Persistence of inflammatory phenotype in residual psoriasic plaques in patients on effective biologic therapy
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE132195 | GEO | 2020/05/13
REPOSITORIES: GEO
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Project description:Persistence of inflammatory phenotype in residual psoriasic plaques in patients on effective biologic therapy
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Project description:The deposition of amyloid senile plaques (SPs) play a central role in Alzheimer’s disease (AD), but the mechanisms by which SPs induce neural toxicity are disputed. Genetically engineered mouse models emphasising SPs have had limited success in reproducing the neuropathology of AD, and have also failed to be good indicators of successful amyloid-targeting therapies. Moreover, elderly people with a heavy plaque burden can show normal cognition. Therefore, it is fundamentally important to fully characterize and distinguish the pathological changes elicited by SPs in human and mouse brains. Using laser capture microdissection (LCM) combined with high-throughput mass spectrometry, we quantified ~5000 proteins with high confidence in SPs and non-plaque regions from AD and non-AD human postmortem brain. We found proteomic alteration in SPs is more evident than in non-plaque regions, and identified more than 30 human that are significantly enriched in SPs. We found that AD SPs elicited much more extensive proteomic alterations compared to non-AD SPs. Together, our findings represent the most systematic analysis of sub-proteome of senile plaques and provide a framework for future studies on plaque pathology and AD progression.
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Project description:Staphylococcus aureus causes invasive infections and easily acquires antibiotic resistances. Even antibiotic susceptible S. aureus can survive antibiotic therapy and persist, requiring prolonged treatment and surgical interventions. These so-called persisters display an arrested-growth phenotype, tolerate high antibiotic concentrations and are associated with chronic and recurrent infections. To characterize these persisters, we assessed S. aureus recovered directly from a patient suffering from a persistent infection. We show that host-mediated stress, including acidic-pH, abscesses-environment, and antibiotic exposure promoted persister formation in-vitro and in-vivo. Multi-omics analysis identified molecular changes in S. aureus in response to acid-stress leading to an overall virulent population. However, further analysis of a persister-enriched population revealed major molecular reprogramming in persisters including downregulation of virulence and cell division, and upregulation of ribosomal proteins, nucleotide-, and amino acid- metabolic pathways, suggesting their requirement to fuel and maintain the persister phenotype and highlighting that persisters are not completely metabolically inactive. Additionally, decreased aconitase activity and ATP-levels and accumulation of insoluble proteins involved in transcription, translation and energy-production correlated with persistence in S. aureus, underpinning the molecular mechanisms that drive the persister phenotype. Upon regrowth, these persisters regained their virulence potential and metabolically active phenotype including reduction of insoluble proteins, exhibiting a reversible state, crucial for recurrent infections. We further show that a targeted anti-persister combination therapy using retinoid derivatives and antibiotics significantly reduced lag-phase heterogeneity and persisters in a murine infection model. Our results provide molecular insights into persisters and help explain why persistent S. aureus infections are so difficult-to-treat.
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