Single-cell multi-omics analysis of COVID-19 patients with pre-existing autoimmune diseases shows aberrant immune responses to infection.

In COVID-19, hyperinflammatory and dysregulated immune responses contribute to severity. Patients with pre-existing autoimmune conditions can therefore be at increased risk of severe COVID-19 and/or associated sequelae, yet SARS-CoV-2 infection in this group has been little studied. Here, we performed single-cell analysis of peripheral blood mononuclear cells from patients with three major autoimmune diseases (rheumatoid arthritis, psoriasis, or multiple sclerosis) during SARS-CoV-2 infection. We observed compositional differences between the autoimmune disease groups coupled with altered patterns of gene expression, transcription factor activity, and cell-cell communication that substantially shape the immune response under SARS-CoV-2 infection. While enrichment of HLA-DRlow CD14+ monocytes was observed in all three autoimmune disease groups, type-I interferon signaling as well as inflammatory T cell and monocyte responses varied widely between the three groups of patients. Our results reveal disturbed immune responses to SARS-CoV-2 in patients with pre-existing autoimmunity, highlighting important considerations for disease treatment and follow-up.

An integrated single-cell reference atlas of the human endometrium.

The complex and dynamic cellular composition of the human endometrium remains poorly understood. Previous endometrial single-cell atlases profiled few donors and lacked consensus in defining cell types. We introduce the Human Endometrial Cell Atlas (HECA), a high-resolution single-cell reference atlas (313,527 cells) combining published and new endometrial single-cell transcriptomics datasets of 63 women with and without endometriosis. HECA assigns consensus and identifies previously unreported cell types, mapped in situ using spatial transcriptomics and validated using a new independent single-nuclei dataset (312,246 nuclei, 63 donors). In the functionalis, we identify intricate stromal-epithelial cell coordination via transforming growth factor beta (TGFß) signaling. In the basalis, we define signaling between fibroblasts and an epithelial population expressing progenitor markers. Integration of HECA with large-scale endometriosis genome-wide association study data pinpoints decidualized stromal cells and macrophages as most likely dysregulated in endometriosis. The HECA is a valuable resource for studying endometrial physiology and disorders, and for guiding microphysiological in vitro systems development.

A spatially resolved atlas of the human lung characterizes a gland-associated immune niche.

Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined. To (re)define tissue architecture of lung and airways, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and spatial transcriptomics (queryable at lungcellatlas.org ). Using computational data integration and analysis, we extend beyond the suspension cell paradigm and discover macro and micro-anatomical tissue compartments including previously unannotated cell types in the epithelial, vascular, stromal and nerve bundle micro-environments. We identify and implicate peribronchial fibroblasts in lung disease. Importantly, we discover and validate a survival niche for IgA plasma cells in the airway submucosal glands (SMG). We show that gland epithelial cells recruit B cells and IgA plasma cells, and promote longevity and antibody secretion locally through expression of CCL28, APRIL and IL-6. This new 'gland-associated immune niche' has implications for respiratory health.

Layer formations in the bacteria membrane mimetic DPPE-DPPG/water system induced by sulfadiazine.

The effect of the frequently used antibiotic sulfadiazine (SD) was studied on a bacteria membrane mimetic model system by using differential scanning calorimetric (DSC), small- and wide-angle X-ray scattering (SWAXS) and freeze-fracture methods. The membrane model system consisted of dipalmitoylphosphatidylethanolamine (DPPE, 0.8 molar ratio) and dipalmitoylphosphatidylglycerol (DPPG, 0.2 molar ratio). The SD molar ratio (relative to the lipids) was varied between 10(-3) and 1. In the presence of SD, two transitions between the gel and liquid crystalline phases appear at 60.5 degrees C and about at 65 degrees C. In the temperature domain of the gel phase, the subcell of the chain packing is strongly temperature dependent indicating the increased dominance of the hydration forces during the first transition and the location of SD molecules in the neighbourhood of the polar lipid head groups. The second transition is accompanied by the changes in the nanometer-scale layer arrangements observed by SAXS and in the mum-scale morphology observed by freeze-fracture. Above the temperature of the second transition, the SD-induced metastable structures undergo further formations to produce a more homogeneous state favoured by the geometrical packing of the cylindrical-shaped lipid molecules.

Influence of aminoglycoside antibiotics on the thermal behaviour and structural features of DPPE-DPPG model membranes.

The effects of three aminoglycosides (AGs), tobramycin, streptomycin and spectinomycin on 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE)-1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-1-glycerol] (DPPG)/water systems with 0.05 and 0.2 DPPG/DPPE+DPPG molar fractions were examined by using differential scanning calorimetry (DSC), simultaneous small- and wide-angle X-ray scattering (SWAXS), and freeze-fracture transmission electronmicroscopy (FF-TE) at 10(-1) AG/lipid molar ratio in the doped systems. The effects induced by the AGs strongly depend on DPPG/DPPE+DPPG molar fraction. In the presence of the AGs regular lyotropic structures form as opposed to the complex and badly correlated layer structures of the pure 0.2 DPPG/DPPE+DPPG molar fraction system. The investigated AGs possess different structural and thermotropic effects: tobramycin and streptomycin which are true aminoglycosides decrease the main transition enthalpy in both model systems and induce the formation of correlated layer arrangements, while the occurrence of spectinomycin, a non-aminoglycoside aminocyclitol still ranked as an AG, results in a hexagonal phase as it can be deduced from the SAXS patterns and visually observed in the electronmicrographs.

Structural and morphological changes in bacteria-membrane mimetic DPPE/DPPG/water systems induced by sulfadiazine.

The effects of sulfadiazine (SD), one of the generally used antibiotics was studied on bacteria-membrane mimetic model systems consisting of pure dipalmitoylphosphatidylethanolamine (DPPE) and DPPE/dipalmitoylphosphatidylglycerol (DPPG) at 95/5, 80/20 and 50/50 DPPE/DPPG ratios by using differential scanning calorimetry (DSC), simultaneous small- and wide-angle X-ray scattering (SWAXS) and freeze-fracture technique. In the presence of SD, varied between 10-3 and 1 SD/lipid molar ratios, the 95/5 DPPE/DPPG system shows tendentious destruction in the layer arrangement which is accompanied by minor perturbations in the thermotropic behaviour. Moreover, at this lipid composition the addition of SD results in the formation of stacks of extremely extended flat bilayers. Systems having a higher DPPG molar ratio exhibit complex and diffuse morphologies. At 50/50 DPPE/DPPG ratio DPPG and SD act together and form large spherical vesicles. The uniform morphology is not accompanied by a regular lamellar arrangement. The range of the SD/lipid ratio, where the SD molecules are embedded into the lipid bilayers, extends to about 10-1. Over this limit the separation of SD molecules can be observed at all investigated DPPE/DPPG ratios.

Structural and calorimetrical studies of the effect of different aminoglycosides on DPPC liposomes.

The effects of tobramycin, spectinomycin and streptomycin on 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/water vesicle system were studied by using differential scanning calorimetry (DSC) and simultaneous small- and wide-angle X-ray scattering (SWAXS) in the 0-1 lipid/aminoglycoside molar range. The changes in enthalpy between the thermally adjacent phases are decreased, but the pace of decrease is totally different for the three investigated AGs. The alterations in the lamellar arrangement and the chain packing are rather tendentious and are extended by increased AG concentrations depending on the type of the AG. In the case of tobramycin and streptomycin, still sharp Bragg peaks of SAXS curves shift to smaller values of the scattering variable, while spectinomycin results in an entire loss of multilayer correlation representing an increased amount of unbound bilayers.