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).

TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C.

In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRß repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.

Molecular biology for green recovery-A call for action.

Molecular biology holds a vast potential for tackling climate change and biodiversity loss. Yet, it is largely absent from the current strategies. We call for a community-wide action to bring molecular biology to the forefront of climate change solutions.

The Ocean Decade-Opportunities for Oceans and Human Health Programs to Contribute to Public Health

For more than 4.5 billion people, approximately 15% of their daily per capita intake of animal protein comes from marine products.5 Seafood provides a source of micronutrients and omega-3 fatty acids essential for good physical and mental health. Studies over the past 10 years have demonstrated that spending time in highquality "blue" spaces (through leisure activities or living in a coastal environment) directly supports and enhances health and well-being, combatting obesity and mental health problems, particularly in deprived populations.6 This highlights an enormous potential for these well-being promotion initiatives and healthcare interventions to address both preexisting and emerging health issues beyond the lifetime of the pandemic. There is now a tremendous opportunity and public momentum for health professionals to join with ocean researchers to help policymakers, the business community, and the wider public to address systemic global challenges in a new way (http://bit.ly/2ZDFMS3).7 We need international alliances, transdisciplinary collaborations, and global governance that support innovative, systemic ways of managing ocean resources. ACKNOWLEDGMENTS The research was supported in part by the European Union's Horizon 2020 research and innovation programme (grants 774567 [H2020 SOPHIE Project] and 666773 [H2020 BlueHealth Project]);the UK Natural Environment Research Council and the UK Research and Innovation's Global Challenges Research Fund for the Blue Communities Project;the Blue Climate Initiative Health and Wellbeing Subgroup (https://www.blueclimateinitiative.org);the University of Girona;the City Council of Roses;the Catalan Fishmonger's Association;the Roses Fishers' Association;the Town Council of Tossa de Mar;and the government of Catalonia (the sponsors of the Roses Oceans and Human Health Chair).