Abstract
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.
Highlights
Toxoplasma gondii, a common opportunistic protozoan, is a leading cause of illness and mortality among immunosuppressed individuals and during congenital infections
We investigated, for the first time, changes in the metabolism of spleen of mice infected with T. gondii during acute and chronic phases of infection using non-targeted Liquid chromatography coupled to mass spectrometry (LC-MS)/MS metabolomics
Our findings confirmed that using LC-MS/MSbased metabolomics coupled to chemometric methods can provide a powerful approach for discerning metabolic changes in the spleen of mice infected with T. gondii and for elucidating infection stage-specific metabolic profiles
Summary
Toxoplasma gondii, a common opportunistic protozoan, is a leading cause of illness and mortality among immunosuppressed individuals and during congenital infections. Toxoplasmosis is a common opportunistic infection caused by Toxoplasma gondii, which can infect almost all warmblooded vertebrate animals [1]. This parasite is highly zoonotic, with roughly one-third of the world population reported to be infected [2]. Toxoplasma gondii infection can manifest as an acute infection attributed to the replicating tachyzoite stage, which results in significant immune activation and systemic dissemination to various host tissues [5]. Control of T. gondii replication and transition to the latent form depends on cellmediated immunity; humoral immunity is critical for resistance to T. gondii infection [8, 9]
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