Dataset Information

Hepatic Metabolomics Investigation in Acute and Chronic Murine Toxoplasmosis.

ABSTRACT: Toxoplasma gondii poses a great threat to human health, with no approved vaccine available for the treatment of T. gondii infection. T. gondii infections are not limited to the brain, and may also affect other organs especially the liver. Identification of host liver molecules or pathways involved in T. gondii replication process may lead to the discovery of novel anti-T. gondii targets. Here, we analyzed the metabolic profile of the liver of mice on 11 and 30 days postinfection (dpi) with type II T. gondii Pru strain. Global metabolomics using liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified 389 significant metabolites from acutely infected mice; and 368 from chronically infected mice, when compared with control mice. Multivariate statistical analysis revealed distinct metabolic signatures from acutely infected, chronically infected and control mice. Infection influenced several metabolic processes, in particular those for lipids and amino acids. Metabolic pathways, such as steroid hormone biosynthesis, primary bile acid biosynthesis, bile secretion, and biosynthesis of unsaturated fatty acids were perturbed during the whole infection process, particularly during the acute stage of infection. The present results provide insight into hepatic metabolic changes that occur in BALB/c mice during acute and chronic T. gondii infection.

SUBMITTER: Chen XQ

PROVIDER: S-EPMC5996072 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Hepatic Metabolomics Investigation in Acute and Chronic Murine Toxoplasmosis.

Chen Xiao-Qing XQ Elsheikha Hany M HM Hu Rui-Si RS Hu Gui-Xue GX Guo Shu-Ling SL Zhou Chun-Xue CX Zhu Xing-Quan XQ

Frontiers in cellular and infection microbiology 20180605

Toxoplasma gondii poses a great threat to human health, with no approved vaccine available for the treatment of T. gondii infection. T. gondii infections are not limited to the brain, and may also affect other organs especially the liver. Identification of host liver molecules or pathways involved in T. gondii replication process may lead to the discovery of novel anti-T. gondii targets. Here, we analyzed the metabolic profile of the liver of mice on 11 and 30 ...[more]

PMID: 29922602

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Project description:Toxoplasma gondii is an important zoonotic pathogen infecting one-third of the world's population and numerous animals, causing significant healthcare burden and socioeconomic problems. Vaccination is an efficient way to reduce global sero-prevalence, however, ideal vaccines are not yet available. We recently discovered that the Toxoplasma mutant lacking both lactate dehydrogenases LDH1 and LDH2 (?ldh) grew well in vitro but was unable to propagate in mice, making it a good live vaccine candidate. Here, we tested the protection efficacy of ME49 ?ldh using a mouse model. Vaccinated mice were efficiently protected from the lethal challenge of a variety of wild-type strains, including type 1 strain RH, type 2 strain ME49, type 3 strain VEG, and a field isolate of Chinese 1. The protection efficacies of a single vaccination were nearly 100% for most cases and it worked well against the challenges of both tachyzoites and tissue cysts. Re-challenging parasites were unable to propagate in vaccinated mice, nor did they make tissue cysts. High levels of Toxoplasma-specific IgG were produced 30?days after immunization and stayed high during the whole tests (at least 125?days). However, passive immunization of naïve mice with sera from vaccinated mice did reduce parasite propagation, but the overall protection against parasite infections was rather limited. On the other hand, ?ldh immunization evoked elevated levels of Th1 cytokines like INF-? and IL-12, at early time points. In addition, splenocytes extracted from immunized mice were able to induce quick and robust INF-? and other pro-inflammatory cytokine production upon T. gondii antigen stimulation. Together these results suggest that cellular immune responses are the main contributors to the protective immunity elicited by ?ldh vaccination, and humoral immunity also contributes partially. We also generated uracil auxotrophic mutants in ME49 and compared their immune protection efficiencies to the ?ldh mutants. The results showed that these two types of mutants have similar properties as live vaccine candidates. Taken together, these results suggest that mutants lacking LDH were severely attenuated in virulence but were able to induce strong anti-toxoplasma immune responses, therefore are good candidates for live vaccines.

Project description:BackgroundToxoplasma gondii, a common opportunistic protozoan, is a leading cause of illness and mortality among immunosuppressed individuals and during congenital infections. Current therapeutic strategies for toxoplasmosis are not fully effective at curtailing disease progression in these cases. Given the parasite ability to influence host immunity and metabolism, understanding of the metabolic alterations in the host's immune organs during T. gondii infection may enhance the understanding of the molecular mechanisms that define the pathophysiology of T. gondii infection.MethodsWe investigated the global metabolic changes in the spleen of BALB/c mice at early and late stage of infection with T. gondii using LC-MS/MS-based metabolomics. Multivariate data analysis methods, principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA), were used to identify metabolites that are influenced by T. gondii infection.ResultsMultivariate analyses clearly separated the metabolites of spleen of infected and control mice. A total of 132 differential metabolites were identified, 23 metabolites from acutely infected versus control mice and 109 metabolites from chronically infected versus control mice. Lipids, hormones, lactones, acids, peptides, antibiotics, alkaloids and natural toxins were the most influenced chemical groups. There were 12 shared differential metabolites between acutely infected versus control mice and chronically infected versus control mice, of which 4,4-Dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol was significantly upregulated and ubiquinone-8 was significantly downregulated. Major perturbed metabolic pathways included primary bile acid biosynthesis, steroid hormone biosynthesis, biotin metabolism, and steroid biosynthesis, with arachidonic acid metabolism being the most significantly impacted pathway. These metabolic changes suggest a multifactorial nature of the immunometabolic responses of mouse spleen to T. gondii infection.ConclusionsThis study demonstrated that T. gondii infection can cause significant metabolomic alterations in the spleen of infected mice. These findings provide new insights into the molecular mechanisms that underpin the pathogenesis of T. gondii infection.

Dataset Information

Hepatic Metabolomics Investigation in Acute and Chronic Murine Toxoplasmosis.

Publications

Hepatic Metabolomics Investigation in Acute and Chronic Murine Toxoplasmosis.

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