RNAseq on Human APAP-ALF
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1076506 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27968073_1.fastq.gz | Fastqsanger.gz | |||
| SRR27968073_2.fastq.gz | Fastqsanger.gz | |||
| SRR27968074_1.fastq.gz | Fastqsanger.gz | |||
| SRR27968074_2.fastq.gz | Fastqsanger.gz | |||
| SRR27968075_1.fastq.gz | Fastqsanger.gz |
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Project description:Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury, such as plasma alanine aminotransferase activities are poor predictors of acute liver failure (ALF), suggesting the involvement of additional mechanisms independent of hepatocyte death. Previous work demonstrated a severe overdose of APAP results in impaired regeneration, the induction of senescence by p21, and increased mortality. We hypothesized that a discrete population of p21+ hepatocytes acquired a secretory phenotype that directly impedes liver recovery after a severe APAP overdose. Leveraging in-house human APAP explant liver and publicly available singlenuclei RNAseq data, we identified a subpopulation of p21+ hepatocytes enriched in a unique secretome of factors, such as Cxcl14. Spatial transcriptomics in the mouse model of APAP overdose confirmed the presence of a p21+ hepatocyte population that directly surrounded the necrotic areas. In both male and female mice, we found a dose-dependent induction of p21 and persistent circulating levels of the p21-specific constituent, Cxcl14, in the plasma after a severe APAP overdose. In parallel experiments, we targeted either the putative senescent hepatocytes with the senolytic drugs, dasatinib and quercetin, or Cxcl14 with a neutralizing antibody. We found that targeting Cxcl14 greatly enhanced liver recovery after APAP-induced liver injury, while targeting the senescent hepatocyte had no effect. This data supports that the sustained induction of p21 in hepatocytes with persistent Cxcl14 secretion are critical mechanistic events leading to ALF in mice and human patients.
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Project description:Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury, such as plasma alanine aminotransferase activities are poor predictors of acute liver failure (ALF), suggesting the involvement of additional mechanisms independent of hepatocyte death. Previous work demonstrated a severe overdose of APAP results in impaired regeneration, the induction of senescence by p21, and increased mortality. We hypothesized that a discrete population of p21+ hepatocytes acquired a secretory phenotype that directly impedes liver recovery after a severe APAP overdose. Leveraging in-house human APAP explant liver and publicly available singlenuclei RNAseq data, we identified a subpopulation of p21+ hepatocytes enriched in a unique secretome of factors, such as Cxcl14. Spatial transcriptomics in the mouse model of APAP overdose confirmed the presence of a p21+ hepatocyte population that directly surrounded the necrotic areas. In both male and female mice, we found a dose-dependent induction of p21 and persistent circulating levels of the p21-specific constituent, Cxcl14, in the plasma after a severe APAP overdose. In parallel experiments, we targeted either the putative senescent hepatocytes with the senolytic drugs, dasatinib and quercetin, or Cxcl14 with a neutralizing antibody. We found that targeting Cxcl14 greatly enhanced liver recovery after APAP-induced liver injury, while targeting the senescent hepatocyte had no effect. This data supports that the sustained induction of p21 in hepatocytes with persistent Cxcl14 secretion are critical mechanistic events leading to ALF in mice and human patients.
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Project description:Superbugs such as drug-resistant Mycobacterium tuberculosis (DR-M.tb) poses a serious global health threat. Upon infection, M.tb reaches the alveolar space and comes in close contact with soluble components of the human alveolar lining fluid (ALF) for an uncertain period of time prior to and following its encounter with alveolar compartment cells. Homeostatic ALF hydrolases, which main function is maintaining lung health, modify the M.tb cell envelope, driving M.tb-host cell interactions. Still, the contribution of human ALF to M.tb adaptation to the host during infection is poorly understood. Here, we exposed 4 M.tb strains (H37Rv, HN878, CDC1551, W-7642) with different levels of virulence, transmissibility, and drug resistance to human ALF for shorter (15 min) and longer (12 h) periods of time. RNA sequencing was performed to determine the strains’ transcriptional profiles in response to ALF exposure. Gene expression analysis showed a clear temporal and strain-specific adaptation to human ALF. When comparing ALF-exposed vs. unexposed bacteria for each M.tb strain, differential expression (DE) analysis revealed a total of 397 DE genes associated with lipid metabolism, cell envelope and processes, intermediary metabolism and respiration, and regulatory proteins, among others. Most DE was detected at 12 h post-ALF exposure, with DR-M.tb strain W-7642 having the highest number of DE genes. Interestingly, genes from the KstR2 regulon, which controls the degradation of cholesterol C and D rings, were significantly upregulated early in all strains post-ALF exposure. These results indicate that M.tb-ALF contact (15 min to 12 h prior to M.tb recognition by host cells in the alveolar space) drives global metabolic and physiologic changes in M.tb during the initial stages of the infection, with potential implications in infection outcome.
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