Systemic infections, especially in patients with chronic diseases, may result in sepsis: an explosive, uncoordinated immune response that can lead to multisystem organ failure with a high mortality rate. Patients with similar clinical phenotypes or sepsis biomarker expression upon diagnosis may have different outcomes, suggesting that the dynamics of sepsis is critical in disease progression. A within‐subject study of patients with Gram‐negative bacterial sepsis with surviving and fatal outcomes was designed and single‐cell transcriptomic analyses of peripheral blood mononuclear cells (PBMC) collected during the critical period between sepsis diagnosis and 6 h were performed. The single‐cell observations in the study are consistent with trends from public datasets but also identify dynamic effects in individual cell subsets that change within hours. It is shown that platelet and erythroid precursor responses are drivers of fatal sepsis, with transcriptional signatures that are shared with severe COVID‐19 disease. It is also shown that hypoxic stress is a driving factor in immune and metabolic dysfunction of monocytes and erythroid precursors. Last, the data support CD52 as a prognostic biomarker and therapeutic target for sepsis as its expression dynamically increases in lymphocytes and correlates with improved sepsis outcomes. In conclusion, this study describes the first single‐cell study that analyzed short‐term temporal changes in the immune cell populations and their characteristics in surviving or fatal sepsis. Tracking temporal expression changes in specific cell types could lead to more accurate predictions of sepsis outcomes and identify molecular biomarkers and pathways that could be therapeutically controlled to improve the sepsis trajectory toward better outcomes.

Obesity incidence is increasing worldwide with the urgent need to identify new therapeutics. Sex differences in immune cell activation drive obesity-mediated pathologies where males are more susceptible to obesity co-morbidities and exacerbated inflammation. Here, we demonstrate that the macrophage-secreted protein RELMα critically protects females against high fat diet-induced obesity. Compared to male mice, RELMα levels were elevated in both control and high fat dietfed females and correlated with adipose macrophages and eosinophils. RELMα-deficient females gained more weight and had pro-inflammatory macrophage accumulation and eosinophil loss, while both RELMα treatment and eosinophil transfer rescued this phenotype. Single cell RNAsequencing of the adipose stromal vascular fraction was performed and identified sex and RELMα-dependent changes. Genes involved in oxygen sensing and iron homeostasis, including hemoglobin and lncRNA Gm47283, correlated with increased obesity, while eosinophil chemotaxis and response to amyloid-beta were protective. Monocyte-to-macrophage transition was also dysregulated in RELMα-deficient animals. Collectively, these studies implicate a RELMα-macrophage-eosinophil axis in sex-specific protection against obesity and uncover new therapeutic targets for obesity.

Background Sepsis mortality has remained unchanged for greater than a decade, and early recognition continues to be the most important factor in mortality outcome. Plasma resistin concentration is increased in sepsis, but its mechanism and clinical relevance is unclear. As one function, resistin interacts with toll-like receptor 4 in competition with lipopolysaccharide, a main component of the gram-negative bacterial cell wall. It is not known if the type of infection leading to sepsis influences resistin production. The objective of this study was to investigate whether 1) early plasma resistin concentration can predict mortality, 2) elevated plasma resistin concentration is associated with clinical disease severity scores, such as SOFA, mSOFA and APACHE II, and 3) plasma resistin concentrations differ between gram negative versus other etiologies of sepsis. Methods This was an exploratory study in the framework of a prospective observational design. Peripheral venous blood samples were obtained from subjects admitted to the intensive care unit at clinical recognition of sepsis (0 hour) and at 6 and 24 hours. Vasopressor utilization was not a requirement for inclusion. Plasma was analyzed for resistin concentration by ELISA. Cytokine concentrations including IL-6, IL-8, and IL-10 were determined by cytokine bead array. Cytokine data were evaluated against publicly available sepsis RNA expression datasets to compare protein versus RNA expression levels in predicting clinical disease state. Clinical data were collected from electronic health records for clinical severity index calculations and context for interpretation of resistin and cytokine concentrations. Subjects were followed up to 60 days, or until death, whichever came first. Statistical analysis was completed with R package and SPSS software. Results Resistin levels were elevated in subjects admitted to the intensive care unit with sepsis. Four-hundred subjects were screened with 45 subjects included in the final analysis. Thirteen of 45 patients were non-survivors. Mortality within 60 days correlated with significantly higher resistin concentrations than in survivors. A resistin concentration of >126 ng/mL at clinical recognition of sepsis and >197 ng/mL within the first 24 hours were associated with mortality within 60 days with an area under the curve of 0.82 and 0.88, respectively. Most subjects with resistin concentration greater than these threshold values were deceased prior to 30 days. Resistin concentrations correlated with SOFA, mSOFA, and APACHE II scores in addition to having association with increases in inflammatory and sepsis biomarkers. These associations were validated with analysis of RNA expression datasets. Conclusion Plasma resistin concentrations of >126 ng/mL at clinical recognition of sepsis and >197 ng/mL within the first 24 hours of clinical sepsis recognition are associated with all-cause mortality. Resistin concentration wi...

Tobacco smoke is a known carcinogen, mostly due to its genotoxicity, but its effects on the host immune system are also playing an important role. Here, we leveraged recent results on the immune landscape of cancer based on The Cancer Genomic Atlas (TCGA) data analysis and compared the proportions of major classes of tumor-infiltrating immune cells (TIICs) between smokers and never smokers in ten TCGA cancer types. We show that statistically significant changes can be identified in all ten cancers, with increased plasma cell populations and the modified ratio of activated to resting TIICs being the most consistent features distinguishing smokers and never-smokers across different cancers, with both being correlated with survival outcomes. Analysis of existing single-cell RNA-seq data further showed that smoking differentially affects the gene expression profile of cancer patients based on the immune cell type. The smoking-induced changes in the patterns of immune cells and their correlations to survival outcomes are stronger in female smokers. LUSC HNSC LUAD KIRC KIRP KICH 10 TCGA cancer types 7 tissues 2724 cases ESCA PAAD CESC BLCA 61% 39% 63% 37% 48% 24% 28%

Obesity incidence is increasing worldwide with the urgent need to identify new therapeutics. Sex differences in immune cell activation drive obesity-mediated pathologies where males are more susceptible to obesity comorbidities and exacerbated inflammation. Here, we demonstrate that the macrophage-secreted protein RELMα critically protects females against high-fat diet (HFD)-induced obesity. Compared to male mice, serum RELMα levels were higher in both control and HFD-fed females and correlated with frequency of adipose macrophages and eosinophils. RELMα-deficient females gained more weight and had proinflammatory macrophage accumulation and eosinophil loss in the adipose stromal vascular fraction (SVF), while RELMα treatment or eosinophil transfer rescued this phenotype. Single-cell RNA-sequencing of the adipose SVF was performed and identified sex and RELMα-dependent changes. Genes involved in oxygen sensing and iron homeostasis, including hemoglobin and lncRNA Gm47283/Gm21887, correlated with increased obesity, while eosinophil chemotaxis and response to amyloid-beta were protective. Monocyte-to-macrophage transition was also dysregulated in RELMα-deficient animals. Collectively, these studies implicate a RELMα–macrophage–eosinophil axis in sex-specific protection against obesity and uncover new therapeutic targets for obesity.

Background Disparities in COVID-19 disease outcomes exist in Hispanic individuals, especially those with pre-existing health conditions. Infected individuals can develop “long COVID” with sustained impacts on overall quality of life. The goal of this study was to investigate the impact of COVID-19 infection and long COVID in Hispanic individuals and identify immune and endothelial factors that are associated with COVID-19 outcomes.Methods 112 participants in Riverside County, California, were recruited and categorized according to the following criteria: healthy control (n = 23), moderate infection (outpatient, n = 33), and severe infection (hospitalized, n = 33). Differences in outcomes between Hispanic and non-Hispanic individuals and presence/absence of comorbidities were evaluated. Circulating immune and vascular biomarkers and immune cell subsets were measured by ELISA, multiplex analyte assays, and flow cytometry. Follow-up assessments for long COVID, lung health, and immune and vascular changes were conducted (n = 23) including paired analyses of the same participants.Results Compared to uninfected controls, the severe infection group had a higher proportion of Hispanic individuals (n = 23, p = 0.012), but there was no difference between uninfected controls and those with moderate infection (n = 8, p = 0.550). Disease severity was associated with changes in innate monocytes and neutrophils and lymphopenia, disrupted cytokine production (increased IL-8 and IP-10/CXCL10 but reduced IFNλ2/3 and IFNγ), and increased endothelial injury (myoglobin, VCAM-1). In the severe infection group, integration of parameters through machine learning identified NGAL/LCN2, IL-6, and monocyte activation as parameters associated with fatality, whereas anti-coagulant therapy was linked to survival. Recovery from moderate COVID infection resulted in long-term immune changes including increased monocytes/lymphocytes and decreased neutrophils and endothelial markers. This group had a lower proportion of comorbidities (n = 8, p = 1.0) but still reported symptoms associated with long COVID despite recovered lung health.Conclusion This study indicates increased severity of COVID-19 infections in Hispanic individuals of Riverside County, California. Infection resulted in immunological and vascular changes and long COVID symptoms that were sustained for up to 11 months, however, lung function (volume and airflow resistance) was recovered. Given the behavioral and immune impacts of long COVID, the potential for increased susceptibility to infections and decreased quality of life, especially in high-risk populations, warrants further investigation.

Systemic infections, especially in patients with chronic diseases, may result in sepsis: an explosive immune response that can lead to multisystem organ failure with a high mortality rate. Patients with similar clinical phenotypes or sepsis biomarker expression upon diagnosis may have different outcomes, suggesting that the dynamics of sepsis is critical in disease progression. A within-subject study of patients with Gram-negative bacterial sepsis with surviving and fatal outcomes was designed and single-cell transcriptomic analyses of peripheral blood mononuclear cells (PBMC) collected during the critical period between sepsis diagnosis and 6 h were performed. The single-cell observations in the study are consistent with trends from public datasets but also identify dynamic effects in individual cell subsets that change within hours. It is shown that platelet and erythroid precursor responses are drivers of fatal sepsis, with transcriptional signatures that are shared with severe COVID-19 disease. It is also shown that hypoxic stress is a driving factor in immune and metabolic dysfunction of monocytes and erythroid precursors. Last, the data support CD52 as a prognostic biomarker and therapeutic target for sepsis as its expression dynamically increases in lymphocytes and correlates with improved sepsis outcomes. In conclusion, this study describes the first single-cell study that analyzed short-term temporal changes in the immune cell populations and their characteristics in surviving or fatal sepsis. Tracking temporal expression changes in specific cell types could lead to more accurate predictions of sepsis outcomes and identify molecular biomarkers and pathways that could be therapeutically controlled. This research was supported by the UCR School of Medicine (to A.G. and M.G.N.), the Dean Innovation Fund (to J.B. and M.G.N.), and the National Institutes of Health (NIAID, R21AI37830, and R01AI153195 to M.G.N.). The data from this study were generated at the UC San Diego IGM Genomics Center utilizing an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929).

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