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Alterations in the HLA-B*57:01 immunopeptidome by flucloxacillin and immunogenicity of drug-haptenated peptides

ABSTRACT: Flucloxacillin (FLX), a -lactam antibiotic for narrow-spectrum gram-positive bacterial infections, has been associated with severe immune-mediated drug-induced liver injury caused by an influx of T-lymphocytes targeting liver cells potentially recognizing drug-haptenated peptides in the context of HLA-B*57:01.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, B-lymphoblast Cell Line

SUBMITTER: Swamy Kumar Polumuri

LAB HEAD: Michael A. Norcross, MD Montserrat Puig, PhD

PROVIDER: PXD024212 | Pride | 2021-02-17

REPOSITORIES: Pride

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Project description:Fluoxetine (FLX) is the most common selective serotonin reuptake inhibitor pharmaceutical used for the treatment of psychological disorders such as depression and anxiety. Increased prescription use of FLX by human populations has led to its pseudo-persistence in effluent-receiving waterways. Despite emerging concerns of FLX becoming a potential threat to the aquatic environment, there is currently limited information on effects of FLX on aquatic wildlife, including its specific mechanism of action and associated toxicity pathways in fish. The main goal of this study was to identify and validate key molecular toxicity pathways that are predictive of apical endpoints induced by exposure to FLX using the fathead minnow (Pimephales promelas), a model species common to North American freshwater systems. Adult fathead minnows were exposed to three concentrations of FLX (2.42, 10.7, and 56.7 µg/L) and a control for 21 days. After 96 hours, a subset of fish was sampled, and liver and brain tissue were collected to characterize molecular toxicity pathways using whole transcriptome and proteome analyses. In addition, at the end of the 21-day exposure, individuals were assessed for apical outcomes of regulatory relevance including histopathology and fecundity. Differential gene expression observed in the liver of fish exposed to the highest FLX treatment and revealed dysregulation of pathways associated with biosynthesis and metabolism of fatty acids, which may be an upstream molecular response that led to lipid-type vacuolation of hepatocytes, as observed in the histology analysis. Whole proteome analysis of the same fish revealed dysregulation of PPAR signalling, which may be associated with the enrichment of lipid-related pathways observed in the transcriptome. In addition, there was an indication of pathway enrichment of transcription- and translation-related pathways in the proteome. Common dysregulated genes in the brain of the treated fish were related to cellular signalling processes that are influenced by serotonin levels and shown to be involved in reproductive behaviour and, in turn, reproductive success. This was confirmed through a significant decrease in fecundity following the 21-day exposure. Pathways to measurable adverse outcomes are complex, however, this research does provide some important clues to the mechanistic toxicity that FLX inflicts.

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Alterations in the HLA-B*57:01 immunopeptidome by flucloxacillin and immunogenicity of drug-haptenated peptides

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