Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-κB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity–associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.
Allergen immunotherapy can desensitize even subjects with potentially lethal allergies, but the changes induced in T cells that underpin successful immunotherapy remain poorly understood. In a cohort of peanut-allergic participants, we used allergen-specific T-cell sorting and single-cell gene expression to trace the transcriptional "roadmap" of individual CD4+ T cells throughout immunotherapy. We found that successful immunotherapy induces allergen-specific CD4+ T cells to expand and shift toward an "anergic" Th2 T-cell phenotype largely absent in both pretreatment participants and healthy controls. These findings show that sustained success, even after immunotherapy is withdrawn, is associated with the induction, expansion, and maintenance of immunotherapy-specific memory and naive T-cell phenotypes as early as 3 mo into immunotherapy. These results suggest an approach for immune monitoring participants undergoing immunotherapy to predict the success of future treatment and could have implications for immunotherapy targets in other diseases like cancer, autoimmune disease, and transplantation.is a process in which small amounts of allergen are given over time to the allergic individual until they can safely tolerate high amounts of allergen with no signs of clinical symptoms (1-9). In the regimen of oral IT for peanut-allergic patients (identified by an allergic reaction during a standardized blinded food challenge to peanut), small amounts of peanut flour protein are ingested and escalated to a servings-worth of peanut protein (4 g of peanut protein) over a period of 2-3 y (6-7). Most patients require continuous frequent (e.g., daily) exposure to such therapy for beneficial clinical outcomes. Mechanistic studies of oral IT to food allergens, although limited to date, show that plasma markers such as IgE and IgG4 immunoglobulins, skin test markers, component testing, and basophil activation tests are only weakly predictive of long-term clinical success (10-16). T cells are critical upstream regulators of allergic sensitization that are required to help B cells to synthesize IgE/IgG4 immunoglobulins, which then can activate or inhibit basophils and mast cells (10-17). Moreover, successful IT is associated with the development of regulatory T cells (Tregs) that are thought to dampen allergic reactivity to offending allergens (7). We therefore focused on finding T-cell markers of immune tolerance that could be detected early in the peripheral blood during IT. CD4+ T cells can be relatively long-lived (compared with plasma proteins and basophils) and changes detected early in populations of T cells could perhaps predict longer-lasting successful IT. For example, in one of the first studies in peanut allergen IT to withdraw therapy for more than 10 wk, we previously showed that despite negative skin tests to peanut, and high IgG4/low specific IgE levels to peanut, and decreased basophil reactivity to the allergen, some patients who withdrew from therapy for 3-6 mo were still reactive upon rechallenge with peanut (7...
Bronchopulmonary dysplasia (BPD), a chronic lung disease of infancy, is characterized by arrested alveolar development. Pulmonary angiogenesis, mediated by the vascular endothelial growth factor (VEGF) pathway, is essential for alveolarization. However, the transcriptional regulators mediating pulmonary angiogenesis remain unknown. We previously demonstrated that NF-κB, a transcription factor traditionally associated with inflammation, plays a unique protective role in the neonatal lung. Therefore, we hypothesized that constitutive NF-κB activity is essential for postnatal lung development. Blocking NF-κB activity in 6-day-old neonatal mice induced the alveolar simplification similar to that observed in BPD and significantly reduced pulmonary capillary density. Studies to determine the mechanism responsible for this effect identified greater constitutive NF-κB in neonatal lung and in primary pulmonary endothelial cells (PEC) compared with adult. Moreover, inhibiting constitutive NF-κB activity in the neonatal PEC with either pharmacological inhibitors or RNA interference blocked PEC survival, decreased proliferation, and impaired in vitro angiogenesis. Finally, by chromatin immunoprecipitation, NF-κB was found to be a direct regulator of the angiogenic mediator, VEGF-receptor-2, in the neonatal pulmonary vasculature. Taken together, our data identify an entirely novel role for NF-κB in promoting physiological angiogenesis and alveolarization in the developing lung. Our data suggest that disruption of NF-κB signaling may contribute to the pathogenesis of BPD and that enhancement of NF-κB may represent a viable therapeutic strategy to promote lung growth and regeneration in pulmonary diseases marked by impaired angiogenesis.
Greer, and Boehringer Ingelheim and is a scientific advisory board member for Alladapt Immunotherapeutics. ML is currently an employee at AnaptysBio. DP was an investigator for the study and received funds from AnaptysBio.
IgE-mediated peanut allergic is common, often serious, and usually lifelong. Not all individuals who produce peanut-specific IgE will react upon consumption of peanut and can eat the food without adverse reactions, known as sensitized tolerance. Here, we employ high-dimensional mass cytometry to define the circulating immune cell signatures associated with sensitized tolerance and clinical allergy to peanut in the first year of life. Key features of clinical peanut allergic are increased frequency of activated B cells (CD19 hi HLADR hi), overproduction of TNFα and increased frequency of peanut-specific memory CD4 T cells. Infants with sensitized tolerance display reduced frequency but hyper-responsive naive CD4 T cells and an increased frequency of plasmacytoid dendritic cells. This work demonstrates the utility and power of high-dimensional mass cytometry analysis to interrogate the cellular interactions that are associated with allergic sensitization and clinical food allergy in the first year of life.
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