Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, and it remains unclear whether T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and single-cell proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune-complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Increased generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. Proportions of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a were associated with fatal outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.

Adipose tissue, colloquially known as "fat," is an extraordinarily flexible and heterogeneous organ. While historically viewed as a passive site for energy storage, we now appreciate that adipose tissue regulates many aspects of whole-body physiology, including food intake, maintenance of energy levels, insulin sensitivity, body temperature, and immune responses. A crucial property of adipose tissue is its high degree of plasticity. Physiologic stimuli induce dramatic alterations in adipose-tissue metabolism, structure, and phenotype to meet the needs of the organism. Limitations to this plasticity cause diminished or aberrant responses to physiologic cues and drive the progression of cardiometabolic disease along with other pathological consequences of obesity.

Comment in Cancer Cell. 2022 Feb 14;40(2):134-135.

Author information: (1)Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (2)Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK. (3)Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK; Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. (4)Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel. (5)Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. (6)Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, UK. (7)Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (8)Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Peter Medawar Building for Pathogen Research, Oxford, UK; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. (9)Peter Medawar Building for Pathogen Research, Oxford, UK. (10)Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Peter Medawar Building for Pathogen Research, Oxford, UK; Translational Gastroenterology Unit, University of Oxford, Oxford, UK. (11)Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (12)NIHR Oxford Biomedical Research Centre, Oxford, UK; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. (13)Department of Infectious Diseases and HIV Medicine, University Hospitals of Leicester NHS Trust, Leicester, UK; Department of Respiratory Sciences, University of Leicester, Leicester, UK. (14)Department of Infectious Diseases and HIV Medicine, University Hospitals of Leicester NHS Trust, Leicester, UK. (15)Medical Sciences Division, University of Oxford, Oxford, UK. (16)Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (17)Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. (18)Institute of Global Health, University of Siena, Siena, Brazil; Department of Paediatrics, University of Oxford, Oxford, UK. (19)Laboratório de Ecologia de Doenças Transmissíveis na Amazônia, Instituto Leônidas e Maria Deane, Fiocruz, Manaus, Amazonas, Brazil. (20)Fundação de Vigilância em Saúde do Amazonas, Manaus, Amazonas, Brazil. (21)Laboratorio de vírus respiratórios-IOC/FIOCRUZ, Rio de Janeiro, Brazil. (22)Laboratorio de vírus respiratórios-IOC/FIOCRUZ, Rio de Janeiro, Brazil; Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA. (23)South African Medical Research Council, Vaccines and Infectious Diseases Analytics Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Department of Science and Technology, National Research Foundation, South African Research Chair Initiative in Vaccine Preventable Diseases, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. (24)National Infection Service, Public Health England (PHE), Porton Down, Salisbury, UK. (25)National Heart & Lung Institute, Imperial College, London, UK. (26)Genetics and Genomics, Roslin Institute, University of Edinburgh, Edinburgh, UK. (27)NIHR Health Protection Research Unit, Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK. (28)Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. (29)Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital and Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan. (30)MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. (31)Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; National Infection Service, Public Health England (PHE), Porton Down, Salisbury, UK. (32)Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Peter Medawar Building for Pathogen Research, Oxford, UK; Translational Gastroenterology Unit, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK. (33)Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Peter Medawar Building for Pathogen Research, Oxford, UK; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand; Nuffield Department of Medicine, University of Oxford, Oxford, UK. (34)Nuffield Department of Medicine, University of Oxford, Oxford, UK. (35)Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. (36)Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; Siriraj Center of Research Excellence in Dengue & Emerging Pathogens, Dean Office for Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Electronic address: jmongkol@well.ox.ac.uk. (37)Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK. Electronic address: ren@strubi.ox.ac.uk. (38)Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel. Electronic address: gideon.schreiber@weizmann.ac.il. (39)Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK; Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, UK; Instruct-ERIC, Oxford House, Parkway Court, John Smith Drive, Oxford, UK. Electronic address: dave@strubi.ox.ac.uk. (40)Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. Electronic address: gavin.screaton@medsci.ox.ac.uk.

Comment in Nat Rev Immunol. 2022 Feb;22(2):75. Cell. 2022 Feb 3;185(3):411-413. Cell. 2022 Feb 3;185(3):414-416.

Comment in Cell. 2022 Feb 3;185(3):416-418.

The human gut microbiota resides within a diverse chemical environment challenging our ability to understand the forces shaping this ecosystem. Here, we reveal that fitness of the Bacteroidales, the dominant order of bacteria in the human gut, is an emergent property of glycans and one specific metabolite, butyrate. Distinct sugars serve as strain-variable fitness switches activating context-dependent inhibitory functions of butyrate. Differential fitness effects of butyrate within the Bacteroides are mediated by species-level variation in Acyl-CoA thioesterase activity and nucleotide polymorphisms regulating an Acyl-CoA transferase. Using in vivo multi-omic profiles, we demonstrate Bacteroides fitness in the human gut is associated together, but not independently, with Acyl-CoA transferase expression and butyrate. Our data reveal that each strain of the Bacteroides exists within a unique fitness landscape based on the interaction of chemical components unpredictable by the effect of each part alone mediated by flexibility in the core genome.

Comment on Cell. 2022 Feb 3;185(3):457-466.e4. Cell. 2022 Feb 3;185(3):447-456.e11. Cell. 2022 Feb 3;185(3):467-484.e15.

Update of medRxiv. 2021 Oct 20;:

Comment on Cell. 2022 Feb 3;185(3):547-562.e22.

Comment on Cell. 2022 Feb 3;185(3):457-466.e4. Cell. 2022 Feb 3;185(3):447-456.e11. Cell. 2022 Feb 3;185(3):467-484.e15.

The lack of racial diversity among the winners of United States biomedical research prizes reflects a chronic problem of the underappreciation of certain groups of biomedical scientists. Asians continue to be severely underrepresented as awardees of United States biomedical research prizes, a trend that shows no obvious recent improvement.

Comment in Nat Rev Immunol. 2022 Feb;22(2):75. Cell. 2022 Feb 3;185(3):411-413. Cell. 2022 Feb 3;185(3):414-416. Signal Transduct Target Ther. 2022 Apr 27;7(1):140.

Comment in Curr Biol. 2022 Mar 14;32(5):R215-R218.

Comment in Nat Rev Immunol. 2022 Mar;22(3):144-145. Trends Immunol. 2022 Apr;43(4):277-279.

Author information: (1)Department of Emergency Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address: pmudd@wustl.edu. (2)Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (3)Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA. (4)Division of Allergy and Immunology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA. (5)Infection and Immunity Program & Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. (6)Clinical Trials Unit, Washington University School of Medicine, Saint Louis, MO 63110, USA. (7)Department of Microbiology and Immunology, University of Melbourne, at Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3052, Australia. (8)Institute of Clinical Molecular Biology, Christian-Albrecht University of Kiel, Kiel 24105, Germany. (9)David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA. (10)Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, USA. (11)Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (12)Division of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA. (13)Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, Saint Louis, MO 63110, USA; Clinical Trials Unit, Washington University School of Medicine, Saint Louis, MO 63110, USA; Division of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO 63110, USA. (14)Infection and Immunity Program & Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK. (15)Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: paul.thomas@stjude.org. (16)Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address: ellebedy@wustl.edu.

Comment in Neuron. 2022 Apr 6;110(7):1097-1099.

Single-cell (sc)RNA-seq, together with RNA velocity and metabolic labeling, reveals cellular states and transitions at unprecedented resolution. Fully exploiting these data, however, requires kinetic models capable of unveiling governing regulatory functions. Here, we introduce an analytical framework dynamo (https://github.com/aristoteleo/dynamo-release), which infers absolute RNA velocity, reconstructs continuous vector fields that predict cell fates, employs differential geometry to extract underlying regulations, and ultimately predicts optimal reprogramming paths and perturbation outcomes. We highlight dynamo's power to overcome fundamental limitations of conventional splicing-based RNA velocity analyses to enable accurate velocity estimations on a metabolically labeled human hematopoiesis scRNA-seq dataset. Furthermore, differential geometry analyses reveal mechanisms driving early megakaryocyte appearance and elucidate asymmetrical regulation within the PU.1-GATA1 circuit. Leveraging the least-action-path method, dynamo accurately predicts drivers of numerous hematopoietic transitions. Finally, in silico perturbations predict cell-fate diversions induced by gene perturbations. Dynamo, thus, represents an important step in advancing quantitative and predictive theories of cell-state transitions.

Comment in Trends Neurosci. 2022 May;45(5):339-341.

The coronavirus disease 2019 (COVID-19) pandemic continues worldwide with many variants arising, some of which are variants of concern (VOCs). A recent VOC, omicron (B.1.1.529), which obtains a large number of mutations in the receptor-binding domain (RBD) of the spike protein, has risen to intense scientific and public attention. Here, we studied the binding properties between the human receptor ACE2 (hACE2) and the VOC RBDs and resolved the crystal and cryoelectron microscopy structures of the omicron RBD-hACE2 complex as well as the crystal structure of the delta RBD-hACE2 complex. We found that, unlike alpha, beta, and gamma, omicron RBD binds to hACE2 at a similar affinity to that of the prototype RBD, which might be due to compensation of multiple mutations for both immune escape and transmissibility. The complex structures of omicron RBD-hACE2 and delta RBD-hACE2 reveal the structural basis of how RBD-specific mutations bind to hACE2.

Sex hormones exert a profound influence on gendered behaviors. How individual sex hormone-responsive neuronal populations regulate diverse sex-typical behaviors is unclear. We performed orthogonal, genetically targeted sequencing of four estrogen receptor 1-expressing (Esr1+) populations and identified 1,415 genes expressed differentially between sexes or estrous states. Unique subsets of these genes were distributed across all 137 transcriptomically defined Esr1+ cell types, including estrous stage-specific ones, that comprise the four populations. We used differentially expressed genes labeling single Esr1+ cell types as entry points to functionally characterize two such cell types, BNSTprTac1/Esr1 and VMHvlCckar/Esr1. We observed that these two cell types, but not the other Esr1+ cell types in these populations, are essential for sex recognition in males and mating in females, respectively. Furthermore, VMHvlCckar/Esr1 cell type projections are distinct from those of other VMHvlEsr1 cell types. Together, projection and functional specialization of dimorphic cell types enables sex hormone-responsive populations to regulate diverse social behaviors.

Comment in Cell. 2022 Feb 17;185(4):579-581.

Comment in Nat Methods. 2022 Mar;19(3):269.

HIV-1 Env mediates viral entry into host cells and is the sole target for neutralizing antibodies. However, Env structure and organization in its native virion context has eluded detailed characterization. Here, we used cryo-electron tomography to analyze Env in mature and immature HIV-1 particles. Immature particles showed distinct Env positioning relative to the underlying Gag lattice, providing insights into long-standing questions about Env incorporation. A 9.1-Å sub-tomogram-averaged reconstruction of virion-bound Env in conjunction with structural mass spectrometry revealed unexpected features, including a variable central core of the gp41 subunit, heterogeneous glycosylation between protomers, and a flexible stalk that allows Env tilting and variable exposure of neutralizing epitopes. Together, our results provide an integrative understanding of HIV assembly and structural variation in Env antigen presentation.

Comment on Nature. 2022 Jan;601(7894):600-605.

Comment on Cell. 2022 Feb 17;185(4):614-629.e21.