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The galactosaminogalactan (GAG) is a cell wall component of Aspergillus fumigatus that has potent anti-inflammatory effects in mice. However, the mechanisms responsible for the anti-inflammatory property of GAG remain to be elucidated. In the present study we used in vitro PBMC stimulation assays to demonstrate, that GAG inhibits proinflammatory T-helper (Th)1 and Th17 cytokine production in human PBMCs by inducing Interleukin-1 receptor antagonist (IL-1Ra), a potent anti-inflammatory cytokine that blocks IL-1 signalling. GAG cannot suppress human T-helper cytokine production in the presence of neutralizing antibodies against IL-1Ra. In a mouse model of invasive aspergillosis, GAG induces IL-1Ra in vivo, and the increased susceptibility to invasive aspergillosis in the presence of GAG in wild type mice is not observed in mice deficient for IL-1Ra. Additionally, we demonstrate that the capacity of GAG to induce IL-1Ra could also be used for treatment of inflammatory diseases, as GAG was able to reduce severity of an experimental model of allergic aspergillosis, and in a murine DSS-induced colitis model. In the setting of invasive aspergillosis, GAG has a significant immunomodulatory function by inducing IL-1Ra and notably IL-1Ra knockout mice are completely protected to invasive pulmonary aspergillosis. This opens new treatment strategies that target IL-1Ra in the setting of acute invasive fungal infection. However, the observation that GAG can also protect mice from allergy and colitis makes GAG or a derivative structure of GAG a potential treatment compound for IL-1 driven inflammatory diseases.

A large variety of fungi are present in the environment, among which a proportion colonizes the human body, usually without causing any harm. However, depending on the host immune status, commensals can become opportunistic pathogens that induce diseases ranging from superficial non-harmful infection to life-threatening systemic disease. The interplay between the host and the fungal commensal flora is being orchestrated by an efficient recognition of the microorganisms, which in turn ensures a proper balance between tolerance of the normal fungal flora and induction of immune defense mechanisms when invasion occurs. Pattern recognition receptors (PRRs) play a significant role in maintaining this balance due to their capacity to sense fungi and induce host responses such as the induction of proinflammatory cytokines involved in the activation of innate and adaptive immune responses. In the present review, we will discuss the most recent findings regarding the recognition of Candida albicans and Aspergillus fumigatus and the different types of immune cells that play a role in antifungal host defense.

Background Fungal skull base osteomyelitis (SBO) is a severe complication of otitis externa or sinonasal infection, and is mainly caused by Aspergillus species. Here we investigate innate and adaptive immune responses in patients with Aspergillus SBO to identify defects in the immune response that could explain the susceptibility to this devastating disease. Methods Peripheral blood mononuclear cells isolated from six patients with Aspergillus SBO and healthy volunteers were stimulated with various microbial stimuli, among which also the fungal pathogens Candida albicans and Aspergillus fumigatus. The proinflammatory cytokines IL-6, TNFα and IL-1β, and the T-helper cell-derived cytokines IFNγ, IL-17 and IL-22 were measured in cell culture supernatants by ELISA. Results Proinflammatory cytokine responses did not differ between SBO patients and healthy volunteers. The Candida - and Aspergillus -specific Th17 response (production of IL-17 and IL-22) was significantly decreased in the SBO patients compared to healthy individuals, while Th1 cytokine response (IFNγ production) did not differ between the two groups. Conclusions We show that patients with Aspergillus skull base osteomyelitis infection have specific defects in Th17 responses. Since IL-17 and IL-22 are important for stimulating antifungal host defense, we hypothesize that strategies that have the ability to improve IL-17 and IL-22 production may be useful as adjuvant immunotherapy in patients with Aspergillus SBO.

The galactosaminogalactan (GAG) is a cell wall component of Aspergillus fumigatus that has potent anti-inflammatory effects in mice. However, the mechanisms responsible for the anti-inflammatory property of GAG remain to be elucidated. In the present study we used in vitro PBMC stimulation assays to demonstrate, that GAG inhibits proinflammatory T-helper (Th)1 and Th17 cytokine production in human PBMCs by inducing Interleukin-1 receptor antagonist (IL-1Ra), a potent anti-inflammatory cytokine that blocks IL-1 signalling. GAG cannot suppress human T-helper cytokine production in the presence of neutralizing antibodies against IL-1Ra. In a mouse model of invasive aspergillosis, GAG induces IL-1Ra in vivo, and the increased susceptibility to invasive aspergillosis in the presence of GAG in wild type mice is not observed in mice deficient for IL-1Ra. Additionally, we demonstrate that the capacity of GAG to induce IL-1Ra could also be used for treatment of inflammatory diseases, as GAG was able to reduce severity of an experimental model of allergic aspergillosis, and in a murine DSS-induced colitis model. In the setting of invasive aspergillosis, GAG has a significant immunomodulatory function by inducing IL-1Ra and notably IL-1Ra knockout mice are completely protected to invasive pulmonary aspergillosis. This opens new treatment strategies that target IL-1Ra in the setting of acute invasive fungal infection. However, the observation that GAG can also protect mice from allergy and colitis makes GAG or a derivative structure of GAG a potential treatment compound for IL-1 driven inflammatory diseases.

Coagulase-negative staphylococci (CoNS) are among the most frequently recovered bacteria in routine clinical care. Their incidence has steadily increased over the past decades in parallel to the advancement in medicine, especially in regard to the utilization of foreign body devices. Many new species have been described within the past years, while clinical information to most of those species is still sparse. In addition, interspecies differences that render some species more virulent than others have to be taken into account. The distinct populations in which CoNS infections play a prominent role are preterm neonates, patients with implanted medical devices, immunodeficient patients, and those with other relevant comorbidities. Due to the property of CoNS to colonize the human skin, contamination of blood cultures or other samples occurs frequently. Hence, the main diagnostic hurdle is to correctly identify the cases in which CoNS are causative agents rather than contaminants. However, neither phenotypic nor genetic tools have been able to provide a satisfying solution to this problem. Another dilemma of CoNS in clinical practice pertains to their extensive antimicrobial resistance profile, especially in healthcare settings. Therefore, true infections caused by CoNS most often necessitate the use of second-line antimicrobial drugs.

In Brazil’s Atlantic Forest (AF) biodiversity conservation is of key importance since the fungal pathogen Batrachochytrium dendrobatidis (Bd) has led to the rapid loss of amphibian populations here and worldwide. The impact of Bd on amphibians is determined by the host's immune system, of which the skin microbiome is a critical component. The richness and diversity of such cutaneous bacterial communities are known to be shaped by abiotic factors which thus may indirectly modulate host susceptibility to Bd . This study aimed to contribute to understanding the environment-host–pathogen interaction determining skin bacterial communities in 819 treefrogs (Anura: Hylidae and Phyllomedusidae) from 71 species sampled across the AF. We investigated whether abiotic factors influence the bacterial community richness and structure on the amphibian skin. We further tested for an association between skin bacterial community structure and Bd co-occurrence. Our data revealed that temperature, precipitation, and elevation consistently correlate with richness and diversity of the skin microbiome and also predict Bd infection status. Surprisingly, our data suggest a weak but significant positive correlation of Bd infection intensity and bacterial richness. We highlight the prospect of future experimental studies on the impact of changing environmental conditions associated with global change on environment-host–pathogen interactions in the AF.

The spatial variation and underlying mechanisms of pattern formation in the rhizosphere microbiome are not well understood. We demonstrate that specific patterns in the distribution of recently fixed carbon within the plant root system influence the spatial organization of the rhizosphere microbiota. Non-invasive analysis of carbon allocation in the maize root system by 11 C tracer-based positron emission tomography combined with magnetic resonance imaging reveals high spatial heterogeneity with highest 11 C-signal accumulations at root tips and differences between root types. Strong correlations exist between root internal carbon allocation and rhizodeposition as evident from 13 CO 2 labeling. These patterns are reflected in the bacterial, fungal and protistan community structure in rhizosphere soil with differences depending on root structure and related spatial heterogeneities in carbon allocation. Especially the active consumers of 13 C-labeled rhizodeposits are responsive to photosynthate distribution with differences in 13 C-labeling according to their spatial localization within the root system. Thus, root photosynthate allocation supports distinct habitats in the plant root system and is a key determinant of microbial food web development, evident from 13 C-labeling of diverse bacterial and protistan predators, especially at root bases, resulting in characteristic spatiotemporal patterns in the rhizosphere microbiome. The combination of isotopic tracers with root phenotyping reveals specific patterns in photosynthate allocation. These patterns are reflected in rhizodeposition and result in spatially distinct microbiomes within the plant root system.

ObjectiveThe aim of the study was to deepen our insights into central compensatory processes of brain networks in patients with cerebellar ataxia (CA) before and with treatment with acetyl-dl-leucine (AL) by means of resting-state [18F]-FDG-PET brain imaging.MethodsRetrospective analyses of [18F]-FDG-PET data in 22 patients with CA (with vestibular and ocular motor disturbances) of different etiologies who were scanned before (PET A) and on AL treatment (PET B). Group subtraction analyses, e.g., for responders and non-responders, comparisons with healthy controls and correlation analyses of regional cerebral glucose metabolism (rCGM) with symptom duration, ataxia (SARA) and quality of life (QoL) scores were calculated.ResultsPrior to treatment rCGM was consistently downregulated at the cerebellar level and increased in multisensory cortical areas, e.g., somatosensory, primary and secondary visual (including V5, precuneus), secondary vestibular (temporal gyrus, anterior insula), and premotor/supplementary motor areas. With AL (PET B vs. A) cerebellar hypometabolism was deepened and sensorimotor hypermetabolism increased only in responders with clinical benefit, but not for the non-responders and the whole CA group. A positive correlation of ataxia improvement with rCGM was found in visual and vestibular cortices, a negative correlation in cerebellar and brainstem areas. QoL showed a positive correlation with rCGM in the cerebellum and symptom duration in premotor and somatosensory areas.ConclusionsCentral compensatory processes in CA mainly involve multisensory visual, vestibular, and somatosensory networks as well as premotor/primary motor areas at the cortical level. The enhanced divergence of cortical sensorimotor up- and cerebellar downregulation with AL in responders could reflect amplification of inhibitory cerebellar mechanisms.

Background Complex regional pain syndrome (CRPS) develops after injury and is characterized by disproportionate pain, oedema, and functional loss. CRPS has clinical signs of neuropathy as well as neurogenic inflammation. Here, we asked whether skin biopsies could be used to differentiate the contribution of these two systems to ultimately guide therapy. To this end, the cutaneous sensory system including nerve fibres and the recently described nociceptive Schwann cells as well as the cutaneous immune system were analysed. Methods We systematically deep-phenotyped CRPS patients and immunolabelled glabrous skin biopsies from the affected ipsilateral and non-affected contralateral finger of 19 acute (< 12 months) and 6 chronic (> 12 months after trauma) CRPS patients as well as 25 sex- and age-matched healthy controls (HC). Murine foot pads harvested one week after sham or chronic constriction injury were immunolabelled to assess intraepidermal Schwann cells. Results Intraepidermal Schwann cells were detected in human skin of the finger—but their density was much lower compared to mice. Acute and chronic CRPS patients suffered from moderate to severe CRPS symptoms and corresponding pain. Most patients had CRPS type I in the warm category. Their cutaneous neuroglial complex was completely unaffected despite sensory plus signs, e.g. allodynia and hyperalgesia. Cutaneous innate sentinel immune cells, e.g. mast cells and Langerhans cells, infiltrated or proliferated ipsilaterally independently of each other—but only in acute CRPS. No additional adaptive immune cells, e.g. T cells and plasma cells, infiltrated the skin. Conclusions Diagnostic skin punch biopsies could be used to diagnose individual pathophysiology in a very heterogenous disease like acute CRPS to guide tailored treatment in the future. Since numbers of inflammatory cells and pain did not necessarily correlate, more in-depth analysis of individual patients is necessary.

Topological insulators represent a novel state of matter with surface charge carriers having a massless Dirac dispersion and locked helical spin polarization. Many exciting experiments have been proposed by theory, yet their execution has been hampered by the extrinsic conductivity associated with the unavoidable presence of defects in Bi₂Te₃ and Bi₂Se₃ bulk single crystals, as well as impurities on their surfaces. Here we present the preparation of Bi₂Te₃ thin films that are insulating in the bulk and the fourpoint probe measurement of the conductivity of the Dirac states on surfaces that are intrinsically clean. The total amount of charge carriers in the experiment is of the order of 10¹² cm⁻² only, and mobilities up to 4,600 cm²/Vs have been observed. These values are achieved by carrying out the preparation, structural characterization, angle-resolved and X-ray photoemission analysis, and temperature-dependent four-point probe conductivity measurement all in situ under ultra-high-vacuum conditions. This experimental approach opens the way to prepare devices that can exploit the intrinsic topological properties of the Dirac surface states.