Multi-Omics Studies Demonstrate Toxoplasma gondii-Induced Metabolic Reprogramming of Murine Dendritic Cells

Abstract

Toxoplasma gondii is capable of actively invading almost any mammalian cell type including phagocytes. Early events in phagocytic cells such as dendritic cells are not only key to establishing parasite infection, but conversely play a pivotal role in initiating host immunity. It is now recognized that in addition to changes in canonical immune markers and mediators, alteration in metabolism occurs upon activation of phagocytic cells. These metabolic changes are important for supporting the developing immune response, but can affect the availability of nutrients for intracellular pathogens including T. gondii. However, the interaction of T. gondii with these cells and particularly how infection changes their metabolism has not been extensively investigated. Herein, we use a multi-omics approach comprising transcriptomics and metabolomics validated with functional assays to better understand early events in these cells following infection. Analysis of the transcriptome of T. gondii infected bone marrow derived dendritic cells (BMDCs) revealed significant alterations in transcripts associated with cellular metabolism, activation of T cells, inflammation mediated chemokine and cytokine signaling pathways. Multivariant analysis of metabolomic data sets acquired through non-targeted liquid chromatography mass spectroscopy (LCMS) identified metabolites associated with glycolysis, the TCA cycle, oxidative phosphorylation and arginine metabolism as major discriminants between control uninfected and T. gondii infected cells. Consistent with these observations, glucose uptake and lactate dehydrogenase activity were upregulated in T. gondii infected BMDC cultures compared with control BMDCs. Conversely, BMDC mitochondrial membrane potential was reduced in T. gondii-infected cells relative to mitochondria of control BMDCs. These changes to energy metabolism, similar to what has been described following LPS stimulation of BMDCs and macrophages are often termed the Warburg effect. This metabolic reprogramming of cells has been suggested to be an important adaption that provides energy and precursors to facilitate phagocytosis, antigen processing and cytokine production. Other changes to BMDC metabolism are evident following T. gondii infection and include upregulation of arginine degradation concomitant with increased arginase-1 activity and ornithine and proline production. As T. gondii is an arginine auxotroph the resultant reduced cellular arginine levels are likely to curtail parasite multiplication. These results highlight the complex interplay of BMDCs and parasite metabolism within the developing immune response and the consequences for adaptive immunity and pathogen clearance.

Modeling the Ruminant Placenta-Pathogen Interactions in Apicomplexan Parasites: Current and Future Perspectives

“…Proteome changes revealed protein synthesis, protein turnover, and metabolism as the main host pathways disturbed by infection. Similar findings have been reported for other parasites, as manipulation of host metabolic events determines infection establishment and the initiation of host immune responses ( 58 , 133 – 135 ). As observed in the transcriptomic study, infection with the low-virulence isolate Nc-Spain1H exerted a higher perturbation on F3 cell proteome with the exception of those profiles enriched in mitochondrial proteins, which were equally altered by high- and low-virulence isolates.…”

Proteomic Characterization of Host-Pathogen Interactions during Bovine Trophoblast Cell Line Infection by Neospora caninum

“…These findings showed host metabolism was highly regulated by parasite infection, mainly with the Nc-Spain1H isolate. This result has been previously shown for this and other parasites [5,[18][19][20], and host metabolic events are important for establishment of infection, initiating host immunity and determining the eventual success of infection; therefore, it would be worth deepening knowledge of the types of Neospora host-metabolism regulation. The main variable processes throughout the tachyzoite lytic cycle were related to protein synthesis and turnover ("ribosome" and "proteasome") and to metabolism: "carbon metabolism", "glycolysis/gluconeogenesis", "pentose phosphate pathway", "amino sugar and nucleotide sugar metabolism", "cysteine and methionine metabolism", and "biosynthesis of antibiotics".…”

“…These findings showed host metabolism was highly regulated by parasite infection, mainly with the Nc-Spain1H isolate. This result has been previously shown for this and other parasites [5,[18][19][20], and host metabolic events are important for establishment of infection, initiating host immunity and determining the eventual success of infection; therefore, it would be worth deepening knowledge of the types of Neospora host-metabolism regulation.…”

MicroRNAs: Biological Regulators in Pathogen–Host Interactions

“…T. gondii is a highly successful parasite due, in part, to its silent colonization of its host [139,140]. Almost all types of immune cells are recruited to control infection with T. gondii: macrophages, neutrophils, dendritic cells, lymphocytes, and NK cells [139,[141][142][143][144]. Although, almost all infections are silent and this parasite is able to change the host's miRNA profile, modifying the way that it responds to the infection.…”