The coronavirus disease 2019 (COVID-19) pandemic poses a current world-wide public health threat. However, little is known about its hallmarks compared to other infectious diseases. Here, we report ...the single-cell transcriptional landscape of longitudinally collected peripheral blood mononuclear cells (PBMCs) in both COVID-19- and influenza A virus (IAV)-infected patients. We observed increase of plasma cells in both COVID-19 and IAV patients and XIAP associated factor 1 (XAF1)-, tumor necrosis factor (TNF)-, and FAS-induced T cell apoptosis in COVID-19 patients. Further analyses revealed distinct signaling pathways activated in COVID-19 (STAT1 and IRF3) versus IAV (STAT3 and NFκB) patients and substantial differences in the expression of key factors. These factors include relatively increase of interleukin (IL)6R and IL6ST expression in COVID-19 patients but similarly increased IL-6 concentrations compared to IAV patients, supporting the clinical observations of increased proinflammatory cytokines in COVID-19 patients. Thus, we provide the landscape of PBMCs and unveil distinct immune response pathways in COVID-19 and IAV patients.
Display omitted
•We generated a single-cell atlas of PBMCs in both COVID-19 and influenza patients•Plasma cells increase significantly in both COVID-19 and influenza patients•COVID-19 is featured with XAF1-, TNF-, and FAS-induced T cell apoptosis•COVID-19 activates distinct pathway (STAT1/IRF3) versus influenza (STAT3/NFκB)
COVID-19 and influenza are both respiratory infections with cytokine release syndrome. Zhu et al. use single-cell RNA sequencing of longitudinally collected PBMCs in both patients to reveal distinct immune response landscapes of the two diseases and identify virus-specific cell composition and immune response pathways.
SARS-CoV-2 is the cause of the current global pandemic of COVID-19; this virus infects multiple organs, such as the lungs and gastrointestinal tract. The microbiome in these organs, including the ...bacteriome and virome, responds to infection and might also influence disease progression and treatment outcome. In a cohort of 13 COVID-19 patients in Beijing, China, we observed that the gut virome and bacteriome in the COVID-19 patients were notably different from those of five healthy controls. We identified a bacterial dysbiosis signature by observing reduced diversity and viral shifts in patients, and among the patients, the bacterial/viral compositions were different between patients of different severities, although these differences are not entirely distinguishable from the effect of antibiotics. Severe cases of COVID-19 exhibited a greater abundance of opportunistic pathogens but were depleted for butyrate-producing groups of bacteria compared with mild to moderate cases. We replicated our findings in a mouse COVID-19 model, confirmed virome differences and bacteriome dysbiosis due to SARS-CoV-2 infection, and observed that immune/infection-related genes were differentially expressed in gut epithelial cells during infection, possibly explaining the virome and bacteriome dynamics. Our results suggest that the components of the microbiome, including the bacteriome and virome, are affected by SARS-CoV-2 infections, while their compositional signatures could reflect or even contribute to disease severity and recovery processes.
Hepatocellular carcinoma (HCC), a primary liver cancer, is closely associated with the gut microbiota. However, the role of gut fungi in the development of HCC remains unclear. The aim of this study ...was to explore the influence of intestinal
on HCC. Here, We found that patients with HCC showed significantly decreased diversity of the gut mycobiome and increased abundance of
, compared to the patients with liver cirrhosis. The gavage of
in the WT models increased the tumor size and weight and influenced the plasma metabolome, which was indicated by alterations in 117 metabolites, such as L-carnitine and L-acetylcarnitine, and several KEGG enriched pathways, such as phenylalanine metabolism and citrate cycle. Moreover, the expression of nucleotide oligomerization domain-like receptor family pyrin domain containing 6 (NLRP6) in the intestinal tissues and primary intestinal epithelial cells of the WT mice interacted with
increased. Notably, the colonization of
had no effect on tumor growth in
mice. In conclusion, the abnormal colonization of
reprogrammed HCC metabolism and contributed to the progression of HCC dependent on NLRP6, which provided new targets for the treatment of HCC.
Aiming at the problem of device-to-device (D2D) communication mode selection and resource optimization under the joint resource allocation mode in the 5G communication network, a probabilistic ...integrated resource allocation strategy and a quasi-convex optimization algorithm based on channel probability statistical characteristics are proposed. This strategy and algorithm guarantee D2D. Communication maximizes total system throughput while maximizing access. The analysis results show that this algorithm can significantly optimize the total throughput of the system and reduce the communication interference between the users, which proves the rationality and efficiency of the communication model. The research results obtained in Muwen can provide a theoretical basis for analyzing more complex D2D communication systems and provide a numerical basis for designing heuristic algorithms.
Oncolytic virotherapy belongs to a kind of active immunotherapy, which could trigger a potent antitumor immune response, showing great potential in clinical application. OVs could induce immune ...responses through the dual mechanisms of selective tumor killing without destroying normal tissues and induction of systemic antitumor immunity. In this study, we successfully rescued a chimeric oncolytic influenza virus carrying a human CTLA4 antibody in the background of the A/PR/8/34 (PR8) virus. The chimeric virus, called rFlu-huCTLA4, contained the heavy and light chains of the human CTLA4 antibody in the PB1 and PA segments of the PR8 virus, respectively. The first-generation hemagglutination (HA) titers of the rFlu-huCTLA4 virus ranged from 2
to 2
, which could be passaged stably in specific pathogen-free (SPF) chicken embryos from P1 to P5. The morphology and size distribution of the chimeric virus were consistent with those of the
influenza virus. The rFlu-huCTLA4 virus could effectively replicate in various cells in time- and dose-dependent manners. ELISA assay revealed that the secreted huCTLA4 antibody levels in chicken embryos increased gradually over time. Furthermore, MTS and crystal violet analysis showed that the selective cytotoxicity of the virus was higher in hepatocellular carcinoma cells (HepG2 and Huh7) than in normal liver cells (MIHA).
experiments displayed that intratumoral injection with rFlu-huCTLA4 reduced tumor growth and increased the survival of mice compared with the PR8 group. More importantly, in the rFlu-huCTLA4 group, we found that CD4+ and CD8 +T cells were significantly increased in tumor-bearing BALB/c mice. Taken together, these findings demonstrated that the chimeric oncolytic virus rFlu-huCTLA4 could selectively destroy hepatocellular carcinoma cells
and
and may provide a promising clinical strategy for targeted immunotherapy of HCC with the oncolytic flu virus.
CD11c
CD8
T cells are an unconventional CD8
T cell subset that exerts antiviral activity in infectious diseases. However, its characteristics in hepatocellular carcinoma (HCC) have not been ...elucidated.
Twenty-six patients with hepatitis B virus (HBV)-related HCC and 25 healthy controls (HC) were enrolled. The frequency and phenotype of CD11c
CD8
T cells in peripheral blood and tumors in situ were detected by flow cytometry and immunohistochemistry.
Both the HCC group and HC group had similar frequency and phenotype characteristics of CD11c
CD8
T cells in the periphery. CD11c
CD8
T cells were mainly composed of effector T cells, most of which were CD45RA
CCR7-. Compared with CD11c-CD8
T cells, CD11c
CD8
T cells had a higher proportion of CD38 and HLA-DR double positive, and expressed high levels of granzyme-B (GB) and degranulation marker CD107a, and produced high levels of interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ). However, the ability of degranulation and TNF-α production of CD11c
CD8
T cells in patients with HCC were significantly lower than that in healthy controls. The GB expression level of peripheral CD11c
CD8
T cells in patients with advanced stage of HCC was significantly lower than that in patients with early stage of HCC, and the GB expression level of liver-infiltrating CD11c
CD8
T cells in tumor tissues was lower than that in non-tumor tissues. More importantly, the GB expression level of peripheral CD11c
CD8
T cells was negatively correlated with tumor volume.
These findings indicate that CD11c
CD8
T cells may have potential anti-tumor activity and that GB
CD11c
CD8
T cells are associated with disease progression in patients with HBV-related HCC.
Human metapneumovirus (HMPV) is a common virus associated with acute respiratory distress syndrome in pediatric patients. There are no HMPV vaccines or therapeutics that have been approved for ...prevention or treatment. In this study, we constructed a novel recombinant influenza virus carrying partial HMPV fusion protein (HMPV-F), termed rFLU-HMPV/F-NS, utilizing reverse genetics, which contained (HMPV-F) in the background of NS segments of influenza virus A/PuertoRico/8/34(PR8). The morphological characteristics of rFLU-HMPV/F-NS were consistent with the wild-type flu virus. Additionally, immunofluorescence results showed that fusion proteins in the chimeric rFLU-HMPV/F-NS could work well, and the virus could be stably passaged in SPF chicken embryos. Furthermore, intranasal immunization with rFLU-HMPV/F-NS in BALB/c mice induced robust humoral, mucosal and Th1-type dominant cellular immune responses
. More importantly, we discovered that rFLU-HMPV/F-NS afforded significant protective efficacy against the wild-type HMPV and influenza virus challenge, with significantly attenuated pathological changes and reduced viral titers in the lung tissues of immunized mice. Collectively, these findings demonstrated that chimeric recombinant rFLU-HMPV/F-NS as a promising HMPV candidate vaccine has potentials for the development of HMPV vaccine.
Oncolytic virotherapy is a promising strategy for the treatment of cancer. Influenza A virus has shown potential as an oncolytic agent. In this study, a recombinant PR8 influenza viral vector, called ...delNS1-GM-CSF, was generated with a partial deletion in NS and the granulocyte-macrophage colony-stimulating factor (GM-CSF) coding sequence inserted into the influenza nonstructural protein 1 gene. The morphological characteristics of delNS1-GM-CSF were examined. The delNS1-GM-CSF virus replicated well in various cell lines, including MDCK, A549, SMCC7721, and HepG2 cells. Moreover, selective cytotoxicity of the virus was observed in various hepatocellular carcinoma (HCC) cell lines, while no effect was demonstrated in the normal liver cell line LO2, as indicated by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide and crystal violet assays. Importantly, using a model based on the growth of HepG2 cells as a xenograft in nude mice, it was found that a reassortant delNS1-GM-CSF virus inhibited tumor growth significantly following intratumoral injection in a dose-dependent manner. Ex vivo results showed that the tumor inhibition efficacy of delNS1-GM-CSF was observed in HCC clinical samples. Taken together, these results are the first to demonstrate that influenza A viruses may have potential as oncolytic virotherapeutic agents against HCC.
Hepatocellular carcinoma (HCC) is the most common neoplasm and is a leading cause of cancer-related death. Despite advances in the diagnosis and management of HCC, its prognosis remain unfavorable. ...Accumulating evidence has shown that long intergenic noncoding RNAs (lincRNAs) play central roles in the development of HCC. In this study, we identified a long intergenic noncoding RNA referred to as lincRNA P7 in HCC and explored its clinical significance and biological functions in HCC. The expression level of lincRNA P7 was significantly aberrantly deceased in HCC cancer tissues and cells lines. Gain- and loss-of-function experiments revealed that overexpression of lincRNA P7 significantly inhibited the proliferation of HCC-derived cancer cells, whereas lincRNA P7 knockdown promoted cell growth. Mechanistically, lincRNA P7 blocked Erk1/2 signaling and repressed activation of the STAT1 pathway. In nude mouse models, we show that overexpression of lincRNA P7 effectively repressed HCC xenograft tumor growth
. Moreover, a clinical investigation demonstrated that down-regulated lincRNA P7 expression correlated with liver cirrhosis, Hepatitis B virus (HBV) infection, clinical stage of the tumor and recurrence. A Kaplan-Meier survival analysis showed that the expression of lincRNA P7 was significantly related to overall survival (
= 0.003) and recurrence-free survival (
= 0.031). Collectively, our findings suggested that the down-regulation of lincRNA P7 predicts poor clinical outcomes for HCC patients and might be a powerful candidate prognostic biomarker and target in HCC.
PDF
