The intestinal microflora, typically equated with bacteria, influences diseases such as obesity and inflammatory bowel disease. Here, we show that the mammalian gut contains a rich fungal community ...that interacts with the immune system through the innate immune receptor Dectin-1. Mice lacking Dectin-1 exhibited increased susceptibility to chemically induced colitis, which was the result of altered responses to indigenous fungi. In humans, we identified a polymorphism in the gene for Dectin-1 (CLEC7A) that is strongly linked to a severe form of ulcerative colitis. Together, our findings reveal a eukaryotic fungal community in the gut (the "mycobiome") that coexists with bacteria and substantially expands the repertoire of organisms interacting with the intestinal immune system to influence health and disease.
Innate immune cells must be able to distinguish between direct binding to microbes and detection of components shed from the surface of microbes located at a distance. Dectin-1 (also known as CLEC7A) ...is a pattern-recognition receptor expressed by myeloid phagocytes (macrophages, dendritic cells and neutrophils) that detects β-glucans in fungal cell walls and triggers direct cellular antimicrobial activity, including phagocytosis and production of reactive oxygen species (ROS). In contrast to inflammatory responses stimulated upon detection of soluble ligands by other pattern-recognition receptors, such as Toll-like receptors (TLRs), these responses are only useful when a cell comes into direct contact with a microbe and must not be spuriously activated by soluble stimuli. In this study we show that, despite its ability to bind both soluble and particulate β-glucan polymers, Dectin-1 signalling is only activated by particulate β-glucans, which cluster the receptor in synapse-like structures from which regulatory tyrosine phosphatases CD45 and CD148 (also known as PTPRC and PTPRJ, respectively) are excluded (Supplementary Fig. 1). The 'phagocytic synapse' now provides a model mechanism by which innate immune receptors can distinguish direct microbial contact from detection of microbes at a distance, thereby initiating direct cellular antimicrobial responses only when they are required.
Circadian rhythms are important for all aspects of biology; virtually every aspect of biological function varies according to time of day. Although this is well known, variation across the day is ...also often ignored in the design and reporting of research. For this review, we analyzed the top 50 cited papers across 10 major domains of the biological sciences in the calendar year 2015. We repeated this analysis for the year 2019, hypothesizing that the awarding of a Nobel Prize in 2017 for achievements in the field of circadian biology would highlight the importance of circadian rhythms for scientists across many disciplines, and improve time-of-day reporting.
Our analyses of these 1000 empirical papers, however, revealed that most failed to include sufficient temporal details when describing experimental methods and that few systematic differences in time-of-day reporting existed between 2015 and 2019. Overall, only 6.1% of reports included time-of-day information about experimental measures and manipulations sufficient to permit replication.
Circadian rhythms are a defining feature of biological systems, and knowing when in the circadian day these systems are evaluated is fundamentally important information. Failing to account for time of day hampers reproducibility across laboratories, complicates interpretation of results, and reduces the value of data based predominantly on nocturnal animals when extrapolating to diurnal humans.
Staphylococcus aureus (S. aureus) is one of the most common bacterial infections worldwide, and antibiotic resistant strains such as Methicillin-Resistant S. aureus (MRSA) are a major threat and ...burden to public health. MRSA not only infects immunocompromised patients but also healthy individuals and has rapidly spread from the healthcare setting to the outside community. However, all vaccines tested in clinical trials to date have failed. Immunocompromised individuals such as patients with HIV or decreased levels of CD4+ T cells are highly susceptible to S. aureus infections, and they are also at increased risk of developing fungal infections. We therefore wondered whether stimulation of antifungal immunity might promote the type of immune responses needed for effective host defense against S. aureus. Here we show that vaccination of mice with a fungal β-glucan particle (GP) loaded with S. aureus antigens provides protective immunity to S. aureus. We generated glucan particles loaded with the four S. aureus proteins ClfA, IsdA, MntC, and SdrE, creating the 4X-SA-GP vaccine. Vaccination of mice with three doses of 4X-SA-GP promoted protection in a systemic model of S. aureus infection with a significant reduction in the bacterial burden in the spleen and kidneys. 4X-SA-GP vaccination induced antigen-specific Th1 and Th17 CD4+ T cell and antibody responses and provided long-term protection. This work suggests that the GP vaccine system has potential as a novel approach to developing vaccines for S. aureus.
The pattern recognition receptors TLR2 and Dectin-1 play key roles in coordinating the responses of macrophages and dendritic cells (DC) to fungi. Induction of proinflammatory cytokines is instructed ...by signals from both TLR2 and Dectin-1. A recent report identified a role for CARD9 in innate anti-fungal responses, demonstrating CARD9-Bcl10-mediated activation of NF-kappaB and proinflammatory cytokine induction in murine bone marrow-derived DC stimulated via Dectin-1. We now report that Dectin-1-CARD9 signals fail to activate NF-kappaB and drive TNF-alpha induction in murine bone marrow-derived macrophages. However, priming of bone marrow-derived macrophages with GM-CSF or IFN-gamma permits Dectin-1-CARD9-mediated TNF-alpha induction. Analysis of other macrophage/DC populations revealed further variation in the ability of Dectin-1-CARD9 signaling to drive TNF-alpha production. Resident peritoneal cells and alveolar macrophages produce TNF-alpha upon Dectin-1 ligation, while thioglycollate-elicited peritoneal macrophages and Flt3L-derived DC do not. We present data demonstrating that CARD9 is recruited to phagosomes via its CARD domain where it enhances TLR-induced cytokine production even in cells in which Dectin-1 is insufficient to drive cytokine production. In such cells, Dectin-1, CARD9, and Bcl10 levels are not limiting, and data indicate that these cells express additional factors that restrict Dectin-1-CARD9 signaling for TNF-alpha induction.
Abstract
Objectives
Negative social relationships are associated with poor health, chronic illness, and mortality. Yet, we know little about the dynamics of negative aspects of relationships within ...individual’s closest relationships over time, how those experiences vary by age, and the implications of those relationships for well-being.
Method
A total of 592 participants (ages 25–97; M = 57.5; 63.3% women) from the Social Relations Study completed monthly web surveys for up to 12 months. Each month they reported negative relationship quality with their three closest network members and multiple dimensions of well-being (positive affect, negative affect, self-rated health, and sleep quality).
Results
Multilevel models revealed older individuals reported less negativity in their relationships than younger people, but fewer age differences in the closest tie. Greater negative relationship quality predicted poor well-being (i.e., greater negative affect, sleep problems). Links between negative relations and well-being were less strong among older individuals; especially in the closest ties.
Discussion
Results were partially consistent with the strength and vulnerability integration (SAVI) model, which proposes fewer age-related improvements in emotion regulation when individuals are unable to avoid tensions. Despite feeling just as negative as younger individuals, older individuals may be more resilient to tensions in their closest relationships.
Direct Antimicrobial Activity of IFN-β Kaplan, Amber; Lee, Michelle W; Wolf, Andrea J ...
The Journal of immunology (1950),
05/2017, Letnik:
198, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Type I IFNs are a cytokine family essential for antiviral defense. More recently, type I IFNs were shown to be important during bacterial infections. In this article, we show that, in addition to ...known cytokine functions, IFN-β is antimicrobial. Parts of the IFN-β molecular surface (especially helix 4) are cationic and amphipathic, both classic characteristics of antimicrobial peptides, and we observed that IFN-β can directly kill
Further, a mutant
that is more sensitive to antimicrobial peptides was killed more efficiently by IFN-β than was the wild-type
, and immunoblotting showed that IFN-β interacts with the bacterial cell surface. To determine whether specific parts of IFN-β are antimicrobial, we synthesized IFN-β helix 4 and found that it is sufficient to permeate model prokaryotic membranes using synchrotron x-ray diffraction and that it is sufficient to kill
These results suggest that, in addition to its well-known signaling activity, IFN-β may be directly antimicrobial and be part of a growing family of cytokines and chemokines, called kinocidins, that also have antimicrobial properties.
Abstract This paper presents a meta-analysis of studies examining prevalence of psychopathology among offspring of anxiety-disordered parents, with the purpose of determining overall risk among these ...offspring for developing anxiety and depressive disorders. Pooled odds ratios for these disorders among high-risk offspring, compared to offspring of psychiatric and non-psychiatric controls, were calculated. Sixteen papers (including three follow-up studies) were identified, encompassing 1892 offspring (ages 4–25 years). Results revealed that: (1) offspring of parents with anxiety disorders have greater risk for anxiety and depressive disorders than offspring of non-psychiatric controls (ORs = 3.91 and 2.67, respectively) and greater risk for anxiety disorders than offspring of psychiatric controls (OR = 1.84); (2) offspring of anxious parents have significantly greater odds of having each type of anxiety disorder and MDD compared to offspring of non-psychiatric controls (ORs range from 1.96 to 8.69); and (3) offspring of parents with anxiety only, anxiety plus MDD, and MDD only have similar odds of having anxiety and depressive disorders but significantly higher odds than offspring of parents without disorder. Results suggest that parental anxiety disorders confer significant risk for anxiety and depression in offspring. Additional studies are needed to examine whether there are differences among specific parental anxiety disorders.
Background Elevated levels of an endogenous Na/K-ATPase inhibitor marinobufagenin accompany salt-sensitive hypertension and are implicated in cardiac fibrosis. Immunoneutralization of marinobufagenin ...reduces blood pressure in Dahl salt-sensitive (Dahl-S) rats. The effect of the anti-marinobufagenin monoclonal antibody on blood pressure, left ventricular (LV) and renal remodeling, and gene expression were investigated in hypertensive Dahl-S rats. Methods and Results Dahl-S rats were fed high NaCl (8%, HS; n=14) or low NaCl (0.1%, LS; n=14) diets for 8 weeks. Animals were administered control antibody (LS control antibody, LSC; HS control antibody, HSC; n=7 per group) or anti-marinobufagenin antibody once on week 7 of diet intervention (n=7 per group). Levels of marinobufagenin, LV, and kidney mRNAs and proteins implicated in profibrotic signaling were assessed. Systolic blood pressure was elevated (211±8 versus 133±3 mm Hg,
<0.01), marinobufagenin increased 2-fold in plasma (
<0.05) and 5-fold in urine (
<0.01), LV and kidney weights increased, and levels of LV collagen-1 rose 3.5-fold in HSC versus LSC. Anti-marinobufagenin antibody treatment decreased systolic blood pressure by 24 mm Hg (
<0.01) and reduced organ weights and level of LV collagen-1 (
<0.01) in hypertensive Dahl salt-sensitive rats with anti-marinobufagenin antibody versus HSC. The expression of genes related to transforming growth factor-β-dependent signaling was upregulated in the left ventricles and kidneys in HSC versus LSC groups and became downregulated following administration of anti-marinobufagenin antibody to hypertensive Dahl-S rats. Marinobufagenin also activated transforming growth factor-β signaling in cultured ventricular myocytes from Dahl-S rats. Conclusions Immunoneutralization of heightened marinobufagenin levels in hypertensive Dahl-S rats resulted in a downregulation of genes implicated in transforming growth factor-β pathway, which indicates that marinobufagenin is an activator of profibrotic transforming growth factor-β-dependent signaling in salt-sensitive hypertension.
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