Coronavirus disease 2019 (COVID-19) represents a global crisis, yet major knowledge gaps remain about human immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We analyzed immune responses in 76 COVID-19 patients and 69 healthy individuals from Hong Kong and Atlanta, Georgia, United States. In the peripheral blood mononuclear cells (PBMCs) of COVID-19 patients, we observed reduced expression of human leukocyte antigen class DR (HLA-DR) and proinflammatory cytokines by myeloid cells as well as impaired mammalian target of rapamycin (mTOR) signaling and interferon-α (IFN-α) production by plasmacytoid dendritic cells. By contrast, we detected enhanced plasma levels of inflammatory mediators—including EN-RAGE, TNFSF14, and oncostatin M—which correlated with disease severity and increased bacterial products in plasma. Single-cell transcriptomics revealed a lack of type I IFNs, reduced HLA-DR in the myeloid cells of patients with severe COVID-19, and transient expression of IFN-stimulated genes. This was consistent with bulk PBMC transcriptomics and transient, low IFN-α levels in plasma during infection. These results reveal mechanisms and potential therapeutic targets for COVID-19.

Systems vaccinology of the BNT162b2 mRNA vaccine in humans P ra bh u S. A ru na ch al am , M ad el ei ne K. D.

Despite the success of the BNT162b2 mRNA vaccine, the immunological mechanisms that underlie its efficacy are poorly understood. Here we analyzed the innate and adaptive responses to BNT162b2 in mice, and show that immunization stimulated potent antibody and antigen-specific T cell responses, as well as strikingly enhanced innate responses after secondary immunization, which was concurrent with enhanced serum interferon (IFN)-γ levels 1 d following secondary immunization. Notably, we found that natural killer cells and CD8 + T cells in the draining lymph nodes are the major producers of this circulating IFN-γ. Analysis of knockout mice revealed that induction of antibody and T cell responses to BNT162b2 was not dependent on signaling via Toll-like receptors 2, 3, 4, 5 and 7 nor inflammasome activation, nor the necroptosis or pyroptosis cell death pathways. Rather, the CD8 + T cell response induced by BNT162b2 was dependent on type I interferon-dependent MDA5 signaling. These results provide insights into the molecular mechanisms by which the BNT162b2 vaccine stimulates immune responses.

Recent studies have emphasized causative links between aberrant microRNA expression patterns and cancer progression. miR-183 is dysregulated in certain types of human cancers. The expression pattern, clinical significance, and biological role of miR-183 in osteosarcoma, however, remain largely undefined. In this paired analysis, we found that miR-183 was markedly down-regulated in osteosarcoma cells and tissues compared with matching normal bone tissues using RT-qPCR. Statistical analyses revealed that the expression levels of miR-183 significantly correlated with lung metastasis as well as with local recurrence of osteosarcoma. miR-183 expression was inversely correlated with Ezrin mRNA and protein expression levels in osteosarcoma cells as well as in a subset of primary osteosarcoma. Ectopically expressed miR-183 inhibited migratory and invasive abilities of osteosarcoma cells, whereas knockdown of endogenous miR-183 significantly enhanced these abilities. Using a luciferase reporter carrying the 3'-untranslated region (3'-UTR) of Ezrin, we identified Ezrin as a direct target of miR-183. Moreover, ectopic expression of Ezrin could significantly rescue miR-183-suppressed migration and invasion. Of interest, suppression of Ezrin by miR-183 caused a reduction of phosphorylated p44/42 (p-p44/42). Finally, suppression of Ezrin by RNAi mimicked miR-183 action in the suppression of migration and invasion, which was associated with down-regulation of p-p44/42. Taken together, these results suggest that as a tumor suppressor miRNA, miR-183 plays an important role in the aggressiveness of osteosarcoma.

Background:Recent studies have reported miR-145 dysregulated in colorectal cancer (CRC). In this study, miR-145 profiles were compared between CRC and corresponding non-tumour tissues.Methods:The expression levels of miR-145 were analysed in CRC cell lines and tumour tissues by real-time PCR. A luciferase reporter assay confirmed direct targets. The functional effects of miR-145 were examined in transfected CRC cells in vitro and in vivo using established assays.Results:Downregulation of miR-145 was detected in most primary CRC tumours, and was significantly correlated with a more aggressive phenotype of CRC in patients. In CRC cell lines, ectopic overexpression of miR-145 inhibited cell proliferation, motility and invasion in vitro. Stable overexpression of miR-145 suppressed tumour growth and pulmonary metastasis in vivo. Further studies indicated that miR-145 may directly interact with the 3′-untranslated region (3′-UTR) of Fascin-1 messenger RNA (mRNA), downregulating its mRNA and protein expression levels. In clinical specimens, Fascin-1 expression was negatively correlated with miR-145 expression.Conclusions:MiR-145 has a critical role in the inhibition of invasive and metastatic capacities of CRC, probably through directly targeting Fascin-1. This miRNA may be involved in the development and progression of CRC.