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Typhoid toxin of Salmonella Typhi elicits host antimicrobial response during acute typhoid fever

ABSTRACT: Salmonella Typhi secretes typhoid toxin that activates cellular DNA damage responses (DDR) during acute typhoid fever. Human infection challenge studies revealed that the toxin suppresses bacteraemia via unknown mechanisms. By applying proteomics to the plasma of bacteraemic participants, we identified that wild-type toxigenic Salmonella induced release of lysozyme (LYZ) and apolipoprotein C3 (APOC3). LYZ and APOC3 were expressed and secreted in cultured cells treated with purified typhoid toxin or infected with toxigenic Salmonella. Toxin-induced LYZ and APOC3 were dependent upon DDRs and could be inhibited by targeting kinases ATM and ATR. LYZ caused loss of Salmonella morphology characterised by spheroplast formation. Spheroplast formation was mediated by LYZ with EDTA or lactoferrin, which was identified by proteomics in participants with typhoid fever. LYZ alone inhibited secretion of T3SS virulence effector proteins SipB and SopE. Our findings indicate that toxin-induced DDRs elicit antimicrobial responses, which suppress Salmonella bacteraemia during typhoid fever.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Typhoid Fever

SUBMITTER: Mark Collins

LAB HEAD: Mark Collins

PROVIDER: PXD058381 | Pride | 2025-10-28

REPOSITORIES: Pride

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Project description:Purpose: To investigate the expression and function of apolipoprotein C3 (APOC3) in diabetic retinopathy (DR). Methods: The quantitative expression of APOC3 in aqueous humor of patients with DR was detected using our proteomic datasets (PXD046630 and PXD053634). A multiplex immunoassay was used to examine the level of APOC3 in serum of patients with DR. Western blot, immunohistochemistry and enzyme-linked immunosorbent assays were used to measure APOC3 expression in liver, duodenum, retina and serum of db/db mice and oxygen induced retinopathy (OIR) mice, and in the human retinal microvascular endothelial cells (hRMECs) exposed to high glucose, hypoxia or both of them. Cell proliferation, migration and tube formation assays were used to assessed the phenotypic characteristics of hRMECs treated with recombinant APOC3 (r-APOC3), hypoxia and both of them. RNA sequence analysis and inhibition assay were conducted to explore the pathway in r-APOC3 and hypoxia stimulation. Results: APOC3 expression were significantly increased in aqueous humor and serum of patients with DR, as well as in liver, duodenum, serum, and retina of db/db mice and OIR mice, while did not markedly change in both hRMECs and their conditioned medium when exposed to high glucose, hypoxia or both of them. r-APOC3 combined with hypoxia significantly enhanced the proliferation, migration and tube formation of hRMECs, and promoted the upregulation of MYC, VEGF and IL6. Inhibition of MYC expression alleviated the phenotypic changes in hRMECs treated with r-APOC3 combined with hypoxia. Purpose: To investigate the expression and function of apolipoprotein C3 (APOC3) in diabetic retinopathy (DR). Methods: The quantitative expression of APOC3 in aqueous humor of patients with DR was detected using our proteomic datasets (PXD046630 and PXD053634). A multiplex immunoassay was used to examine the level of APOC3 in serum of patients with DR. Western blot, immunohistochemistry and enzyme-linked immunosorbent assays were used to measure APOC3 expression in liver, duodenum, retina and serum of db/db mice and oxygen induced retinopathy (OIR) mice, and in the human retinal microvascular endothelial cells (hRMECs) exposed to high glucose, hypoxia or both of them. Cell proliferation, migration and tube formation assays were used to assessed the phenotypic characteristics of hRMECs treated with recombinant APOC3 (r-APOC3), hypoxia and both of them. RNA sequence analysis and inhibition assay were conducted to explore the pathway in r-APOC3 and hypoxia stimulation. Results: APOC3 expression were significantly increased in aqueous humor and serum of patients with DR, as well as in liver, duodenum, serum, and retina of db/db mice and OIR mice, while did not markedly change in both hRMECs and their conditioned medium when exposed to high glucose, hypoxia or both of them. r-APOC3 combined with hypoxia significantly enhanced the proliferation, migration and tube formation of hRMECs, and promoted the upregulation of MYC, VEGF and IL6. Inhibition of MYC expression alleviated the phenotypic changes in hRMECs treated with r-APOC3 combined with hypoxia.

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Typhoid toxin of Salmonella Typhi elicits host antimicrobial response during acute typhoid fever

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