The Toxoplasma gondii Rhoptry Kinome Is Essential for Chronic Infection

Fox, Barbara A.; Rommereim, Leah M.; Guevara, Rebekah B.; Falla, Alejandra; Triana, Miryam Andrea Hortua; Sun, Yanbo; Bzik, David J.

doi:10.1128/mbio.00193-16

Cited by 84 publications

(98 citation statements)

References 56 publications

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“…These two proteins are members of the extensive ROPK kinase family, an extended set of proteins that include a mix of active and inactive protein kinases [56] and whose prototypic member is the predicted pseudokinase ROP2. The precise functions of ROP34 and ROP35 are not known but ROP35 was recently reported to be necessary for high cyst burdens during the chronic stage of a mouse infection [57]. …”

Section: Resultsmentioning

confidence: 99%

An in vitro model of intestinal infection reveals a developmentally regulated transcriptome of Toxoplasma sporozoites and a NF-κB-like signature in infected host cells

et al. 2017

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Toxoplasmosis is a zoonotic infection affecting approximately 30% of the world’s human population. After sexual reproduction in the definitive feline host, Toxoplasma oocysts, each containing 8 sporozoites, are shed into the environment where they can go on to infect humans and other warm-blooded intermediate hosts. Here, we use an in vitro model to assess host transcriptomic changes that occur in the earliest stages of such infections. We show that infection of rat intestinal epithelial cells with mature sporozoites primarily results in higher expression of genes associated with Tumor Necrosis Factor alpha (TNFα) signaling via NF-κB. Furthermore, we find that, consistent with their biology, these mature, invaded sporozoites display a transcriptome intermediate between the previously reported day 10 oocysts and that of their tachyzoite counterparts. Thus, this study uncovers novel host and pathogen factors that may be critical for the establishment of a successful intracellular niche following sporozoite-initiated infection.

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Section: Resultsmentioning

confidence: 99%

An in vitro model of intestinal infection reveals a developmentally regulated transcriptome of Toxoplasma sporozoites and a NF-κB-like signature in infected host cells

et al. 2017

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“…, ; Yamamoto & Takeda, ), processes which are crucial for these parasites to survive within nucleated host cells and establish a chronic infection (Fox et al . , ). Conversely, none of the known Plasmodium ROPs have been shown to have kinase activity.…”

Section: Introductionmentioning

confidence: 97%

ThePlasmodiumrhoptry associated protein complex is important for parasitophorous vacuole membrane structure and intraerythrocytic parasite growth

Ghosh

Kennedy²,

Sanders

et al. 2017

Cellular Microbiology

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Plasmodium parasites must invade erythrocytes in order to cause the disease malaria. The invasion process involves the coordinated secretion of parasite proteins from apical organelles that include the rhoptries. The rhoptry is comprised of two compartments: the neck and the bulb. Rhoptry neck proteins are involved in host cell adhesion and formation of the tight junction that forms between the invading parasite and erythrocyte, whereas the role of rhoptry bulb proteins remains ill-defined due to the lack of functional studies. In this study, we show that the rhoptry-associated protein (RAP) complex is not required for rhoptry morphology or erythrocyte invasion. Instead, post-invasion when the parasite is bounded by a parasitophorous vacuolar membrane (PVM), the RAP complex facilitates the survival of the parasite in its new intracellular environment. Consequently, conditional knockdown of members of the RAP complex leads to altered PVM structure, delayed intra-erythrocytic growth, and reduced parasitaemias in infected mice. This study provides evidence that rhoptry bulb proteins localising to the parasite-host cell interface are not simply by-products of the invasion process but contribute to the growth of Plasmodium in vivo.

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“…NEKs are involved in cell cycle regulation, while Aurora kinases play pivotal roles in endodyogeny, duplication rate and parasite virulence [33]. Taken together, the presence of a variety of ROPKs in S. neurona is interesting given the fact that in T. gondii , ROPKs are key virulence factors [63]. …”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Identification and Evolutionary Analysis of Sarcocystis neurona Protein Kinases

Murungi

Kariithi

2017

Pathogens

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The apicomplexan parasite Sarcocystis neurona causes equine protozoal myeloencephalitis (EPM), a degenerative neurological disease of horses. Due to its host range expansion, S. neurona is an emerging threat that requires close monitoring. In apicomplexans, protein kinases (PKs) have been implicated in a myriad of critical functions, such as host cell invasion, cell cycle progression and host immune response evasion. Here, we used various bioinformatics methods to define the kinome of S. neurona and phylogenetic relatedness of its PKs to other apicomplexans. We identified 97 putative PKs clustering within the various eukaryotic kinase groups. Although containing the universally-conserved PKA (AGC group), S. neurona kinome was devoid of PKB and PKC. Moreover, the kinome contains the six-conserved apicomplexan CDPKs (CAMK group). Several OPK atypical kinases, including ROPKs 19A, 27, 30, 33, 35 and 37 were identified. Notably, S. neurona is devoid of the virulence-associated ROPKs 5, 6, 18 and 38, as well as the Alpha and RIO kinases. Two out of the three S. neurona CK1 enzymes had high sequence similarities to Toxoplasma gondii TgCK1-α and TgCK1-β and the Plasmodium PfCK1. Further experimental studies on the S. neurona putative PKs identified in this study are required to validate the functional roles of the PKs and to understand their involvement in mechanisms that regulate various cellular processes and host-parasite interactions. Given the essentiality of apicomplexan PKs in the survival of apicomplexans, the current study offers a platform for future development of novel therapeutics for EPM, for instance via application of PK inhibitors to block parasite invasion and development in their host.

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The Toxoplasma gondii Rhoptry Kinome Is Essential for Chronic Infection

Cited by 84 publications

References 56 publications

An in vitro model of intestinal infection reveals a developmentally regulated transcriptome of Toxoplasma sporozoites and a NF-κB-like signature in infected host cells

An in vitro model of intestinal infection reveals a developmentally regulated transcriptome of Toxoplasma sporozoites and a NF-κB-like signature in infected host cells

ThePlasmodiumrhoptry associated protein complex is important for parasitophorous vacuole membrane structure and intraerythrocytic parasite growth

Genome-Wide Identification and Evolutionary Analysis of Sarcocystis neurona Protein Kinases

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