Integrative genomic approaches highlight a family of parasite-specific kinases that regulate host responses.
Apicomplexan parasites release factors via specialized secretory organelles (rhoptries, micronemes) that are thought to control host cell responses. In order to explore parasite-mediated modulation of host cell signaling pathways, we exploited a phylogenomic approach to characterize the Toxoplasma gondii kinome, defining a 44 member family of coccidian-specific secreted kinases, some of which have been previously implicated in virulence. Comparative genomic analysis suggests that "ROPK" genes are under positive selection, and expression profiling demonstrates that most are differentially expressed between strains and/or during differentiation. Integrating diverse genomic-scale analyses points to ROP38 as likely to be particularly important in parasite biology. Upregulating expression of this previously uncharacterized gene in transgenic parasites dramatically suppresses transcriptional responses in the infected cell. Specifically, parasite ROP38 downregulates host genes associated with MAPK signaling and the control of apoptosis and proliferation. These results highlight the value of integrative genomic approaches in prioritizing candidates for functional validation.
Peixoto
Lucia
L
Department of Biology and Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Chen
Feng
F
Harb
Omar S
OS
Davis
Paul H
PH
Beiting
Daniel P
DP
Brownback
Catie Small
CS
Ouloguem
Dinkorma
D
Roos
David S
DS
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism / Q000469:parasitology; D023281:Genomics; D006790:Host-Parasite Interactions; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D010770:Phosphotransferases / Q000235:genetics*; D011506:Proteins / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics*; D014122:Toxoplasma / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D014123:Toxoplasmosis / Q000469:parasitology*
D008565:Membrane Proteins; D011506:Proteins; D015800:Protozoan Proteins; D010770:Phosphotransferases