SB individuals generated a higher activation of C3 cleavage to C3a (C3a/C3 ratio) than LNB patients after activation with ACA1, p < 0.001, but no significant differences were found in response to Lu59. In conclusion, Lu59 induced higher complement activation than ACA1 and individuals with previous SB showed increased generation of C3a compared with patients with previous LNB. In our study population, this mechanism could lead to less elimination of spirochetes in LNB patients and thereby be a factor contributing to the clinical outcome.

Candida albicans is one of the most common fungal pathogens of humans. Prior work introduced the planarian Schmidtea mediterranea as a new model system to study the host response to fungal infection at the organismal level. In the current study, we analyzed host-pathogen changes that occurred in situ during early infection with C. albicans. We found that the transcription factor Bcr1 and its downstream adhesin Als3 are required for C. albicans to adhere to and colonize the planarian epithelial surface, and that adherence of C. albicans triggers a multi-system host response that is mediated by the Dectin signaling pathway. This infection response is characterized by two peaks of stem cell divisions and transcriptional changes in differentiated tissues including the nervous and the excretory systems. This response bears some resemblance to a wound-like response to physical injury; however, it takes place without visible tissue damage and it engages a distinct set of progenitor cells. Overall, we identified two C. albicans proteins that mediate epithelial infection of planarians and a comprehensive host response facilitated by diverse tissues to effectively clear the infection.

The respiratory Influenza A Viruses (IAVs) and emerging zoonotic viruses such as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pose a significant threat to human health. To accelerate our understanding of the host–pathogen response to respiratory viruses, the use of more complex in vitro systems such as normal human bronchial epithelial (NHBE) cell culture models has gained prominence as an alternative to animal models. NHBE cells were differentiated under air-liquid interface (ALI) conditions to form an in vitro pseudostratified epithelium. The responses of well-differentiated (wd) NHBE cells were examined following infection with the 2009 pandemic Influenza A/H1N1pdm09 strain or following challenge with the dsRNA mimic, poly(I:C). At 30 h postinfection with H1N1pdm09, the integrity of the airway epithelium was severely impaired and apical junction complex damage was exhibited by the disassembly of zona occludens-1 (ZO-1) from the cell cytoskeleton. wdNHBE cells produced an innate immune response to IAV-infection with increased transcription of pro- and anti-inflammatory cytokines and chemokines and the antiviral viperin but reduced expression of the mucin-encoding MUC5B, which may impair mucociliary clearance. Poly(I:C) produced similar responses to IAV, with the exception of MUC5B expression which was more than 3-fold higher than for control cells. This study demonstrates that wdNHBE cells are an appropriate ex-vivo model system to investigate the pathogenesis of respiratory viruses.

This work supports the massive presence of potential immunomodulatory peptides in the human gut metaproteome. These peptides were identified through the MAHMI database as potentially anti-inflammatory, and sixteen of them synthesized for characterize their mechanism of action. From them, peptide HM14 was encrypted in an extracellular protein produced by Bifidobacterium longum, a common member of the human microbiota, and displayed the highest anti-inflammatory capability. Molecular mechanism of action of HM14 pointed to a specific interaction between this immunomodulatory peptide and antigen presenting cells, which resulted in a higher formation of iTreg cells. Moreover, HM14 was effective in decreasing pro-inflammatory parameters in PBMCs isolated from a cohort of Crohn’s patients. Finally, non-targeted metabolomics confirmed the ability of HM14 to modulate the metabolic activity of PBMCs to fulfil its energy and biosynthetic requirements. Overall, our combined in silico/multiomics approach supports the human gut metaproteome as a source for immunomodulatory peptides.

Cardiovascular diseases (CVDs) are the leading cause of death in the industrialized world. Most CVDs are associated with increased inflammation that arises mainly from innate immune system activation related to cardiac damage. Sustained activation of the innate immune system frequently results in maladaptive inflammatory responses that promote cardiovascular dysfunction and remodeling. Much research has focused on determining whether some mediators of the innate immune system are potential targets for CVD therapy. The innate immune system has specific receptors—termed pattern recognition receptors (PRRs)—that not only recognize pathogen-associated molecular patterns, but also sense danger-associated molecular signals. Activation of PRRs triggers the inflammatory response in different physiological systems, including the cardiovascular system. The classic PRRs, toll-like receptors (TLRs), and the more recently discovered nucleotide-binding oligomerization domain-like receptors (NLRs), have been recently proposed as key partners in the progression of several CVDs (e.g., atherosclerosis and heart failure). The present review discusses the key findings related to the involvement of TLRs and NLRs in the progression of several vascular and cardiac diseases, with a focus on whether some NLR subtypes (nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing receptor 3 and nucleotide-binding oligomerization domain-containing protein 1) can be candidates for the development of new therapeutic strategies for several CVDs.

Animal health is affected by many factors such as metabolic stress, the immune system, and epidemiological features that interconnect. The immune system has evolved along with the phylogenetic evolution as a highly refined sensing and response system, poised to react against diverse infectious and non-infectious stressors for better survival and adaptation. It is now known that high genetic merit for milk yield is correlated with a defective control of the inflammatory response, underlying the occurrence of several production diseases. This is evident in the mastitis model where high-yielding dairy cows show high disease prevalence of the mammary gland with reduced effectiveness of the innate immune system and poor control over the inflammatory response to microbial agents. There is growing evidence of epigenetic effects on innate immunity genes underlying the response to common microbial agents. The aforementioned agents, along with other non-infectious stressors, can give rise to abnormal activation of the innate immune system, underlying serious disease conditions, and affecting milk yield. Furthermore, the microbiome also plays a role in shaping immune functions and disease resistance as a whole. Accordingly, proper modulation of the microbiome can be pivotal to successful disease control strategies. These strategies can benefit from a fundamental re-appraisal of native cattle breeds as models of disease resistance based on successful coping of both infectious and non-infectious stressors.

The germline-encoded innate immune system is the human body’s initial defense system against foreign pathogens. Essential to this system are pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs). A key PRR system, the cGAS/STING pathway, recognizes foreign DNA in the cytoplasm of a cell. Upon binding foreign DNA, cGAS creates second messenger 2’-3’-cGAMP which activates STING at the endoplasmic reticulum. Once activated, STING translocates to the Golgi, where it recruits the kinase TBK1 and transcription factor IRF3. TBK1 phosphorylates IRF3, enabling the transcription factor to translocate to the nucleus and induce the transcription of type-I interferon (IFN-I) genes. Mechanisms that regulate the cGAS/STING pathway are needed to ensure that an IFN-I response is mounted against only foreign or harmful material at the correct place and time. While cGAS typically only mounts a response to DNA in the cytoplasm of a cell, nuclear and cytoplasmic contents are mixed during mitosis, therefore giving cGAS access to genomic DNA. It is unknown whether cGAS mounts an IFN-I response to exogenous DNA during mitosis, and if not, what mechanisms are in place to ensure the pathway is inactive during cellular division. Human papillomavirus (HPV) causes one of the most commonly transmitted sexual infections and is attributed to nearly 5% of all human cancers. HPV infects the basal cells of differentiated cutaneous and mucosal epithelium. Work from our lab and others has shown that the viral genome hides within cellular organelles until the onset of mitosis. This trafficking mechanism is unique, but the evolutionary rationale for such vesicular, mitosis- dependent egress is unknown. Further, it is unknown how HPV evades detection during both initial infection and genome maintenance. Overall, we hypothesize that HPV evades detection by cGAS/STING during both initial infection and viral persistence to support the viral lifecycle. We specula

Long noncoding RNAs (lncRNAs) can regulate target gene expression by acting in cis (locally) or in trans (non-locally). Here, we performed genome-wide expression analysis of Toll-like receptor (TLR)-stimulated human macrophages to identify pairs of cis-acting lncRNAs and protein-coding genes involved in innate immunity. A total of 229 gene pairs were identified, many of which were commonly regulated by signaling through multiple TLRs and were involved in the cytokine responses to infection by group B Streptococcus We focused on elucidating the function of one lncRNA, named lnc-MARCKS or ROCKI (Regulator of Cytokines and Inflammation), which was induced by multiple TLR stimuli and acted as a master regulator of inflammatory responses. ROCKI interacted with APEX1 (apurinic/apyrimidinic endodeoxyribonuclease 1) to form a ribonucleoprotein complex at the MARCKS promoter. In turn, ROCKI-APEX1 recruited the histone deacetylase HDAC1, which removed the H3K27ac modification from the promoter, thus reducing MARCKS transcription and subsequent Ca2+ signaling and inflammatory gene expression. Finally, genetic variants affecting ROCKI expression were linked to a reduced risk of certain inflammatory and infectious disease in humans, including inflammatory bowel disease and tuberculosis. Collectively, these data highlight the importance of cis-acting lncRNAs in TLR signaling, innate immunity, and pathophysiological inflammation.

The current understanding of the evolutionary emergence of the immune system in organisms is still unclear to this day. It is acknowledged that some aspects of the immune system definitely improved the survival of living organisms, whether it be plant, or bacteria, vertebrates or invertebrates. The different immune proteins and complexes are constantly being studied to understand exactly how the immune system play a role in the human development. In this review, we proposea developmental and evolutionary explanation to how we present an immune system, understand the selective pressure in immune cells, explain the relationship of bacteria or viruses to their host, and analyze the augmentation of human vulnerability to diseases.

Alterations of gut microbes play a role in the pathogenesis and progression of many disorders including liver and gastrointestinal diseases. Both qualitative and quantitative changes in gut microbiota have been associated with liver disease. Intestinal dysbiosis can disrupt the integrity of the intestinal barrier leading to pathological bacterial translocation and the initiation of an inflammatory response in the liver. In order to sustain symbiosis and protect from pathological bacterial translocation, antimicrobial proteins (AMPs) such as a-defensins and C-type lectins are expressed in the gastrointestinal tract. In this review, we provide an overview of the role of AMPs in different chronic liver disease such as alcoholic steatohepatitis, non-alcoholic fatty liver disease, and cirrhosis. In addition, potential approaches to modulate the function of AMPs and prevent bacterial translocation are discussed.

Background: Immunity has been suggested to be important in the pathogenesis of dementia. However, the contribution of innate versus adaptive immunity in the development of dementia is not clear. In this study, we aimed to investigate (1) the association between components of innate immunity (granulocytes and platelets) and

The human respiratory tract is exposed to environmental irritants on a daily basis. The innate immune system is composed of different cellular components including the resident airway epithelium and macrophages and acts as the first line of defense to protect the lung against inhaled irritants. Activation of innate immune pathways is associated with the release of different mediators like cytokines, chemokines, lipid mediators and complement factors to mediate the recruitment of different immune cells into the airway lumen. The role of the innate immune system in chronic airways disease is currently a major area of research in the field and the focus of this thesis. RAGE and TLR4 are two major innate immune receptors implicated in the pathogenesis of asthma and COPD. We used TLR4, RAGE and TLR4/RAGE deficient mice to study the individual and combined role of these receptors in the airway response to acute cigarette-smoke exposure. We found that RAGE but not TLR4 deficiency protected against cigarette-smoke induced neutrophilic airway inflammation, mediator release and airway hyperreactivity (AHR). Interestingly, TLR4 deficiency exacerbated AHR. Together these findings, suggest that RAGE rather than TLR4 should be pursued as a therapeutic target in COPD. In contrast to our findings above however, we found that dual inhibition of TLR4/RAGE signaling, but not individual inhibition of these receptor pathways, protects against corticosteroid-resistant airway neutrophilia and AHR in an experimental model of severe asthma. Also, by performing a global phosphoproteomics analysis of lung tissue samples, we identified novel signaling pathways activated down-stream of TLR4/RAGE ligation in severe experimental asthma. We also investigated the role of macrophage migration inhibitory factor (MIF) in severe asthma. We demonstrated increased expression of MIF, S100A8/A9 and TLR4, and reduced expression of annexin A1 (ANXA1) in subjects with predominant airway neutrophilic inflammat

Infectious prions comprising abnormal prion protein, which is produced by structural conversion of normal prion protein, are responsible for transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease in humans. Prions are infectious agents that do not possess a genome and the pathogenic protein was not thought to evoke any immune response. Although we previously reported that interferon regulatory factor 3 (IRF3) was likely to be involved in the pathogenesis of prion diseases, suggesting the protective role of host innate immune responses mediated by IRF3 signalling, this remained to be clarified. Here, we investigated the reciprocal interactions of type I interferon evoked by IRF3 activation and prion infection and found that infecting prions cause the suppression of endogenous interferon expression. Conversely, treatment with recombinant interferons in an ex vivo model was able to inhibit prion infection. In addition, cells and mice deficient in type I interferon receptor (subunit interferon alpha/beta receptor 1), exhibited higher susceptibility to 22L-prion infection. Moreover, in in vivo and ex vivo prion-infected models, treatment with RO8191, a selective type I interferon receptor agonist, inhibited prion invasion and prolonged the survival period of infected mice. Taken together, these data indicated that the interferon signalling interferes with prion propagation and some interferon-stimulated genes might play protective roles in the brain. These findings may allow for the development of new strategies to combat fatal diseases., Brain : a journal of neurology, 142(4), pp.1035-1050; 2019

The phylum Mollusca includes over 200,000 living species characterized by a huge diversity which leads to their biological success. Indeed, many of these animals are in the top 100 of the most invasive species. In this review a description of the immune mechanisms of this phylum is presented. It will follow a space-time approach to track the pathogen-host interactions and how the molluscs respond to this challenge: from the initial contact in the mucus to the eventual clearance of the pathogen and going through the fine tune of the defense response

Cardiovascular (CV) events are increased 36-fold in patients with end-stage renal disease. However, randomized controlled trials to lower LDL cholesterol (LDL-C) and serum total cholesterol (TC) have not shown significant mortality improvements. An inverse association of TC and LDL-C with all-cause and CV mortality has been observed in patients on chronic dialysis. Lipoproteins also may protect against infectious diseases. We used data from 37,250 patients in the international Monitoring Dialysis Outcomes (MONDO) database to evaluate the association between lipids and infection-related or CV mortality. The study began on the first day of lipid measurement and continued for up to 4 years. We applied Cox proportional models with time-varying covariates to study associations of LDL-C, HDL cholesterol (HDL-C), and triglycerides (TGs) with all-cause, CV, infectious, and other causes of death. Overall, 6,147 patients died (19.2% from CV, 13.2% from infection, and 67.6% from other causes). After multivariable adjustment, higher LDL-C, HDL-C, and TGs were independently associated with lower all-cause death risk. Neither LDL-C nor TGs were associated with CV death, and HDL-C was associated with lower CV risk. Higher LDL-C and HDL-C were associated with a lower risk of death from infection or other non-CV causes. LDL-C was associated with reduced all-cause and infectious, but not CV mortality, which resulted in the inverse association with all-cause mortality.

The innate immune system uses a multitude of receptors and intracellular signalling pathways to sense pathogens and danger signals. Recent studies have discovered that an array of these intracellular signalling proteins assemble into oligomeric signalling platforms, consequently amplifying the transmission of signal from the stimulated receptor to the activation of relevant transcription machinery. Unexpectedly, it was also discovered that some of these proteins present in innate immune signalling can form fibrils. These fibrils can elongate in a prion-like manner to create super-sized signalling platforms. Through screening over 100 innate immune intracellular signalling proteins using single molecule fluorescence, we defined the oligomerisation and aggregation propensity of these proteins, tracking the specific signature of polymerisation. We identified multiple candidates forming super-sized protein aggregates; and were able to conclude that 19 of these proteins could self-propagate aggregation, just as prions do. 4 of these proteins had been previously published as being ‘prion-like’, leaving 15 novel prion-like polymers identified.Our observations suggest that prion-like polymerisation underlies the backbone of intracellular communication and drives the complex interplay that exists among the major signalling cascades of the innate immune system. Our disease-associated mutagenesis data highlights the crucial functions that these large signalling platforms have in the optimal execution of defence against pathogens and intracellular homeostasis and will contribute to the development of therapies aimed at aiding and regulating this critical first line of defence.

Fish production by intensive aquaculture, is an economically important strategy to produce food. However, intensive sh farming generates oxidative stress and suppress the immune system, causing loss of product quality and increasing sh mortality rates. To diminish these effects, plants as a source of polyphenols with antioxidants and immunostimulant properties were administered to carnivorous farmed sh. The aim of this study was to describe the effects of plant polyphenols as antioxidants and immunostimulants on carnivorous sh, and to promote their use as functional ingredients in aquaculture. Plants as a source of polyphenols showed the ability to improve the immune and antioxidant defense systems of the analyzed species, resulting in a tissue of better nutritional quality and a higher endogenous antioxidant content. However, the biological properties of polyphenols are dependent on the type of plant and their concentration within it, the dose and the time of administration, as well as the food matrix, which determines their bioaccessibility and bioavailability in the organism. There is little information on the effec of polyphenols in post mortem quality; therefore, further studies should be conducted., El cultivo intensivo de peces es una estrategia económicamente importante para producir alimento. Sin embargo, las prácticas de cultivo intensivo generan estrés oxidativo e inmunosupresión, lo que ocasiona pérdidas de la calidad del espécimen y aumento en la mortalidad. Para contrarrestar estos efectos, se ha optado por la administración de vegetales como fuente de polifenoles con propiedades antioxidantes e inmunoestimulantes en peces carnívoros de cultivo. El objetivo de este trabajo fue describir los efectos de los polifenoles de origen vegetal como antioxidantes e inmunoestimulantes en peces carnívoros, y promover su uso como ingredientes funcionales en la acuicultura. Los vegetales como fuente de polifenoles tienen la capacidad de mejorar los sistemas de defensa inmune y antioxidante de las especies analiza- das, con un tejido de mejor calidad nutricional y un mayor contenido endógeno de antioxidantes. No obstante, las propiedades biológicas de los polifenoles dependen del tipo y concentración en el vegetal, de la dosis y el tiempo de administración, así como de la matriz alimentaria, la cual determina la bioaccesibilidad y biodisponibilidad de los polifenoles en el organismo. Es escasa la información generada sobre el efecto de los polifenoles en la calidad post mortem, por lo que se deben realizar más estudios.

Liver cancer has become the second most deadly malignant disease, with no efficient targeted or immune therapeutic agents available yet. While dissecting the roles of cytoplasmic signaling molecules in hepatocarcinogenesis using an inducible mouse gene targeting system, Mx1-cre, we identified a potent liver tumor-inhibitory effect of synthetic double-stranded RNA (dsRNA), polyinosinic-polycytidylic acid (pIC), an inducer of the Mx1-cre system. Injection of pIC at the pre-cancer stage robustly suppressed liver tumorigenesis either induced by chemical carcinogens or by Pten loss and associated hepatosteatosis. The immunostimulatory dsRNA inhibited liver cancer initiation, apparently by boosting multiple anti-tumor activities of innate immunity, including induction of immunoregulatory cytokines, activation of NK cells and dendritic cells, and reprogramming of macrophage polarization. This study paves the way for the development of preventive and early interfering strategies for liver cancer to reduce the rapidly increasing incidences of liver cancer in an ever-growing population with chronic liver disorders.

Given the scavenging properties of ficolins, we hypothesized that variation in the plasma concentrations of the three ficolins may be associated with development of lupus nephritis (LN), type of LN, end-stage renal disease (ESRD), and/or mortality among patients with systemic lupus erythematosus (SLE). SLE patients attending a Danish tertiary rheumatology referral center were included. Plasma concentrations of ficolin-1, ficolin-2, and ficolin-3 were determined and dichotomized by the median into high and low. LN was defined by clinical criteria; type of LN by renal biopsy; ESRD follow-up time was defined as time from onset of LN to the development of ESRD or censoring at the end of follow-up. The study included 112 SLE patients with median disease duration of 8 years of which 53 (47%) had LN at the time of inclusion. During a median follow-up of 10 years, five patients developed ESRD. Sixteen patients died. Odds ratios (ORs) of LN were 1.2 (95% CI: 0.6–2.7), 4.1 (95% CI: 1.7–9.7), and 0.9 (95% CI: 0.4–2.0) for patients with low ficolin-1, ficolin-2, and ficolin-3 plasma levels, respectively. The distribution of histological classes differed between patients with high and low plasma levels of ficolin-1 (p = 0.009). Patients with high ficolin-1 plasma levels had an increased risk of ESRD. There was no association between the levels of the analyzed plasma ficolins and mortality. Low plasma ficolin-2 levels were associated with an increased risk of having LN. High plasma levels of ficolin-1 were associated with the histological subtype of LN and development of ESRD.

[Background]: Heart failure (HF) is a complex syndrome associated with a maladaptive innate immune system response that leads to deleterious cardiac remodeling. However, the underlying mechanisms of this syndrome are poorly understood. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a newly recognized innate immune sensor involved in cardiovascular diseases. [Objectives]: This study evaluated the role of NOD1 in HF progression. [Methods]: NOD1 was examined in human failing myocardium and in a post-myocardial infarction (PMI) HF model evaluated in wild-type (wt-PMI) and Nod1 mice (Nod1-PMI). [Results]: The NOD1 pathway was up-regulated in human and murine failing myocardia. Compared with wt-PMI, hearts from Nod1-PMI mice had better cardiac function and attenuated structural remodeling. Ameliorated cardiac function in Nod1-PMI mice was associated with prevention of Ca dynamic impairment linked to HF, including smaller and longer intracellular Ca concentration transients and a lesser sarcoplasmic reticulum Ca load due to a down-regulation of the sarcoplasmic reticulum Ca-adenosine triphosphatase pump and by augmented levels of the Na/Ca exchanger. Increased diastolic Ca release in wt-PMI cardiomyocytes was related to hyperphosphorylation of ryanodine receptors, which was blunted in Nod1-PMI cardiomyocytes. Pharmacological blockade of NOD1 also prevented Ca mishandling in wt-PMI mice. Nod1-PMI mice showed significantly fewer ventricular arrhythmias and lower mortality after isoproterenol administration. These effects were associated with lower aberrant systolic Ca release and with a prevention of the hyperphosphorylation of ryanodine receptors under isoproterenol administration in Nod1-PMI mice. [Conclusions]: NOD1 modulated intracellular Ca mishandling in HF, emerging as a new target for HF therapy.

Today, dementia such as, Alzheimer’s disease (AD), vascular diseases and motor neurodegenerative diseases, such as Parkinson’s disease (PD), represent a major public health problem. For instance, PD affect to more than 10 million people worldwide and almost 50 million people are affected by dementia. In fact, every year 9,9 millions new patients are diagnosed. Dementia is one of the major causes of disability among elderly people. The mechanisms affecting the disease progression for PD and AD share some common mechanism, such as the immune responses in the neural tissue. The immune system plays a major role in restoring the balance in our organism after injury and is divided in innate and adaptive immunity. The innate immune response is considered the first mechanism responding to the disease stimulus. The activation of the innate immune response can be triggered by different factors and elicit the activation of several cell types. Among the main cell types involved in the innate immune response, we find: microglial cells, astrocytes and oligodendrocytes. Following the innate immune action, the adaptive immune system is activated and B and T cells are recruited by antigen presenting cells to act on the response. The main task of the inflammatory response is to restore the tissue homeostasis after insult. The nature of the insult can vary, going from pathogens to tissue damage. To resolve the injury and restore the balance in the organism, these cells types can secrete a wide array of molecules, such as pro and anti-inflammatory molecules, growth factors and chemokines, all of them involved in the regulation of the innate immune response. The main cell type involved in the inflammatory response in the brain are microglial cells. They are considered the ”macrophages of the brain”. Microglial cells can develop different functions such as: phagocytosis, synaptic remodeling or opsonization. Hence, microglial cell activation is essential for the well function of the brain

Atherosclerosis is a chronic inflammatory disease characterized by infiltration of blood vessels by lipids and leukocytes. There is a growing body of evidence that among risk factors that promote atherosclerosis, the metabolic syndrome is a powerful and revalent predictor of cardiovascular events. The systemic inflammatory process associated with the metabolic syndrome has numerous deleterious effects that promote plaque activation, which is responsible for clinical events. Interactions between the innate immune system with lipidderived products seem to play a major role in the pathophysiology of atherosclerosis in relation with the metabolic syndrome. The multiple links among adipose tissue, the vascular wall, and the immune system are the topics of this review, which examines the roles of oxidized lowdensity lipoprotein, inflammatory cytokines, and adipokines in triggering and perpetuating a danger signal response that promotes the development of atherosclerosis. Furthermore, therapeutic options that specifically target the metabolic syndrome components are reviewed in light of recent developments.

Infants born to human immunodeficiency virus (HIV) infected women are HIV-exposed but the majority remains uninfected [i.e. HIV-exposed uninfected (HEU)]. HEU infants suffer greater morbidity and mortality from infections compared to HIV-unexposed (HU) peers. The reason(s) for these worse outcomes are uncertain, but could be related to an altered immune system state. This review comprehensively summarizes the current literature investigating the adaptive and innate immune system of HEU infants. HEU infants have altered cell-mediated immunity, including impaired T-cell maturation with documented hypo- as well as hyper-responsiveness to T-cell activation. And although prevaccination vaccine-specific antibody levels are often lower in HEU than HU, most HEU infants mount adequate humoral immune response following primary vaccination with diphtheria toxoid, haemophilus influenzae type b, whole cell pertussis, measles, hepatitis B, tetanus toxoid, and pneumococcal conjugate vaccines. However, HEU infants are often found to have lower absolute neutrophil counts as compared to HU infants. On the other hand, an increase of innate immune cytokine production and expression of co-stimulatory markers has been noted in HEU infants, but this increase appears to be restricted to the first few weeks of life. The immune system of HEU children beyond infancy remains largely unexplored., SCOPUS: re.j, info:eu-repo/semantics/published

Microglia are the resident macrophages of the central nervous system (CNS). Like other tissue macrophages, microglia have many different functions under physiological as well as pathological conditions. Microglia can contribute to the initiation, progression and resolution of disease processes and microglia activation is a common hallmark of many CNS diseases. By consequence modulation of microglial activation represents an interesting therapeutic strategy. In this thesis, we studied the modulation of microglia activation via different mechanisms and agents. The research presented in this thesis focuses on microglia activation by receptors of the innate immune system known as Toll-like receptors (TLR). TLR-mediated activation can be caused by cellular encounters with microbial ligands (pathogen-associated molecular patterns) as well as by encounters with damaged cell-derived ligands (danger-associated molecular patterns). This broad array of ligands renders it likely that TLR-mediated microglial activation has relevance to various situations where CNS homeostasis is disturbed. The studies in this thesis have been performed at the Alternatives Unit of the Biomedical Primate Research Centre (BPRC). Our group focuses on the development of in vitro methodology that can be used to reduce, refine or replace in vivo animal experiments. For the research presented in this thesis, we used primary microglia cultures derived from healthy adult rhesus monkeys (macaca mulatta) as a model for adult human microglia. This model has important advantages in terms of genetic and donor age similarities over the use of microglia derived from embryonic, neonatal or adult in bred rodents. Additionally, advantage over the use of adult human microglia is the total control over ante mortem (disease history, process of dying) and post mortem (post mortem time) conditions. Importantly, no monkeys are sacrificed for the exclusive purpose of initiating primary cell cultures. We use brain tissue t