Loss of GM-CSF-dependent instruction of alveolar macrophages in COVID-19 provides a rationale for inhaled GM-CSF treatment.

GM-CSF promotes myelopoiesis and inflammation, and GM-CSF blockade is being evaluated as a treatment for COVID-19-associated hyperinflammation. Alveolar GM-CSF is, however, required for monocytes to differentiate into alveolar macrophages (AMs) that control alveolar homeostasis. By mapping cross-species AM development to clinical lung samples, we discovered that COVID-19 is marked by defective GM-CSF-dependent AM instruction and accumulation of pro-inflammatory macrophages. In a multi-center, open-label RCT in 81 non-ventilated COVID-19 patients with respiratory failure, we found that inhalation of rhu-GM-CSF did not improve mean oxygenation parameters compared with standard treatment. However, more patients on GM-CSF had a clinical response, and GM-CSF inhalation induced higher numbers of virus-specific CD8 effector lymphocytes and class-switched B cells, without exacerbating systemic hyperinflammation. This translational proof-of-concept study provides a rationale for further testing of inhaled GM-CSF as a non-invasive treatment to improve alveolar gas exchange and simultaneously boost antiviral immunity in COVID-19. This study is registered at ClinicalTrials.gov (NCT04326920) and EudraCT (2020-001254-22).

Ocean acidification causes fundamental changes in the cellular metabolism of the Arctic copepod Calanus glacialis as detected by metabolomic analysis.

Using a targeted metabolomic approach we investigated the effects of low seawater pH on energy metabolism in two late copepodite stages (CIV and CV) of the keystone Arctic copepod species Calanus glacialis. Exposure to decreasing seawater pH (from 8.0 to 7.0) caused increased ATP, ADP and NAD+ and decreased AMP concentrations in stage CIV, and increased ATP and phospho-L-arginine and decreased AMP concentrations in stage CV. Metabolic pathway enrichment analysis showed enrichment of the TCA cycle and a range of amino acid metabolic pathways in both stages. Concentrations of lactate, malate, fumarate and alpha-ketoglutarate (all involved in the TCA cycle) increased in stage CIV, whereas only alpha-ketoglutarate increased in stage CV. Based on the pattern of concentration changes in glucose, pyruvate, TCA cycle metabolites, and free amino acids, we hypothesise that ocean acidification will lead to a shift in energy production from carbohydrate metabolism in the glycolysis toward amino acid metabolism in the TCA cycle and oxidative phosphorylation in stage CIV. In stage CV, concentrations of most of the analysed free fatty acids increased, suggesting in particular that ocean acidification increases the metabolism of stored wax esters in this stage. Moreover, aminoacyl-tRNA biosynthesis was enriched in both stages indicating increased enzyme production to handle low pH stress.

Effects of oil and global environmental drivers on two keystone marine invertebrates.

Ocean warming (OW) and acidification (OA) are key features of global change and are predicted to have negative consequences for marine species and ecosystems. At a smaller scale increasing oil and gas activities at northern high latitudes could lead to greater risk of petroleum pollution, potentially exacerbating the effects of such global stressors. However, knowledge of combined effects is limited. This study employed a scenario-based, collapsed design to investigate the impact of one local acute stressor (North Sea crude oil) and two chronic global drivers (pH for OA and temperature for OW), alone or in combination on aspects of the biology of larval stages of two key invertebrates: the northern shrimp (Pandalus borealis) and the green sea urchin (Strongylocentrotus droebachiensis). Both local and global drivers had negative effects on survival, development and growth of the larval stages. These effects were species- and stage-dependent. No statistical interactions were observed between local and global drivers and the combined effects of the two drivers were approximately equal to the sum of their separate effects. This study highlights the importance of adjusting regulation associated with oil spill prevention to maximize the resilience of marine organisms to predicted future global conditions.

Adjustments of molecular key components of branchial ion and pH regulation in Atlantic cod (Gadus morhua) in response to ocean acidification and warming.

Marine teleost fish sustain compensation of extracellular pH after exposure to hypercapnia by means of efficient ion and acid-base regulation. Elevated rates of ion and acid-base regulation under hypercapnia may be stimulated further by elevated temperature. Here, we characterized the regulation of transepithelial ion transporters (NKCC1, NBC1, SLC26A6, NHE1 and 2) and ATPases (Na(+)/K(+) ATPase and V-type H(+) ATPase) in gills of Atlantic cod (Gadus morhua) after 4 weeks of exposure to ambient and future PCO2 levels (550 µatm, 1200 µatm, 2200 µatm) at optimum (10 °C) and summer maximum temperature (18 °C), respectively. Gene expression of most branchial ion transporters revealed temperature- and dose-dependent responses to elevated PCO2. Transcriptional regulation resulted in stable protein expression at 10 °C, whereas expression of most transport proteins increased at medium PCO2 and 18 °C. mRNA and protein expression of distinct ion transport proteins were closely co-regulated, substantiating cellular functional relationships. Na(+)/K(+) ATPase capacities were PCO2 independent, but increased with acclimation temperature, whereas H(+) ATPase capacities were thermally compensated but decreased at medium PCO2 and 10 °C. When functional capacities of branchial ATPases were compared with mitochondrial F1Fo ATP-synthase strong correlations of F1Fo ATP-synthase and ATPase capacities generally indicate close coordination of branchial aerobic ATP demand and supply. Our data indicate physiological plasticity in the gills of cod to adjust to a warming, acidifying ocean within limits. In light of the interacting and non-linear, dose-dependent effects of both climate factors the role of these mechanisms in shaping resilience under climate change remains to be explored.

Effect of pH and temperature on antioxidant responses of the thick shell mussel Mytilus coruscus.

This study evaluated the combined effects of seawater pH decrease and temperature increase on the activity of antioxidant enzymes in the thick shell mussel Mytilus coruscus, an ecological and economic bivalve species widely distributed along the East China Sea. Mussels were exposed to three pH levels (8.1, 7.7 and 7.3) and two temperatures (25 °C and 30 °C) for 14 days. Activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione (GSH), acid phosphatase (ACP), alkaline phosphatase (AKP) and glutamic-pyruvic transaminase (GPT) were measured in gills and digestive glands after 1, 3, 7 and 14 days of exposure. All enzymatic activities were significantly impacted by pH, temperature. Enzymatic activities at the high temperature were significantly higher than those at the low temperature, and the mussels exposed to pH 7.3 showed significantly higher activities than those under higher pH condition for all enzymes except ACP. There was no interaction between temperature and pH in two third of the measured activities suggesting similar mode of action for both drivers. Interaction was only consistently significant for GPX. PCA revealed positive relationships between the measured biochemical indicators in both gills and digestive glands. Overall, our results suggest that decreased pH and increased temperature induce a similar anti-oxidative response in the thick shell mussel.