Adipose tissue physiology and homeostasis depends on a healthy vascular network. Vascular malfunction is a hallmark of obesity, and vascular endothelial dysfunction, in particular, precipitates metabolic diseases, including obesity and type two diabetes. Although single-cell transcriptomics approaches have defined atlases of human white adipose tissue (WAT) cells, the associated adipose vascular cells remain relatively undefined. Specifically, there is limited information on their heterogeneity and function, and roles in metabolic disease. To address this gap, we created a single-cell transcriptome atlas of human subcutaneous adipose tissue (SAT), comprising nearly 70,000 vascular cells from 65 individuals. We identified eight adipose endothelial cell (AdEC) populations, comprising seven canonical subtypes and a previously undescribed, heterogeneous population we named sub-AdECs. Sub-AdECs exhibit gene signatures characteristic of multiple cell types, including mesenchymal, adipocytic, and immune cells, suggesting they possess diverse properties and identities. Furthermore, we compare the transcriptomes of vascular cells from individuals living with or without obesity and type two diabetes and find metabolic disease-associated inflammatory and fibrotic transcriptomic patterns. The atlas and accompanying analyses establish a solid foundation for future investigations into the biology of vascular cells within WAT and their contributions to metabolic diseases.

The observation that experimental helminth infection can be associated with immunomodulation and suppression of inflammatory diseases at distal tissue sites, has been used as rationale for trialing helminths such as Necator americanus for the treatment of inflammatory disorders in humans. However, the lack of sufficient knowledge of the immunological interplay between human host and parasite in a controlled infection setting limits ongoing clinical intervention studies. In this one-year longitudinal study, healthy volunteers were recruited and infected with N. americanus. Changes in immune responses, microbiome, plasma metabolome and gut physiology were examined over the course of the one-year period. All participants were successfully infected as confirmed by detectable eggs in the feces and adult worms visualized in the intestine. In general, individual variation in immune cells, serum cytokines, fecal microbiome and plasma metabolites were greater than changes induced by the infection. Nevertheless, eosinophils, serum IL-5, and fecal eosinophil degranulation markers transiently increased in the acute phase of infection. In addition, while we observed stability in microbial community composition through the course of infection, we found a difference in the microbial community composition of participants with moderate gastrointestinal symptoms. No significant changes were observed in gut physiology measured using SmartpillTM, except for a decrease in small bowel pH. Untargeted plasma metabolomics analysis of participant plasma over the course of infection revealed enrichment in tryptophan metabolism following infection which was associated with increased CTLA-4 expression on regulatory T cells (TREGS), CRTH2+ T helper 2 cells (TH2) and CCR6+ T helper 9 cells (TH9). In conclusion, hookworm infection is well tolerated and represents an innovative platform for investigating immunomodulatory properties of hookworm infection in a therapeutic clinical setting.

The observation that experimental helminth infection can be associated with immunomodulation and suppression of inflammatory diseases at distal tissue sites, has been used as rationale for trialing helminths such as Necator americanus for the treatment of inflammatory disorders in humans. However, the lack of sufficient knowledge of the immunological interplay between human host and parasite in a controlled infection setting limits ongoing clinical intervention studies. In this one-year longitudinal study, healthy volunteers were recruited and infected with N. americanus . Changes in immune responses, microbiome, plasma metabolome and gut physiology were examined over the course of the one-year period. All participants were successfully infected as confirmed by detectable eggs in the feces and adult worms visualized in the intestine. In general, individual variation in immune cells, serum cytokines, fecal microbiome and plasma metabolites were greater than changes induced by the infection. Nevertheless, eosinophils, serum IL-5, and fecal eosinophil degranulation markers transiently increased in the acute phase of infection. In addition, while we observed stability in microbial community composition through the course of infection, we found a difference in the microbial community composition of participants with moderate gastrointestinal symptoms. No significant changes were observed in gut physiology measured using Smartpill TM , except for a decrease in small bowel pH. Untargeted plasma metabolomics analysis of participant plasma over the course of infection revealed enrichment in tryptophan metabolism following infection which was associated with increased CTLA-4 expression on regulatory T cells (T REGS ), CRTH2 + T helper 2 cells (T H 2) and CCR6 + T helper 9 cells (T H 9). In conclusion, hookworm infection is well tolerated and represents an innovative platform for investigating immunomodulatory properties of hookworm infection in a therapeutic clinical setting. One Sentence Summary Controlled human hookworm infection changes immune-linked metabolic pathways

The increasing incidence of hepatitis C virus (HCV) infections underscores the need for an effective vaccine. Successful vaccines to other viruses generally depend on a long-lasting humoral response. However, data on the half-life of HCV-specific responses are lacking. Here we study archived sera and mononuclear cells that were prospectively collected up to 18 years after cure of chronic HCV infection to determine the role of HCV antigen in maintaining neutralizing antibody and B cell responses. We show that HCV-neutralizing activity decreases rapidly in potency and breadth after curative treatment. In contrast, HCV-specific memory B cells persist, and display a restored resting phenotype, normalized chemokine receptor expression and preserved ability to differentiate into antibody-secreting cells. The short half-life of HCV-neutralizing activity is consistent with a lack of long-lived plasma cells. The persistence of HCV-specific memory B cells and the reduced inflammation after cure provide an opportunity for vaccination to induce protective immunity against re-infection.
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We assessed SARS-CoV-2-specific CD4+ and CD8+ T cell responses in samples from 89 acute COVID-19 patients, utilizing blood samples collected during the first wave of COVID-19 in Italy. The goal of the study was to examine correlations between SARS-CoV-2-specific T cell responses in the early phase comparing mild, moderate, or severe COVID-19 disease outcomes. T cell responses to the spike (S) and non-S proteins were measured in a combined activation-induced marker (AIM) and intracellular cytokine staining (ICS) assay. Early CD4+ T cell responses to SARS-CoV-2 S correlated with milder disease by both AIM and IFNγ ICS readouts. The correlation of S-specific CD4+ T cell responses with milder disease severity was most striking within the first two weeks of symptom onset compared to later time points. Furthermore, donors with milder disease were associated with polyantigenic CD4+ T cell responses that recognized more prominently non-S proteins in addition to S, while severe acute COVID-19 was characterized by lower magnitudes of CD4+ T cell responses and a narrower repertoire. In conclusion, this study highlights that both the magnitude and breadth of early SARS-CoV-2-specific CD4+ T cell responses correlated with milder disease outcomes in acute COVID-19 patients.