One of the most remarkable features of the obligate intracellular parasite, Toxoplasma gondii, is its ability to infect almost any nucleated cell in an extremely broad host range. During asexual growth in such cells, the parasite can adopt either of two forms: the rapidly dividing tachyzoite and the more slowly growing encysted form, the bradyzoite. This application addresses the molecular basis of the interaction between the tachyzoite form and the individual host cells in which it resides. Key to this interaction are a set of highly specialized secretory organelles known as rhoptries. These club-shaped structures are found at the apical end of all members of the Apicomplexa, including the causative agent of human malaria, Plasmodium. The rhoptries release their contents when these parasites invade into a host cell and this release appears key to both the physical act of invasion as well as to the co-opting of host cell functions once the parasite is inside. Recent work has shown that rhoptry neck proteins (RONs) help create the ring of physical contact between the host cell and invading parasite, the so-called moving junction. Rhoptry bulb proteins (ROPs), on the other hand appear to function within the cytosol/nucleus of the infected cell as well as on the parasitophorous vacuole that surrounds the dividing parasites. The work described in this application will determine how key RONs and ROPs perform their critical functions including identification of their location and topology and the host pathways/proteins with which they interact. The relevance of particular ROP functions to the interaction with the host as a whole will also be determined.

Public Health Relevance

Toxoplasma gondii is a single-celled parasite of many warm-blooded animals, including humans in whom it can cause severe infection of the central nervous system. Disease is most serious in the developing fetus and in persons who are immunocompromised by HIV/AIDS or other circumstances (lymphoma patients, transplant recipients, etc.). Our work will shed light on how this parasite infects and ultimately takes over a human cell.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI021423-27
Application #
8288112
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
1985-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
27
Fiscal Year
2012
Total Cost
$506,880
Indirect Cost
$189,313
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Christian, David A; Koshy, Anita A; Reuter, Morgan A et al. (2014) Use of transgenic parasites and host reporters to dissect events that promote interleukin-12 production during toxoplasmosis. Infect Immun 82:4056-67
Franco, Magdalena; Shastri, Anjali J; Boothroyd, John C (2014) Infection by Toxoplasma gondii specifically induces host c-Myc and the genes this pivotal transcription factor regulates. Eukaryot Cell 13:483-93
Poukchanski, Anna; Fritz, Heather M; Tonkin, Michelle L et al. (2013) Toxoplasma gondii sporozoites invade host cells using two novel paralogues of RON2 and AMA1. PLoS One 8:e70637
Child, Matthew A; Hall, Carolyn I; Beck, Josh R et al. (2013) Small-molecule inhibition of a depalmitoylase enhances Toxoplasma host-cell invasion. Nat Chem Biol 9:651-6
Boothroyd, John C (2013) Have it your way: how polymorphic, injected kinases and pseudokinases enable toxoplasma to subvert host defenses. PLoS Pathog 9:e1003296
Jensen, Kirk D C; Wang, Yiding; Wojno, Elia D Tait et al. (2011) Toxoplasma polymorphic effectors determine macrophage polarization and intestinal inflammation. Cell Host Microbe 9:472-83
Tyler, Jessica S; Boothroyd, John C (2011) The C-terminus of Toxoplasma RON2 provides the crucial link between AMA1 and the host-associated invasion complex. PLoS Pathog 7:e1001282
Caffaro, Carolina E; Boothroyd, John C (2011) Evidence for host cells as the major contributor of lipids in the intravacuolar network of Toxoplasma-infected cells. Eukaryot Cell 10:1095-9
Tyler, Jessica S; Treeck, Moritz; Boothroyd, John C (2011) Focus on the ringleader: the role of AMA1 in apicomplexan invasion and replication. Trends Parasitol 27:410-20
Morgado, Pedro; Ong, Yi-Ching; Boothroyd, John C et al. (2011) Toxoplasma gondii induces B7-2 expression through activation of JNK signal transduction. Infect Immun 79:4401-12

Showing the most recent 10 out of 89 publications