Neuropeptides Control the Dynamic Behavior of Airway Mucosal Dendritic Cells

The airway mucosal epithelium is permanently exposed to airborne particles. A network of immune cells patrols at this interface to the environment. The interplay of immune cells is orchestrated by different mediators. In the current study we investigated the impact of neuronal signals on key functions of dendritic cells (DC). Using two-photon microscopic time-lapse analysis of living lung sections from CD11c-EYFP transgenic mice we studied the influence of neuropeptides on airway DC motility. Additionally, using a confocal microscopic approach, the phagocytotic capacity of CD11c⁺ cells after neuropeptide stimulation was determined. Electrical field stimulation (EFS) leads to an unspecific release of neuropeptides from nerves. After EFS and treatment with the neuropeptides vasoactive intestinal peptide (VIP) or calcitonin gene-related peptide (CGRP), airway DC in living lung slices showed an altered motility. Furthermore, the EFS-mediated effect could partially be blocked by pre-treatment with the receptor antagonist CGRP_8–37. Additionally, the phagocytotic capacity of bone marrow-derived and whole lung CD11c⁺ cells could be inhibited by neuropeptides CGRP, VIP, and Substance P. We then cross-linked these data with the in vivo situation by analyzing DC motility in two different OVA asthma models. Both in the acute and prolonged OVA asthma model altered neuropeptide amounts and DC motility in the airways could be measured. In summary, our data suggest that neuropeptides modulate key features motility and phagocytosis of mouse airway DC. Therefore altered neuropeptide levels in airways during allergic inflammation have impact on regulation of airway immune mechanisms and therefore might contribute to the pathophysiology of asthma.     

In vitro endothelial cell activation and inflammatory responses in end-stage heart failure.

BACKGROUND: vascular endothelial cell activation and dysfunction are observed in patients with severe heart failure and may contribute to systemic manifestations of this syndrome. It remains unknown whether inflammatory activation of these cells occurs in these patients because of increased circulating proinflammatory mediators. Aim: to determine whether the serum from patients with heart failure possesses a net proinflammatory bioactivity to active proinflammatory pathways in cultured endothelial cells. METHODS: serum was obtained from stable patients with end-stage heart failure undergoing elective cardiac transplantation (Tx) and severely decompensated patients with heart failure requiring emergency left ventricular assist device (LVAD) implantation. Net proinflammatory bioactivity of serum was investigated by monitoring IkappaBalpha degradation and E-selectin expression in cultured human pulmonary artery endothelial cells (HPAEC) following incubation with serum samples. Serum cytokine concentrations were measured by ELISA and neutralizing antibodies were used to determine the role of specific factors in the observed bioactivity. RESULT: serum from both patient groups induced HPAEC IkappaBalpha degradation. Low basal HPAEC E-selectin expression significantly increased following treatment with Tx but not LVAD serum. Serum tumor necrosis factor-alpha (TNF-alpha) and IL-10 concentrations were higher in patients with LVAD than those with Tx, and soluble TNF-alpha receptor expression was high in both groups. Neither TNF-alpha nor IL-10 blocking experiments altered either bioassay result. CONCLUSION: activation of a specific profile of pro- and anti-inflammatory mediators is associated with heart failure resulting in HPAEC nuclear factor (NF)-kappaB activation. However, E-selectin expression is further regulated by unidentified factors. TNF-alpha is upregulated but appears to play no part in NFkappaB activation in these patients. These findings could have important therapeutic implications.     

Determinants of Neutralization Resistance in the Envelope Glycoproteins of a Simian-Human Immunodeficiency Virus Passaged In Vivo

In vivo passage of a simian-human immunodeficiency virus (SHIV-89.6) generated a virus, SHIV-89.6P, that exhibited increased resistance to some neutralizing antibodies (G. B. Karlsson et al., J. Exp. Med. 188:1159-1171, 1998). Here we examine the range of human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies to which the passaged virus became resistant and identify envelope glycoprotein determinants of antibody resistance. Compared with the envelope glycoproteins derived from the parental SHIV-89.6, the envelope glycoproteins of the passaged virus were resistant to antibodies directed against the gp120 V3 variable loop and the CD4 binding site. By contrast, both viral envelope glycoproteins were equally sensitive to neutralization by two antibodies, 2G12 and 2F5, that recognize poorly immunogenic structures on gp120 and gp41, respectively. Changes in the V2 and V3 variable loops of gp120 were necessary and sufficient for full resistance to the IgG1b12 antibody, which is directed against the CD4 binding site. Changes in the V3 loop specified complete resistance to a V3 loop-directed antibody, while changes in the V1/V2 loops conferred partial resistance to this antibody. The epitopes of the neutralizing antibodies were not disrupted by the resistance-associated changes. These results indicate that in vivo selection occurs for HIV-1 envelope glycoproteins with variable loop conformations that restrict the access of antibodies to immunogenic neutralization epitopes.     

A comprehensive aerobiological study of the airborne pollen in the Irish environment

Respiratory allergies triggered by pollen allergens represent a significant health concern to the Irish public. Up to now, Ireland has largely refrained from participating in long-term aerobiological studies. Recently, pollen monitoring has commenced in several sampling locations around Ireland. The first results of the pollen monitoring campaigns for Dublin (urban) and Carlow (rural) concerning the period 2017–2019 and 2018–2019, respectively, are presented herein. Additional unpublished pollen data from 1978–1980 and, 2010–2011 were also incorporated in creating the first pollen calendar for Dublin. During the monitoring period over 60 pollen types were identified with an average Annual Pollen Integral (APIn) of 32,217 Pollen × day/m³ for Dublin and 78,411 Pollen × day/m³ for Carlow. The most prevalent pollen types in Dublin were: Poaceae (32%), Urticaceae (29%), Cupressaceae/Taxaceae (11%), Betula (10%), Quercus (4%), Pinus (3%), Fraxinus (2%), Alnus (2%) and Platanus (1%). The predominant pollen types in Carlow were identified as Poaceae (70%), Urticaceae (12%), Betula (10%), Quercus (2%), Fraxinus (1%) and Pinus (1%). These prevalent pollen types increased in annual pollen concentration in both locations from 2018 to 2019 except for Fraxinus. Although higher pollen concentrations were observed for the Carlow (rural) site a greater variety of pollen types were identified for the Dublin (urban) site. The general annual trend in the pollen season began with the release of tree pollen in early spring, followed by the release of grass and herbaceous pollen which dominated the summer months with the annual pollen season coming to an end in October. This behaviour was illustrated for 21 different pollen types in the Dublin pollen calendar. The correlation between ambient pollen concentration and meteorological parameters was also examined and differed greatly depending on the location and study year. A striking feature was a substantial fraction of the recorded pollen sampled in Dublin did not correlate with the prevailing wind directions. However, using non-parametric wind regression, specific source regions could be determined such as Alnus originating from the Southeast, Betula originating from the East and Poaceae originating from the Southwest.

     

TMEM41B and VMP1 are scramblases and regulate the distribution of cholesterol and phosphatidylserine

TMEM41B and VMP1 are integral membrane proteins of the endoplasmic reticulum (ER) and regulate the formation of autophagosomes, lipid droplets (LDs), and lipoproteins. Recently, TMEM41B was identified as a crucial host factor for infection by all coronaviruses and flaviviruses. The molecular function of TMEM41B and VMP1, which belong to a large evolutionarily conserved family, remains elusive. Here, we show that TMEM41B and VMP1 are phospholipid scramblases whose deficiency impairs the normal cellular distribution of cholesterol and phosphatidylserine. Their mechanism of action on LD formation is likely to be different from that of seipin. Their role in maintaining cellular phosphatidylserine and cholesterol homeostasis may partially explain their requirement for viral infection. Our results suggest that the proper sorting and distribution of cellular lipids are essential for organelle biogenesis and viral infection.     

Seasonal fluctuations of zooplankton biomass in Lake Xolotlán (Managua)

Seasonal fluctuations of zooplankton biomass (dry weight) were determined during a year in two localities of Lake Xolotlán (Managua). Biomass estimations of the most common species of rotifers, cladocerans and copepods were made. The maximal zooplankton biomass was observed in February–April (dry season) in coincidence with the period of highest phytoplankton abundance. Copepods contributed with 78% and 84% to the mean zooplankton biomass at points 1 and 7, respectively. Cladocera biomass was lowest during most of the year, and it was probably controlled by fish predation. Development of rotifer biomass was more intense during the rainy season, when detritus particles were more abundant. Daily fluctuations of zooplankton biomass were not pronounced.     

Spatiotemporal analysis of mycolactone distribution in vivo reveals partial diffusion in the central nervous system

Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU) disease, is unique amongst human pathogens in its capacity to produce a lipid toxin called mycolactone. While previous studies have demonstrated that bacterially-released mycolactone diffuses beyond infection foci, the spatiotemporal distribution of mycolactone remained largely unknown. Here, we used the zebrafish model to provide the first global kinetic analysis of mycolactone’s diffusion in vivo, and multicellular co-culture systems to address the critical question of the toxin’s access to the brain.Zebrafish larvae were injected with a fluorescent-derivative of mycolactone to visualize the in vivo diffusion of the toxin from the peripheral circulation. A rapid, body-wide distribution of mycolactone was observed, with selective accumulation in tissues near the injection site and brain, together with an important excretion through the gastro-intestinal tract. Our conclusion that mycolactone reached the central nervous system was reinforced by an in cellulo model of human blood brain barrier and a mouse model of M. ulcerans-infection.Here we show that mycolactone has a broad but heterogenous profile of distribution in vivo. Our investigations in vitro and in vivo support the view that a fraction of bacterially-produced mycolactone gains access to the central nervous system. The relative persistence of mycolactone in the bloodstream suggests that assays of circulating mycolactone are relevant for BU disease monitoring and treatment optimization.     

Mapping and monitoring tick (Acari,Ixodida) distribution,seasonality, and host associations in the United Kingdom between 2017 and 2020

Tick-borne disease risk is intrinsically linked to the distribution of tick vector species. To assess risk and anticipate disease emergence, an understanding of tick distribution, host associations, and seasonality is needed. This can be achieved, to some extent, using passive surveillance supported by engagement with the public, animal health, and public health experts. The Tick Surveillance Scheme (TSS) collects data and maps tick distribution across the United Kingdom (UK). Between 2017 and 2020, 3720 tick records were received and 39 tick species were detected. Most records were acquired in the UK, with a subset associated with recent overseas travel. The dominant UK acquired species was Ixodes ricinus (Ixodida: Ixodidae, Linnaeus), the main vector of Lyme borreliosis. Records peaked during May and June, highlighting a key risk period for tick bites. Other key UK species were detected, including Dermacentor reticulatus (Ixodida: Ixodidae, Fabricius) and Haemaphysalis punctata (Ixodida: Ixodidae, Canestrini & Fanzago) as well as several rarer species that may present novel tick-borne disease risk to humans and other animals. Updated tick distribution maps highlight areas in the UK where tick exposure has occurred. There is evidence of increasing human tick exposure over time, including during the COVID-19 pandemic, but seasonal patterns remain unchanged.