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Differential proteomic analysis in a host–parasite interaction of host cells infected with Toxoplasma gondii

ABSTRACT: Toxoplasma gondii, a representative model organism of the phylum Apicomplexa, can infect almost all warm-blooded organisms including humans. Invasion of host cells in a host–parasite interaction is the key step necessary for T. gondii to complete its life cycle. Here, we investigate global proteomic changes based on TMT analysis in both the host cells (human foreskin fibroblasts, HFFs) and T. gondii during intracellular infection. A total of 3477 and 1434 proteins were quantified, of which 378 and 1100 proteins were differentially expressed (p-value<0.05 and ≥1.5-fold change)in Homo sapiens and T. gondii proteins, respectively. In HFF cells, Gene Ontology (GO) and KEGG pathway analyses revealed a large number of differentially expressed proteins (DEPs) enriched in metabolic processes and immune-associated signaling pathways, such as NF-κB, cAMP, and Rap1 signaling pathways. T. gondii DEPs involved in pathway analysis and GO annotations included cellular protein metabolic process, peptide metabolic process, and peptide biosynthetic processes and indicated that cell biosynthesis and metabolism were increased during T. gondii infection. These findings reveal new proteomic differences in the parasite–host interaction during T. gondii infection.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: hui sun

LAB HEAD: hui sun

PROVIDER: PXD021736 | Pride | 2021-05-10

REPOSITORIES: Pride

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Project description:The population structure of Toxoplasma gondii includes three highly prevalent clonal lineages, types I, II, and III, which differ greatly in virulence in the mouse model. Previous studies have implicated a family of serine threonine protein kinases found in rhoptries (ROPs) as important in mediating virulence differences between types I vs. III and II vs. III. Here, we explored the genetic basis of differences in virulence between the highly virulent type I lineage and moderately virulent type II based on a new genetic cross and linkage mapping. Genome-wide association revealed a single quantitative trait locus controls the > 4 log difference in lethality between these strains. Neither ROP16 nor ROP18, previously implicated in virulence differences in T. gondii, were found to contribute to differences between types I and II. Instead, the major virulence locus contained a cluster of pseudokinases denoted as rhoptry protein 5 (ROP5); this locus contains a tandem cluster of polymorphic alleles that differed in expression levels between strains. ROP5 alleles contained only part of the catalytic triad of canonical S/T kinases, and consistent with this they lack demonstrable kinase activity in vitro. Genetic disruption of the rop5 locus in the type I lineage lead to a > 5 log increase in the lethal dose, and surviving mice developed lasting immunity and were protected from an otherwise lethal challenge. These findings reveal that amplification of a polymorphic cluster of pseudokinases plays an important role in pathogenesis of toxoplasmosis in the mouse model. We used a new genotyping protocol based on hybridization of parental and recombinant progeny genomic DNA (gDNA) to Affymetrix gene arrays constructed for T. gondii (http://ancillary.toxodb.org/docs/Array-Tutorial.html). We identified 1,603 single feature polymorphisms (SFP) based on probes that successfully discriminated perfect match (type II) from mismatch (type I) hybridization across all clones and provided reliable SFP markers for this cross.

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Differential proteomic analysis in a host–parasite interaction of host cells infected with Toxoplasma gondii

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