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The infection-exclusive proteome of extracellular vesicles defines bacterial-induced immune response signatures

ABSTRACT: Extracellular vesicles (EVs) are small, lipid bi-layered structures released from various cell-types throughout the body. These structures are responsible for the delivery of proteins., compounds, and communication signals across spatial distances. EVs are highly important to diverse biological processes within mammalian systems, including roles in cellular maintenance and homeostasis of physiological conditions and response to infection. In this study, we characterize phenotypic traits and proteome remodeling of host EVs derived during a state of infection by the human bacterial pathogen, Klebsiella pneumoniae, compared to an uninfected control. Phenotypic profiling defines consistent size, diameter, and number of EVs from samples across infectious states, whereas a closer look into molecular regulation at the protein level defines core and infection-exclusive proteomes. Within the core proteome (i.e., protein detection common between plasma from uninfected versus infected samples) clustering based on infectious state was observed and significant changes in fibrinogen production with heighted levels upon infection were reported. Conversely, assessment of the infection-exclusive EV proteome highlighted the stark production of immune-associated proteins by Gene Ontology Biological Processes and an enrichment of proteins associated with blood microparticles, membrane-bound, and the extracellular region by Gene Ontology Cellular Compartment. Overall, this study emphasizes complex reprogramming of the EV proteome upon exposure to K. pneumoniae within a murine model of infection and proposes protein-level signatures indicative of bacterial infection.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Plasma

SUBMITTER: Jennifer Geddes-McAlister

LAB HEAD: Dr. Jennifer Geddes-McAlister

PROVIDER: PXD060972 | Pride | 2026-03-13

REPOSITORIES: Pride

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			Action	DRS
	June_29_2023_MSF_309_I1.raw	Raw
	June_29_2023_MSF_309_I2.raw	Raw
	June_29_2023_MSF_309_I3.raw	Raw
	June_29_2023_MSF_309_U1_20230629164453.raw	Raw
	June_29_2023_MSF_309_U2.raw	Raw

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Project description:Background: Acute coronary syndromes (ACS) are associated with aberrant gene expression and epigenetic mechanisms. In particular, de novo DNA methylation is typically linked to gene silencing, but its role in heart disease remains not fully understood. Extracellular vesicles (EVs) are active components in cellular communication for their ability to carry a plethora of signalling biomolecules, thus representing a promising new diagnostic/therapeutic approach in cardiovascular diseases (CVDs). Indeed, there is the need of novel biomarkers for ACS prediction and timely detection. Purpose: We hypothesized that specific epigenetic signals can be carried by EVs. In this regard, we isolated and characterized circulating EVs from ACS patients and evaluated their potential role to influence DNA methylation in target cells. Methods: Circulating EVs were recovered, by ultracentrifugation, from plasma samples of 19 ACS patients and 50 healthy subjects (HS). Nanoparticle tracking analysis (NTA) and western blot (WB) were used to confirm the EVs integrity and purity. Peripheral blood mononuclear cells (PBMCs) of volunteer donors were treated with both ACS and HS derived EVs and genomic DNA was extracted to perform epigenome wide analysis through Reduced Representation Bisulfite Sequencing. ShinyGO, PANTHER, and STRING tools were interrogated to perform GO and PPI network analyses. Flow Cytometry, qRT-PCR, and WB analysis were also performed to evaluate and validate both intra-vesicular and intra-cellular signals. Results: Plasma ACS-derived EVs showed a significant up-regulation of DNA methyltransferases (DNMTs) gene expression levels as compared to HS (P<0.001). Specifically, de novo methylation transcripts, as DNMT3A and DNMT3B were significantly increased in plasma ACS-EVs. DNA methylation analysis of PBMCs from volunteer donors treated with HS- and ACS-derived EVs showed that RNF166 and CCND3 genes resulted the most hyper- and hypo-methylated, respectively, after by ACS-EV treatment. In addition, PPI network analysis specifically evidenced the subnetwork with SRC, as a hub gene, connecting it to NOTCH1, FOXO3, CDC42, IKBKG, RXRA, DGKG, known as important genes already involved in the onset of CVDs. Surprising, other novel genes, BAIAP2, SYP, CHL1, and SHB, which were hypomethylated, were found significantly overexpressed in PBMCs (P<0.005), underlying the fundamental modulating properties of EV cargo in atherosclerosis. Conclusions: These findings support the significant role of ACS plasma-derived EVs, inducing de novo DNA methylation signals, and modulating specific signaling pathways in target cells.

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The infection-exclusive proteome of extracellular vesicles defines bacterial-induced immune response signatures

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