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Shellfish for human consumption is produced in excess of 15 million tons per year, accounting for roughly 14% of global marine aquaculture, with China being the largest producer (89% of world production). However, in the previous two decades, shellfish output in the European Union has been dropping. This review provides information about shellfish aquaculture in Montenegro, in Boka Kotorska Bay, where most farms belong to the group of small farms. Shellfish production in this bay is constantly increasing. Thus, with minor deviations, the production of shellfish increased from 156 tonnes, as was produced in 2012, to 246 tonnes produced in 2020. However, despite the constant growth of production, statistical data indicate that every year a large amount of shellfish is imported, and there is a need for greater production in the country. The shellfish production capacity in Montenegro is still lower than expected, despite the great potential for development. Aquaculture?s development potential is in the areas of increasing production, modernising existing farms, automating production, strengthening the competitiveness and efficiency of the sector, introducing new species, better linking aquaculture with tourism and processing, marine spatial planning, promoting aquaculture products and branding products.

Funder: British Lung Foundation (BLF); doi: https://doi.org/10.13039/501100000351, Funder: Royal Society through a University Research Fellowship and the Engineering and Physical Sciences Research Council (EPRSC), Funder: China Scholarship Council (CSC); doi: https://doi.org/10.13039/501100004543, Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of mesothelioma is predicted to affect middle-income countries during this century owing to their heavy consumption of asbestos. The prognosis for patients with mesothelioma is poor, reflecting a failure of conventional chemotherapy that has ultimately resulted from an inadequate understanding of its biology. However, recent work has revolutionised the study of mesothelioma, identifying genetic and pathophysiological vulnerabilities, including the loss of tumour suppressors, epigenetic dysregulation and susceptibility to nutrient stress. We discuss how this knowledge, combined with advances in immunotherapy, is enabling the development of novel targeted therapies.

To (re)define tissue architecture of the lung and airways at the cellular and molecular level, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and Visium Spatial Transcriptomics. Using computational data integration and analysis, we extend beyond the suspension cell paradigm of lung atlases to date, to define and discover macro and micro-anatomical tissue compartments. We describe novel cell types and states in vascular, stromal and nerve bundle microenvironments. From our spatial transcriptomics, we discover and validate a novel survival niche for IgA plasma cells in the airway submucosal glands (SMG). In this niche we define a supporting role for SMG epithelial cells in mucosal immunity through recruitment and maintenance of IgA plasma, B and CD4 T cells locally at the airway SMG. We identify an immune-supporting role for SMG duct and serous cells with distinct signalling circuits to recruit B cells and IgA plasma cells, promoting longevity and antibody secretion through expression of CCL28, APRIL and IL6. We find high expression of MHC-II in SMG duct and serous cells, which are localised closely with memory CD4 T cells, suggesting local modulation of antigen specific immune responses locally at the glands. This new tissue microenvironment, which we term the “gland-associated immune niche” (GAIN) has major implications for respiratory immunity and infection response. Our single cell and spatial data is available for download and query at lungcellatlas.org.

Organ- and body-scale cell atlases have the potential to transform our understanding of human biology. To capture the variability present in the population, these atlases must include diverse demographics such as age and ethnicity from both healthy and diseased individuals. The growth in both size and number of single-cell datasets, combined with recent advances in computational techniques, for the first time makes it possible to generate such comprehensive large-scale atlases through integration of multiple datasets. Here, we present the integrated Human Lung Cell Atlas (HLCA) combining 46 datasets of the human respiratory system into a single atlas spanning over 2.2 million cells from 444 individuals across health and disease. The HLCA contains a consensus re-annotation of published and newly generated datasets, resolving under- or misannotation of 59% of cells in the original datasets. The HLCA enables recovery of rare cell types, provides consensus marker genes for each cell type, and uncovers gene modules associated with demographic covariates and anatomical location within the respiratory system. To facilitate the use of the HLCA as a reference for single-cell lung research and allow rapid analysis of new data, we provide an interactive web portal to project datasets onto the HLCA. Finally, we demonstrate the value of the HLCA reference for interpreting disease-associated changes. Thus, the HLCA outlines a roadmap for the development and use of organ-scale cell atlases within the Human Cell Atlas.

Organ- and body-scale cell atlases have the potential to transform our understanding of human biology. To capture the variability present in the population, these atlases must include diverse demographics such as age and ethnicity from both healthy and diseased individuals. The growth in both size and number of single-cell datasets, combined with recent advances in computational techniques, for the first time makes it possible to generate such comprehensive large-scale atlases through integration of multiple datasets. Here, we present the integrated Human Lung Cell Atlas (HLCA) combining 46 datasets of the human respiratory system into a single atlas spanning over 2.2 million cells from 444 individuals across health and disease. The HLCA contains a consensus re-annotation of published and newly generated datasets, resolving under- or misannotation of 59% of cells in the original datasets. The HLCA enables recovery of rare cell types, provides consensus marker genes for each cell type, and uncovers gene modules associated with demographic covariates and anatomical location within the respiratory system. To facilitate the use of the HLCA as a reference for single-cell lung research and allow rapid analysis of new data, we provide an interactive web portal to project datasets onto the HLCA. Finally, we demonstrate the value of the HLCA reference for interpreting disease-associated changes. Thus, the HLCA outlines a roadmap for the development and use of organ-scale cell atlases within the Human Cell Atlas.

Macro- and microhabitat preference of Testudo hermanni boettgeri, the eastern subspecies of Hermann’s tortoise, was investigated utilizing modified methodology for the western subspecies which emphasized the importance of habitat heterogeneity preservation. The study objective was to explore the habitat preferences of the eastern subspecies of T. hermanni. Research was conducted within the same year at four localities in Eastern and Southeastern Serbia. Macrohabitat determination was conducted using a 0 to 5 land cover score system (coverage with herbaceous, bushy or tree vegetation) for 4 m2 tortoise encounter surroundings. Microhabitat analysis was carried out by determining the plant species in closest contact with the tortoise in the moment of recording. Plants were classified into six groups: 1) aromatic, 2) bramble, 3) herbaceous, 4) thorny shrub, 5) tree and 6) non-thorny shrubs. test was used for comparison between expected and empirical habitat preference. Results confirmed that the most attractive macrohabitats for Eastern Hermann’s tortoises in this part of the Balkans are meadows and open shrublands, with the addition of dense forest (important in wormer months), what is concordant with earlier data from the Mediterranean part of former Yugoslavia. The most attractive microhabitats were “herbaceous plants”, followed by “bramble”.

In this manuscript, down-conversion nanopowders of SrGd2O4 doped with different concentrations of either Dy3+ or Sm3+ ions were examined in detail. All samples were prepared via glycine-assisted combustion method, primarily burned at 500?C for 1.5 h and additionally calcined at 1000?C for 2 h, at ambient room temperature. The XRD analysis showed that all samples crystallize as single phase and the orthorhombic lattice SrGd2O4. TEM analysis determined high degree of crystallinity of samples with grain size of approximately 200 nm for Dy3+ doped and 150 nm for Sm3+ doped SrGd2O4. For both samples SAED confirmed that diffraction rings correspond to the hkl plane indices of SrGd2O4, while EDS confirmed presence of Dy in crystal structure. Results of luminescent characterization demonstrated all appropriate emission peaks related to either Dy3+ or Sm3+ dopant ions. Investigation of dopant concentration revealed that the lowest values of both dopants have the most prominent emission peaks, while coordinates obtained from the CIE diagram showed emission shifting with the change of concentration.

T1 Figure 1ConclusionsOverall, this largest paediatric single cell COVID-19 study to date showed significant differences in response to SARS-CoV-2 between children and adults, reflecting the changes of the immune landscape over developmental time, which in children are dominated by naive and innate responses.

Tissue architecture is a driving force for morphogenetic processes during development as well as for several physiological and regenerative responses. Far from being a passive static environment, tissue architecture is highly dynamic. Hydrogel technology reproduces in vitro geometrical and mechanical constrains that control the three-dimensional self-organization of (3D) organoids and organ-like cultures. This control is restricted to the initial culture conditions and cannot be adapted to the dynamic morphological changes of complex 3D cultures during their developmental trajectory. Here, we developed a method that overcomes this spatiotemporal limit. Using 2P crosslinking approach, high resolution 3D hydrogel structures can be fabricated within pre-existing hydrogel with spatiotemporal (four-dimensional, 4D) control relative to ex-vivo organotypic or organoid culture. This hydrogel-in-hydrogel bioprinting approach enables to continuously instruct the self-organization of the evolving 3D organ-like cultures.

Common genetic variants modulate the cellular response to viruses and are implicated in a range of immune pathologies, including infectious and autoimmune diseases. The transcriptional antiviral response is known to vary between infected cells from a single individual, yet how genetic variants across individuals modulate the antiviral response (and its cell-to-cell variability) is not well understood. Here, we triggered the antiviral response in human fibroblasts from 68 healthy donors, and profiled tens of thousands of cells using single-cell RNA-seq. We developed GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity), the first statistical approach designed to identify dynamic eQTLs across a transcriptional trajectory of cell populations, without aggregating single-cell data into pseudo-bulk. This allows us to uncover the underlying architecture and variability of antiviral response across responding cells, and to identify more than two thousands eQTLs modulating the dynamic changes during this response. Many of these eQTLs colocalise with risk loci identified in GWAS of infectious and autoimmune diseases. As a case study, we focus on a COVID-19 susceptibility locus, colocalised with the antiviral OAS1 splicing QTL. We validated it in blood cells from a patient cohort and in the infected nasal cells of a patient with the risk allele, demonstrating the utility of GASPACHO to fine-map and functionally characterise a genetic locus. In summary, our novel analytical approach provides a new framework for delineation of the genetic variants that shape a wide spectrum of transcriptional responses at single-cell resolution.

The aim of this work was to validate in the field certain measurement of the heart rate alterations of the bioindicator organism Mytilus galloprovicialis as a tool for ecotoxicological biomonitoring and assessment applications related to coastal and marine environment. The latter was determined by testing the mussels according to the method of functional loading (1-hour lowered salinity stress-exposure). The time of heart rate (HR) recovery (Tᵣₑc) and the coefficient of HR variation (CVHR) in a group of tested animals were used as biomarkers for the assessment of their physiological state. It was found that the values of the biomarkers in mussels from our reference location were 1.3-1.5 times lower than in mussels from differently polluted coastal areas of the Bay. The study also included an investigation of the relationship between the mussel’s cardiac rhythm characteristics and the bioaccumulation of trace elements in their soft tissues, caused by chronic pollution. The conclusion was drawn that this approach to the physiological testing of mussels could be useful in developing a rapid and low-cost method for the assessment of the health of coastal ecosystems.

Paper description: The Hermann’s tortoise and its habitats are among conservation priorities in the European Union. Populations of western subspecies are closely monitored and basic information about eastern subspecies is just starting to emerge. We used precise observation data to model the distribution of Hermann’s tortoise in Serbia and its ecological niche. Both modeled and observed distributions suggest that most suitable habitats are situated in lowland areas of eastern, central and southern Serbia, under semi-open habitats ranging from pastures and shrubs to broad leaf forests. Our results provide crucial information which should be considered when shaping NATURA 2000 sites in Serbia. Abstract: Hermann’s tortoise ( Testudo hermanni ) is among the conservation priorities in the European Union. Consequently, it is included in Annexes II and IV of the EU Habitats Directive, Annex II of the Bern Convention, and Annex II of the CITES Convention. Hermann’s tortoise conservation programs compile insights on the threats affecting population viability, along with factors shaping the species’ distribution. Serbian populations of the eastern subspecies ( Testudo hermanni boettgeri ) seem numerous and therefore prosperous, but recent population viability analyses revealed that they are susceptible to rapid demographic changes and/or habitat destruction. This implies the need for effective population monitoring and protection, as well as mapping and conservation of suitable habitats. In this paper we summarized current knowledge about the geographic distribution of Hermann’s tortoise in Serbia and modeled its ecological niche. Our results corroborate and uphold the known species’ distribution in Serbia. Most suitable habitats are situated in the lowland areas of eastern, central and southern Serbia, under semi-open habitats, such as pastures and shrubs, broadleaf forests, and all successional stages in between. The results provided in this paper should be considered in the selection and shaping of NATURA 2000 sites in Serbia. https://doi.org/10.2298/ABS190406034G Received: April 6, 2019; Revised: May 1, 2019; Accepted: May 7, 2019; Published online: June 5, 2019 How to cite this article: Golubovic A, Tomovic Lj, Nikolic M, Nikolic S, Anđelkovic M, Arsovski D, Ikovic V, Gvozdenovic S, Popovic M. Distribution of Hermann’s tortoise across Serbia with implications for conservation. Arch Biol Sci. 2019;71(3):509-16.

© 2019 Mediterranean Marine Science. This paper presents an attempt to evaluate physiological response differences (cardiac activity) in the Mediterranean mussel Mytilus galloprovincialis and its use as a biomarker to assess water quality in Boka Kotorska Bay. Mussels were sampled in 2014 from three different sites in Boka Kotorska Bay, which faces various anthropogenic pressures. Both the heart rate recovery time (Trec) and the coefficient of variation in the heart rate (CVHR) were tested, in compliance with the standardized test procedure, using short-term reduction of water salinity as a stress factor to study the adaptive capacity of the tested mussels. The highest values of both Trec and CVHR in Port Bijela, Trec = 77.3 ± 7.2 min; CVHR = 10%, indicated that the water quality at this site was worse when compared to other locations (Stoliv and Dobrota). The values at Port Bijela were significantly higher compared to Stoliv and Dobrota. The lowest values of Trec were found in the mussels from Stoliv (47.3 ± 3.8 min), which implies better water quality compared to the other locations. Although, higher values of Trec were obtained for Dobrota (53.3 ± 4.8 min) compared to Stoliv, the differences were not statistically significant. The applied rapid method of environmental biomonitoring using cardiac activity in mussels could be a useful tool in water quality assessment. Thus, the relevant authorities could timely plan and carry out activities to maintain good ecological status of the marine coastal areas of Montenegro, in order to minimize the effect of emergency situations on both animal and human health in the region, as well as limiting wastewater discharge.

While a substantial proportion of adults infected with SARS-CoV-2 progress to develop severe disease, children rarely manifest respiratory complications. Therefore, understanding differences in the local and systemic response to SARS-CoV-2 infection between children and adults may provide important clues about the pathogenesis of SARS-CoV-2 infection. To address this, we first generated a healthy reference multi-omics single cell data set from children (n=30) in whom we have profiled triple matched samples: nasal and tracheal brushings and PBMCs, where we track the developmental changes for 42 airway and 31 blood cell populations from infancy, through childhood to adolescence. This has revealed the presence of naive B and T lymphocytes in neonates and infants with a unique gene expression signature bearing hallmarks of innate immunity. We then contrast the healthy reference with equivalent data from severe paediatric and adult COVID-19 patients (total n=27), from the same three types of samples: upper and lower airways and blood. We found striking differences: children with COVID-19 as opposed to adults had a higher proportion of innate lymphoid and non-clonally expanded naive T cells in peripheral blood, and a limited interferon-response signature. In the airway epithelium, we found the highest viral load in goblet and ciliated cells and describe a novel inflammatory epithelial cell population. These cells represent a transitional regenerative state between secretory and ciliated cells; they were found in healthy children and were enriched in paediatric and adult COVID-19 patients. Epithelial cells display an antiviral and neutrophil-recruiting gene signature that is weaker in severe paediatricversusadult COVID-19. Our matched blood and airway samples allowed us to study the spatial dynamics of infection. Lastly, we provide a user-friendly interface for this data1as a highly granular reference for the study of immune responses in airways and blood in children.

The National Heart, Lung, and Blood Institute of the National Institutes of Health, together with the Longfonds BREATH consortium, convened a working group to review the field of lung regeneration and suggest avenues for future research. The meeting took place on May 22, 2019, at the American Thoracic Society 2019 conference in Dallas, Texas, United States, and brought together investigators studying lung development, adult stem-cell biology, induced pluripotent stem cells, biomaterials, and respiratory disease. The purpose of the working group was 1) to examine the present status of basic science approaches to tackling lung disease and promoting lung regeneration in patients and 2) to determine priorities for future research in the field.

[Abstract]In late 2019 and through 2020, the COVID-19 pandemic swept the world, presenting both scientific and medical challenges associated with understanding and treating a previously unknown disease. To help address the need for great understanding of COVID-19, the scientific community mobilized and banded together rapidly to characterize SARS-CoV-2 infection, pathogenesis and its distinct disease trajectories. The urgency of COVID-19 provided a pressing use-case for leveraging relatively new tools, technologies, and nascent collaborative networks. Single-cell biology is one such example that has emerged over the last decade as a powerful approach that provides unprecedented resolution to the cellular and molecular underpinnings of biological processes. Early foundational work within the single-cell community, including the Human Cell Atlas, utilized published and unpublished data to characterize the putative target cells of SARS-CoV-2 sampled from diverse organs based on expression of the viral receptor ACE2 and associated entry factors TMPRSS2 and CTSL (Muus et al., 2020; Sungnak et al., 2020; Ziegler et al., 2020). This initial characterization of reference data provided an important foundation for framing infection and pathology in the airway as well as other organs. However, initial community analysis was limited to samples derived from uninfected donors and other previously-sampled disease indications. This report provides an overview of a single-cell data resource derived from samples from COVID-19 patients along with initial observations and guidance on data reuse and exploration.

With the growth dynamics of consumer society, globalization and its influences in architecture are present all over the world. Developmental societies, such as Serbia today, are particularly sensitive, and cities in transition and their architecture are subject to the influence of different global trends. In this paper, new forms of construction that become dominant in the first decades of the 21st century in Serbia and the capital city Belgrade, are investigated. Considering the actuality, frequency and scope of construction, as well as the impact on the overall social development, three characteristic forms of construction have been observed: strategic projects of reconstruction and construction, condominiums and social housing facilities. The characteristics of these forms of construction are investigated by forming a base of 24 cases from different parts of the city. By their classification, according to the particularities of the noticed subgroups, the characteristic examples are analysed and determined based on the defined set of criteria.

The World Heritage List was created as a result of the need to protect and conserve cultural and natural heritage. The Ohrid region is one of only 28 sites on UNESCO’s World Heritage List that are both cultural and natural sites. Ohrid is one of the oldest human settlements in Europe, boasting exquisite medieval religious architecture, as well as urban architecture from the 18th and 19th centuries. The site of Plaošnik is a large archaeological and historic location in Ohrid’s old town that witnessed all cultural eras from prehistory to Ottoman, but most importantly it was the location of the oldest Slavic monastery and the first Slavic University in the Balkans. In 2007, the Ministry of Culture of the Republic of Macedonia prepared a controversial plan of activities for the instauration of St. Clement’s University at Plaošnik. The main interest of this study is the position of cultural heritage in the evolution of a town, and the treatment of heritage in this process, shown through the case of Plaošnik; it focuses on the influence of pressure for (re)development projects on the key elements of an area recognized by the World Heritage List, as well as the influence of the World Heritage List, as an international legal instrument, on the preservation of these features.

This paper presents the results of growth rate and condition index analysis of Mytilus galloprovincialis in integrated system and monoculture. The aim of this study was to show if there are differences in growth and condition index of mussels between integrated multi-trophic aquaculture (IMTA) and monoculture farming. The growth rate and condition index were monitored during a 13-month study at three different sites: 1) close to fish cages (NBL), 2) 100 m removed from fish cages (NUD), 3) at a monoculture mussel farm (SVN) around 8 km far away from cages. The most intense growth of mussels was recorded in spring, and the least intense in summer. After 13 months, monitored individuals at all three locations achieved commercial size. The growth rate was very similar at all sites. The condition index showed spatial and temporal differences. Condition index values on site NUD were mostly higher compared to SVN and NBL, which were very similar, exept for the period from October to December when CI was similar on NBL and NUD site and higher in comparation with SVN. CI values on NBL an NUD site during cold period indicate on fact that mussels probably feed on the nutrients from fish farm origins.The highest mortality rate was recorded at the NBL site, probably due to the effects of fouling organisms., Cilj ovog istraživanja bio je pokazati postojanja mogućih razlika u rastu i kondicijskom indeksu dagnji (Mytilus galloprovincialis) u integralnom multi-trofičkom uzgoju i uzgoju u monokulturi. Rast i kondicijski indeks praćeni su tijekom razdoblja od 13 mjeseci na tri postaje: 1) u blizini uzgajališta ribe (NBL), 2) 100 m od uzgajališta ribe (NUD), 3) u monokulturi (SVN) na uzgajalištu koje je oko 8 km udaljeno od kaveza sa ribom. Najintenzivniji rast zabilježen je tijekom proljetnog razdoblja, a najmanje intenzivan tijekom ljetnog. Nakon 13 mjeseci, praćene jedinke su na sve tri pozicije dostigle komercijalnu dužinu. Stopa rasta je bila slična na sve tri pozicije, dok je kondicijski indeks pokazao prostorne i vremenske razlike. Vrijednosti kondicionog indeksa na postaji NUD bile su više od vrijendosti na postajama SVN i NBL, koje su međusobno bile prilično slične, osim u razdoblju od listopada do prosinca kada su vrijednosti kondicijskog indeksa bile slične na postajama NBL i NUD, a veće u usporedbi sa vrijednostima na postaji SVN poziciji. Vrijednosti kondicionog indeksa na postajama NBL i NUD tijekom hladnog perioda godine ukazuju na to da se dagnje vjerovatno hrane nutrijentima porijeklom sa uzgajališta riba. Visoki mortalitet zabilježen je na postaji NBL, najvjerojatnije zbog obraštajnih organizama.

The aim of this paper is to investigate the potential redevelopment perspectives of the former industrial sites. A qualitative analysis of the post-WWII industrial site in Nis, Serbia, and its modernistic legacy was performed, related to the important issues of urban morphology. The qualities which are remaining behind the ?rusty? industrial landscape were examined in view of the contemporary approach to the concept of the sustainable city. The research findings suggest the existence of need for interventions in the actual morphology of the examined urban space in order to fulfill the contemporary trends of placemaking.

Background and aim of the study The animal models of congenital diaphragmatic hernia (CDH) have contributed to identify several signaling pathways potentially associated to the pathogenesis of lung hypoplasia. However, due to their in vivo nature, these models can only demonstrate the consequence of the malformation and thus are not adequate to evaluate different factors which may have influence on pulmonary hypoplasia separately. In particular, it is still unclear at what extent physical constraint produced by herniated abdominal viscera affects the lung development. We aim at developing a novel ex vivo model harnessing an innovative three-dimensional (3D) printing technique to recapitulate the lung development impaired by physical constraint in CDH. Methods Lungs harvested from E12.5 mouse embryos were embedded in Matrigel solution and maintained in air-liquid interphase (ALI) culture conditions. On the following day (equivalent to E13.5), a 3D structure surrounding the outer surface of the left lobe was built by polymerization of a chemically modified Polyethylene-glycol (PEG) solution, which was added to Matrigel and selectively cross-linked through a two-photon laser. Main results The 3D structure mimics the physical constraint observed in CDH. Live imaging demonstrates decreased growth and delayed branching impeded by 3D structure. After 4 days of culture, the size of the lobe and the number of epithelial branching of the lung surrounded by 3D structure were significantly decreased compared to the control lungs cultured without physical constraint. Conclusions We envision our model as an innovative way to investigate the pathogenesis of pulmonary hypoplasia of CDH. This model has a potential to be applied to human embryo, paving the way for a deeper understanding of the molecular pathways implicated in the mechanism of pulmonary hypoplasia.

The European Respiratory Society (ERS) International Congress is the largest respiratory congress and brings together leading experts in all fields of respiratory medicine and research. ERS Assembly 3 shapes the basic and translational science aspects of this congress, aiming to combine cutting-edge novel developments in basic research with novel clinical findings. In this article, we summarise a selection of the scientific highlights from the perspective of the three groups within Assembly 3. In particular, we discuss new insights into the pathophysiology of the human alveolus, novel tools in organoid development and (epi)genome editing, as well as insights from the presented abstracts on novel therapeutic targets being identified for idiopathic pulmonary fibrosis., The amount of basic and translational science presented at #ERSCongress is steadily increasing, showing novel cutting-edge technologies and models. http://bit.ly/2GgXIJi

Temporal resolution of cellular features associated with a severe COVID-19 disease trajectory is required for understanding skewed immune responses and finding outcome predictors. Here, we performed a longitudinal multi-omics study using a two-centre cohort of 14 patients. We analysed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. Validation was performed in two independent cohorts of COVID-19 patients. Severe COVID-19 was characterized by an increase of proliferating, metabolically hyperactive plasmablasts. Coinciding with critical illness, we also identified an expansion of IFN-activated circulating megakaryocytes and increased erythropoiesis with features of hypoxic signalling. Megakaryocyte- and erythroid cell-derived co-expression modules were predictive of fatal disease outcome. The study demonstrates broad cellular effects of SARS-CoV-2 infection beyond classical immune cells and may serve as an entry point to develop biomarkers and targeted treatments of patients with COVID-19., Graphical Abstract, Highlights • SARS-CoV2 infection elicits dynamic changes of circulating cells in the blood • Severe COVID-19 is characterized by increased metabolically active plasmablasts • Elevation of IFN-activated megakaryocytes and erythroid cells in severe COVID-19 • Cell-type specific expression signatures are associated with a fatal COVID-19 outcome, Bernardes et al. explore COVID-19 disease trajectories by performing longitudinal multi-omics analyses in peripheral blood samples from hospitalized patients. The analyses identify increased numbers of plasmablasts, interferon-activated megakaryocytes and erythroid cells as hallmarks of severe disease, and define molecular signatures linked to a fatal COVID-19 disease outcome.

Summary There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection., Graphical Abstract, Highlights • Meta-analysis of human, non-human primate, and mouse single-cell RNA-seq datasets for putative SARS-CoV-2 targets • Type II pneumocytes, nasal secretory cells, and absorptive enterocytes are ACE2 + TMPRSS2 + • Interferon and influenza increase ACE2 in human nasal epithelia and lung tissue • Mouse Ace2 is not upregulated by interferon, raising implications for disease modeling, Analysis of single-cell RNA-seq datasets from human, non-human primate, and mouse barrier tissues identifies putative cellular targets of SARS-CoV-2 on the basis of ACE2 and TMPRSS2 expression. ACE2 represents a previously unappreciated interferon-stimulated gene in human, but not mouse, epithelial tissues, identifying anti-viral induction of a host tissue-protective mechanism, but also a potential means for viral exploitation of the host response.