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"Wagner, Bettina"
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Global warming-related tree growth decline and mortality on the north-eastern Tibetan plateau
Semi-arid forests at the limit of their existence close to the Gobi Desert in Inner Asia might be vulnerable to warming-induced drought stress. Yet, not much is known about the impact of global-change-type droughts on these forests. Here, we show that warming-related tree mortality is recently taking place in high-elevation semi-arid Qinghai spruce (Picea crassifolia Kom.) forests of the north-eastern margin of the Tibetan Plateau (Qilian Mountains). Tree-ring samples were collected from 24 Qinghai spruce forest plots (20 m × 20 m) at three elevations (2600, 2700, 2800 m) along eight elevation transects on north-facing slopes. Three lines of evidence suggest that these forests are increasingly at risk of increased tree mortality as a consequence of global warming, (i) a strong precipitation and air humidity dependence of radial growth, (ii) increasing frequency of missing tree rings, and (iii) a rising tree mortality rate in recent decades. The recent drought episode on the north-eastern Tibetan Plateau may represent a precursor of future global-change-type drought events in large parts of Inner Asia. Warming-related tree mortality of the semi-arid forests may be interpreted as early-warning signs for the densely populated artificial oases surrounding the Gobi Desert, which largely depend on river run-off from the mountain forests on the edge of the Tibetan Plateau.
Journal Article
EGF receptor is required for efficient liver regeneration
Mice lacking the EGF receptor (EGFR) die between midgestation and postnatal day 20 with various defects in neural and epithelial organs. Here, we generated mice carrying a floxed EGFR allele to inactivate the EGFR in fetal and adult liver. Perinatal deletion of EGFR in hepatocytes resulted in decreased body weight, whereas deletion in the adult liver did not affect body mass. Although liver function was not affected, after partial hepatectomy mice lacking EGFR in the liver showed increased mortality accompanied by increased levels of serum transaminases indicating liver damage. Liver regeneration was delayed in the mutants because of reduced hepatocyte proliferation. Analysis of cell cycle progression in EGFR-deficient livers indicated a defective G₁-S phase entry with delayed transcriptional activation and reduced protein expression of cyclin D1 followed by reduced cdk2 and cdk1 expression. Impaired liver regeneration was accompanied by compensatory up-regulation of TNFα in the serum and prolonged activation of c-Jun. Moreover, p38α and NF-κB activation was reduced in regenerating mutant livers, indicating an impaired stress response after hepatectomy. Our studies demonstrate that EGFR is a critical regulator of hepatocyte proliferation in the initial phases of liver regeneration.
Journal Article
Characterization of Nasal Mucosal T Cells in Horses and Their Response to Equine Herpesvirus Type 1
Equine herpesvirus type 1 (EHV-1) enters through the upper respiratory tract (URT). Mucosal immunity at the URT is crucial in limiting viral infection and morbidity. Here, intranasal immune cells were collected from horses (n = 15) during an experimental EHV-1 infection. CD4+ and CD8+ T cells were the major intranasal cell populations before infection and increased significantly by day six and fourteen post-infection, respectively. Nasal mucosal T cells were further characterized in healthy horses. Compared to peripheral blood mononuclear cells (PBMC), mucosal CD8+ T-cell percentages were elevated, while CD4+ T-cell percentages were similar. A small population of CD4+CD8+ T cells was also recovered from mucosal samples. Within the URT tissue, CD4+ cells predominantly accumulated in the epithelial layer, while most CD8+ cells resided deeper in the mucosa or the submucosa below the basement membrane. In vitro stimulation of mucosal cells from healthy horses with (n = 5) or without (n = 5) peripheral T-cell immunity against EHV-1 induced IFN-γ production in nasal T cells upon polyclonal stimulation. However, after EHV-1 re-stimulation, mucosal T cells failed to respond with IFN-γ. This work provided the first characterization of mucosal T-cell phenotypes and functions in the URT of healthy horses and during EHV-1 infection.
Journal Article
Phenotype and function of IgE-binding monocytes in equine Culicoides hypersensitivity
Human IgE-binding monocytes are identified as allergic disease mediators, but it is unknown whether IgE-binding monocytes promote or prevent an allergic response. We identified IgE-binding monocytes in equine peripheral blood as IgE+/MHCIIhigh/CD14low cells that bind IgE through an FcεRI αɣ variant. IgE-binding monocytes were analyzed monthly in Culicoides hypersensitive horses and nonallergic horses living together with natural exposure to Culicoides midges. The phenotype and frequency of IgE-binding monocytes remained consistent in all horses regardless of Culicoides exposure. All horses upregulated IgE-binding monocyte CD16 expression following initial Culicoides exposure. Serum total IgE concentration and monocyte surface IgE densities were positively correlated in all horses. We also demonstrated that IgE-binding monocytes produce IL-10, but not IL-4, IL-17A, or IFN-γ, following IgE crosslinking. In conclusion, we have characterized horse IgE-binding monocytes for the first time and further studies of these cells may provide important connections between regulation and cellular mechanisms of IgE-mediated diseases.
Journal Article
Neonatal and maternal upregulation of antileukoproteinase in horses
The end of gestation, ensuing parturition, and the neonatal period represent highly dynamic phases for immunological changes in both mother and offspring. The regulation of innate immune cells at the maternal-fetal interface during late term pregnancy, after birth, and during microbial colonization of the neonatal gut and other mucosal surfaces, is crucial for controlling inflammation and maintaining homeostasis. Innate immune cells and mucosal epithelial cells express antileukoproteinase (SLPI), which has anti-inflammatory and anti-protease activity that can regulate cellular activation.
Here, we developed and validated new monoclonal antibodies (mAbs) to characterize SLPI for the first time in horses. Peripheral blood and mucosal samples were collected from healthy adults horses and a cohort of mares and their foals directly following parturition to assess this crucial stage.
First, we defined the cell types producing SLPI in peripheral blood by flow cytometry, highlighting the neutrophils and a subset of the CD14+ monocytes as SLPI secreting immune cells. A fluorescent bead-based assay was developed with the new SLPI mAbs and used to establish baseline concentrations for secreted SLPI in serum and secretion samples from mucosal surfaces, including saliva, nasal secretion, colostrum, and milk. This demonstrated constitutive secretion of SLPI in a variety of equine tissues, including high colostrum concentrations. Using immunofluorescence, we identified production of SLPI in mucosal tissue. Finally, longitudinal sampling of clinically healthy mares and foals allowed monitoring of serum SLPI concentrations. In neonates and postpartum mares, SLPI peaked on the day of parturition, with mares returning to the adult normal within a week and foals maintaining significantly higher SLPI secretion until three months of age.
This demonstrated a physiological systemic change in SLPI in both mares and their foals, particularly at the time around birth, likely contributing to the regulation of innate immune responses during this critical period.
Journal Article
Synthetic periphyton as a model system to understand species dynamics in complex microbial freshwater communities
Phototrophic biofilms, also known as periphyton, are microbial freshwater communities that drive crucial ecological processes in streams and lakes. Gaining a deep mechanistic understanding of the biological processes occurring in natural periphyton remains challenging due to the high complexity and variability of such communities. To address this challenge, we rationally developed a workflow to construct a synthetic community by co-culturing 26 phototrophic species (i.e., diatoms, green algae, and cyanobacteria) that were inoculated in a successional sequence to create a periphytic biofilm on glass slides. We show that this community is diverse, stable, and highly reproducible in terms of microbial composition, function, and 3D spatial structure of the biofilm. We also demonstrate the ability to monitor microbial dynamics at the single species level during periphyton development and how their abundances are impacted by stressors such as increased temperature and a herbicide, singly and in combination. Overall, such a synthetic periphyton, grown under controlled conditions, can be used as a model system for theory testing through targeted manipulation.
Journal Article
Mesenchymal stromal cell‐secreted CCL2 promotes antibacterial defense mechanisms through increased antimicrobial peptide expression in keratinocytes
Mesenchymal stromal cells (MSCs) from both humans and horses, which represent a clinically relevant translation animal model for human cutaneous wound healing, were recently found to possess antimicrobial properties against planktonic bacteria, and in the case of equine MSCs, also against biofilms. This, together with previous findings that human and equine MSCs promote angiogenesis and wound healing, makes these cells an attractive approach to treat infected cutaneous wounds in both species. The anti‐biofilm activities of equine MSC, via secretion of cysteine proteases, have only been demonstrated in vitro, thus lacking information about in vivo relevance. Moreover, the effects of the equine MSC secretome on resident skin cells have not yet been explored. The goals of this study were to (a) test the efficacy of the MSC secretome in a physiologically relevant ex vivo equine skin biofilm explant model and (b) explore the impact of the MSC secretome on the antimicrobial defense mechanisms of resident skin cells. Our salient findings were that secreted factors from equine MSCs significantly decreased viability of methicillin‐resistant Staphylococcus aureus bacteria in mature biofilms in this novel skin biofilm explant model. Moreover, we demonstrated that equine MSCs secrete CCL2 that increases the antimicrobial activity of equine keratinocytes by stimulating expression of antimicrobial peptides. Collectively, these data contribute to our understanding of the MSC secretome's antimicrobial properties, both directly by killing bacteria and indirectly by stimulating immune responses of surrounding resident skin cells, thus further supporting the value of MSC secretome‐based treatments for infected wounds. CCL2 secreted by mesenchymal stromal cells promotes cutaneous antibacterial defense mechanisms through increased antimicrobial peptide expression in keratinocytes. The secretome of cultured equine mesenchymal stromal cells (MSCs) was collected as conditioned medium (CM) and applied to methicillin‐susceptible Staphylococcus aureus (MSSA) and methicillin‐resistant Staphylococcus aureus (MRSA) biofilms in an ex vivo cutaneous wound explant model, where it effectively reduced bacteria viability. Primary equine keratinocytes, in two‐dimensional cultures, significantly increased expression of the antimicrobial peptides (AMP) ß‐defensin and cathelicidin after stimulation with the MSC secretome. ß‐defensin expression was mediated by CCL2, a cytokine secreted by MSCs.
Journal Article
Early allergen introduction overrides allergy predisposition in offspring of horses with Culicoides hypersensitivity
The origins of allergy are both genetic and environmental. We performed a full-sibling study to determine the role of early-in-life or delayed allergen introduction on
hypersensitivity development in a cohort with history of an allergic phenotype and Culicoides hypersensitivity. IgE-mediated allergies naturally develop in many mammalian species, and we used a horse model of allergy called
hypersensitivity.
hypersensitivity is a seasonal, recurrent, IgE-mediated allergy caused by the salivary proteins of biting
midges.
The study included four cohorts that lived together in the same environment, only differing in the timing of allergen exposure and the transfer of allergen-specific maternal antibodies. The parent cohort was first exposed to allergens in adulthood, and each full-sibling cohort was first exposed to allergen either in puberty or at birth. All full-siblings had at least one allergic parent with an allergic phenotype, suggesting a predisposition to develop allergy. Allergen-specific IgE and IgG isotypes were measured before and after exposure to
to determine whether maternal-acquired allergen-specific antibodies influenced the rate of
hypersensitivity development. All four cohorts were followed for at least nine years of allergen exposure.
The rate of allergy development was inversely related to the timing of allergen exposure where introduction in adulthood led to the highest rate of allergy development (62.5%), a moderate allergy rate was found for introduction during adolescence (21.4%), and no individuals exposed at birth developed
hypersensitivity. In addition, exposure to maternally-acquired allergen-specific IgE and IgG did not influence the rate of allergy development in the cohorts exposed to allergen at birth.
We provide strong evidence in a full-sibling study that early-in-life allergen exposure, independent of maternal allergen-specific immunoglobulin, prevents
hypersensitivity development in individuals born to parents with an allergic phenotype.
Journal Article
Increase in Virus-Specific Mucosal Antibodies in the Upper Respiratory Tract Following Intramuscular Vaccination of Previously Exposed Horses Against Equine Herpesvirus Type-1/4
Background/Objectives: Equine herpesvirus type-1 (EHV-1) enters through the upper respiratory tract (URT) and causes respiratory disease, abortions, and myeloencephalopathy in equids. Pre-existing immunity at the viral entry site, especially mucosal IgG4/7 antibodies, has recently been shown to correlate with protection from disease and incomplete viral replication at the URT. Here, we tested whether intramuscular (i.m.) vaccination with a commercial inactivated EHV-1/4 vaccine can induce mucosal antibodies (mucAbs) at the URT. Methods: Adult horses with complete EHV-1 vaccination and/or exposure histories were vaccinated i.m. six times within eight months. Before and after each vaccination, blood and nasal swab samples were obtained. Serum and mucAbs were measured in fluorescent bead-based EHV-1 assays. Results: All horses still had existing EHV-1 specific serum and mucAbs prior to vaccination, which were mainly composed of IgG4/7 antibody isotypes. Serum IgG4/7 significantly increased after the first vaccination and stayed high until the end of the study. An additional short-lasting serum IgG1 response was only induced by the first vaccine application. At the URT, mucAbs increased after five out of six i.m. vaccine injections. Like the systemic antibody response, mucAbs were dominated by IgG4/7 and a small IgG1 increase after the first vaccination. Conclusions: Our data emphasize that robust EHV-1 specific mucAb levels are obtained after i.m. vaccination with the inactivated EHV-1/4 vaccine used here. The findings have important implications for evaluating EHV-1/4 vaccines for their ability to induce and maintain protective mucosal IgG4/7 antibodies.
Journal Article