Transcriptomic analyses reveal distinct response of porcine macrophages to Toxoplasma gondii infection

Cui, Jianmin; Shen, Bang

doi:10.1007/s00436-020-06677-5

Cited by 7 publications

(6 citation statements)

References 55 publications

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“…Thus, a major difference between the responses to TLR ligation and protozoan parasite infection exists in pigs. Interestingly, a recent study published by Cui et al (2020) [ 30 ] found no upregulation of IL-12p35 or p40 mRNA by porcine alveolar macrophages following stimulation with T. gondii tachyzoites. In combination with our findings in DC and monocytes, this data suggests that IL-12 is not produced in large quantities by porcine myeloid cells following T. gondii exposure.…”

Section: Discussionmentioning

confidence: 99%

Early Immune Initiation by Porcine Cells following Toxoplasma gondii Infection versus TLR Ligation

Hamid

Schlosser-Brandenburg

Bechtold

et al. 2021

Microorganisms

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Containment of acute Toxoplasma gondii infection is dependent on an efficient interferon gamma response. However, the earliest steps of immune response initiation immediately following exposure to the parasite have not been previously characterized in pigs. Murine and human myeloid cells produce large quantities of interleukin (IL)-12 during early T. gondii infection. We therefore examined IL-12 expression by porcine peripheral blood monocytes and dendritic cell (DC) subsets following toll-like receptor (TLR) ligation and controlled T. gondii tachyzoite infection. We detected IL-12p40 expression by porcine plasmacytoid DC, but not conventional or monocyte-derived DC following TLR ligation. Unexpectedly, we also observed considerable IL-12p40 production by porcine CD3– NKp46+ cells—a classical natural killer cell phenotype—following TLR ligation. However, in response to T. gondii exposure, no IL-12 production was observed by either DC or CD3– NKp46+ cells. Despite this, IL-18 production by DC-enriched peripheral blood mononuclear cells was detected following live T. gondii tachyzoite exposure. Only combined stimulation of porcine peripheral blood mononuclear cells with recombinant IL-12p70 and IL-18 induced innate interferon gamma production by natural killer cells, while T cells and myeloid cells did not respond. Therefore, porcine CD3– NKp46+ cells serve as important IL-12 producers following TLR ligation, while IL-18 likely plays a prominent role in early immune response initiation in the pig following T. gondii infection.

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Section: Discussionmentioning

confidence: 99%

Early Immune Initiation by Porcine Cells following Toxoplasma gondii Infection versus TLR Ligation

Hamid

Schlosser-Brandenburg

Bechtold

et al. 2021

Microorganisms

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“…Then total RNA from each sample was extracted using Transzol UP Reagent (TransGen Biotech Co., Ltd, Beijing, China) according to the manufacturer’s instructions. Subsequently, RNA sequencing was performed as described previously [ 49 ]. Briefly, mRNA was purified and captured by magnetic beads with Oligo (OT) and then was fragmented.…”

Section: Methodsmentioning

confidence: 99%

Metabolic flexibilities and vulnerabilities in the pentose phosphate pathway of the zoonotic pathogen Toxoplasma gondii

Xia

Guo

et al. 2022

PLoS Pathog

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Metabolic pathways underpin the growth and virulence of intracellular parasites and are therefore promising antiparasitic targets. The pentose phosphate pathway (PPP) is vital in most organisms, providing a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) and ribose sugar for nucleotide synthesis; however, it has not yet been studied in Toxoplasma gondii, a widespread intracellular pathogen and a model protozoan organism. Herein, we show that T. gondii has a functional PPP distributed in the cytoplasm and nucleus of its acutely-infectious tachyzoite stage. We produced eight parasite mutants disrupting seven enzymes of the PPP in T. gondii. Our data show that of the seven PPP proteins, the two glucose-6-phosphate dehydrogenases (TgG6PDH1, TgG6PDH2), one of the two 6-phosphogluconate dehydrogenases (Tg6PGDH1), ribulose-5-phosphate epimerase (TgRuPE) and transaldolase (TgTAL) are dispensable in vitro as well as in vivo, disclosing substantial metabolic plasticity in T. gondii. Among these, TgG6PDH2 plays a vital role in defense against oxidative stress by the pathogen. Further, we show that Tg6PGDH2 and ribulose-5-phosphate isomerase (TgRPI) are critical for tachyzoite growth. The depletion of TgRPI impairs the flux of glucose in central carbon pathways, and causes decreased expression of ribosomal, microneme and rhoptry proteins. In summary, our results demonstrate the physiological need of the PPP in T. gondii while unraveling metabolic flexibility and antiparasitic targets.

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“…Total RNA of the DiCre and ΔsbpΔtal tachyzoites isolated using Transzol UP Reagent (TransGen Biotech Co., Ltd, Beijing, China) was assessed for the quality and quantity using a NanoPhotometer (Thermo Fisher Scientific, MA, USA) and 2100 RNA Nano 6000 Assay Kit (Agilent Technologies, CA, USA). Subsequently, RNA sequencing was performed, as reported 53 . The RNA-seq library was sequenced using the Illumina NovaSeq 6000 sequencer.…”

Section: Methodsmentioning

confidence: 99%

Metabolic plasticity, essentiality and therapeutic potential of ribose-5-phosphate synthesis in Toxoplasma gondii

Guo,

Ji,

Guo

et al. 2024

Nat Commun

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Ribose-5-phosphate (R5P) is a precursor for nucleic acid biogenesis; however, the importance and homeostasis of R5P in the intracellular parasite Toxoplasma gondii remain enigmatic. Here, we show that the cytoplasmic sedoheptulose-1,7-bisphosphatase (SBPase) is dispensable. Still, its co-deletion with transaldolase (TAL) impairs the double mutant’s growth and increases 13C-glucose-derived flux into pentose sugars via the transketolase (TKT) enzyme. Deletion of the latter protein affects the parasite’s fitness but is not lethal and is correlated with an increased carbon flux via the oxidative pentose phosphate pathway. Further, loss of TKT leads to a decline in 13C incorporation into glycolysis and the TCA cycle, resulting in a decrease in ATP levels and the inability of phosphoribosyl-pyrophosphate synthetase (PRPS) to convert R5P into 5′-phosphoribosyl-pyrophosphate and thereby contribute to the production of AMP and IMP. Likewise, PRPS is essential for the lytic cycle. Not least, we show that RuPE-mediated metabolic compensation is imperative for the survival of the ΔsbpaseΔtal strain. In conclusion, we demonstrate that multiple routes can flexibly supply R5P to enable parasite growth and identify catalysis by TKT and PRPS as critical enzymatic steps. Our work provides novel biological and therapeutic insights into the network design principles of intracellular parasitism in a clinically-relevant pathogen.

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Transcriptomic analyses reveal distinct response of porcine macrophages to Toxoplasma gondii infection

Cited by 7 publications

References 55 publications

Early Immune Initiation by Porcine Cells following Toxoplasma gondii Infection versus TLR Ligation

Early Immune Initiation by Porcine Cells following Toxoplasma gondii Infection versus TLR Ligation

Metabolic flexibilities and vulnerabilities in the pentose phosphate pathway of the zoonotic pathogen Toxoplasma gondii

Metabolic plasticity, essentiality and therapeutic potential of ribose-5-phosphate synthesis in Toxoplasma gondii

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