Sirt1 overexpression improves senescence-associated pulmonary fibrosis induced by vitamin D deficiency through downregulating IL-11 transcription.

Determining the mechanism of senescence-associated pulmonary fibrosis is crucial for designing more effective treatments for chronic lung diseases. This study aimed to determine the following: whether Sirt1 and serum vitamin D decreased with physiological aging, promoting senescence-associated pulmonary fibrosis by activating TGF-ß1/IL-11/MEK/ERK signaling, whether Sirt1 overexpression prevented TGF-ß1/IL-11/MEK/ERK signaling-mediated senescence-associated pulmonary fibrosis in vitamin D-deficient (Cyp27b1-/- ) mice, and whether Sirt1 downregulated IL-11 expression transcribed by TGF-ß1/Smad2 signaling through deacetylating histone at the IL-11 promoter in pulmonary fibroblasts. Bioinformatics analysis with RNA sequencing data from pulmonary fibroblasts of physiologically aged mice was conducted for correlation analysis. Lungs from young and physiologically aged wild-type (WT) mice were examined for cell senescence, fibrosis markers, and TGF-ß1/IL-11/MEK/ERK signaling proteins, and 1,25(OH)2 D3 and IL-11 levels were detected in serum. Nine-week-old WT, Sirt1 mesenchymal transgene (Sirt1Tg ), Cyp27b1-/- , and Sirt1Tg Cyp27b1-/- mice were observed the pulmonary function, aging, and senescence-associated secretory phenotype and TGF-ß1/IL-11/MEK/ERK signaling. We found that pulmonary Sirt1 and serum vitamin D decreased with physiological aging, activating TGF-ß1/IL-11/MEK/ERK signaling, and promoting senescence-associated pulmonary fibrosis. Sirt1 overexpression improved pulmonary dysfunction, aging, DNA damage, senescence-associated secretory phenotype, and fibrosis through downregulating TGF-ß1/IL-11/MEK/ERK signaling in Cyp27b1-/- mice. Sirt1 negatively regulated IL-11 expression through deacetylating H3K9/14ac mainly at the region from -871 to -724 of IL-11 promoter, also the major binding region of Smad2 which regulated IL-11 expression at the transcriptional level, and subsequently inhibiting TGF-ß1/IL-11/MEK/ERK signaling in pulmonary fibroblasts. This signaling in aging fibroblasts could be a therapeutic target for preventing senescence-associated pulmonary fibrosis induced by vitamin D deficiency.

HLA-A∗02:01 restricted T cell receptors against the highly conserved SARS-CoV-2 polymerase cross-react with human coronaviruses.

Cross-reactivity and direct killing of target cells remain underexplored for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific CD8+ T cells. Isolation of T cell receptors (TCRs) and overexpression in allogeneic cells allows for extensive T cell reactivity profiling. We identify SARS-CoV-2 RNA-dependent RNA polymerase (RdRp/NSP12) as highly conserved, likely due to its critical role in the virus life cycle. We perform single-cell TCRαß sequencing in human leukocyte antigen (HLA)-A∗02:01-restricted, RdRp-specific T cells from SARS-CoV-2-unexposed individuals. Human T cells expressing these TCRαß constructs kill target cell lines engineered to express full-length RdRp. Three TCR constructs recognize homologous epitopes from common cold coronaviruses, indicating CD8+ T cells can recognize evolutionarily diverse coronaviruses. Analysis of individual TCR clones may help define vaccine epitopes that can induce long-term immunity against SARS-CoV-2 and other coronaviruses.

HLA-A∗02:01 restricted T cell receptors against the highly conserved SARS-CoV-2 polymerase cross-react with human coronaviruses

Nesterenko et al. identify T cell responses with potential to confer long term immunity against SARS-CoV-2. The machinery responsible for replicating the viral genome is highly conserved and as shown by Nesterenko et al. can be effectively targeted by CD8+ T cells.