: The obligate intracellular protozoan Toxoplasma gondii can cause lethal disease (toxoplasmosis) during pregnancy or immune dysfunction and debilitating ocular pathology in otherwise healthy people. Rapid cycles of parasite invasion produce the hallmark necrotic lesions seen during reactivated infection. Our long term goal is to understand adhesion and its role in parasite dissemination, cell entry, and tissue colonization. Recent findings indicate that the micronemal adhesive complex TgMIC2-M2AP is a key component of the motility and cell invasion machinery. However, it remains poorly understood how these proteins assemble into a viable complex or what role the complex plays during in vivo infection. Also, the specific contributions of other invasion proteins that function alongside TgMIC2-M2AP remain obscure. Based on observations in related parasites, our general hypothesis is that Toxoplasma microneme proteins contribute to tissue invasion and colonization during infection.
Our specific aims are to 1) Define the domain interactions and sequence of events associated with assembly of the TgMIC2-M2AP complex; 2) Elucidate the role of the TgMIC2-M2AP complex in infection using newly derived knockout and knockdown strains; and 3) Assess the contributions of other novel invasion proteins identified in our recent proteomic screen to cell entry and infection. These studies will provide a deeper understanding of the molecular basis of Toxoplasma adhesion and its role in infection and pathogenesis. Because cell adhesion is an essential feature of the parasite, we anticipate these studies may lead to novel future opportunities to interrupt infection and potentially ameliorate disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046675-10
Application #
7390363
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Rogers, Martin J
Project Start
1999-12-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
10
Fiscal Year
2008
Total Cost
$282,439
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Di Cristina, Manlio; Carruthers, Vern B (2018) New and emerging uses of CRISPR/Cas9 to genetically manipulate apicomplexan parasites. Parasitology 145:1119-1126
Schultz, Aric J; Carruthers, Vern B (2018) Toxoplasma gondii LCAT Primarily Contributes to Tachyzoite Egress. mSphere 3:
Lunghi, Matteo; Spano, Furio; Magini, Alessandro et al. (2016) Alternative splicing mechanisms orchestrating post-transcriptional gene expression: intron retention and the intron-rich genome of apicomplexan parasites. Curr Genet 62:31-8
Sidik, Saima M; Huet, Diego; Ganesan, Suresh M et al. (2016) A Genome-wide CRISPR Screen in Toxoplasma Identifies Essential Apicomplexan Genes. Cell 166:1423-1435.e12
Bullen, Hayley E; Jia, Yonggen; Yamaryo-Botté, Yoshiki et al. (2016) Phosphatidic Acid-Mediated Signaling Regulates Microneme Secretion in Toxoplasma. Cell Host Microbe 19:349-60
Huynh, My-Hang; Carruthers, Vern B (2016) A Toxoplasma gondii Ortholog of Plasmodium GAMA Contributes to Parasite Attachment and Cell Invasion. mSphere 1:
Pszenny, Viviana; Ehrenman, Karen; Romano, Julia D et al. (2016) A Lipolytic Lecithin:Cholesterol Acyltransferase Secreted by Toxoplasma Facilitates Parasite Replication and Egress. J Biol Chem 291:3725-46
Huynh, My-Hang; Liu, Bing; Henry, Maud et al. (2015) Structural basis of Toxoplasma gondii MIC2-associated protein interaction with MIC2. J Biol Chem 290:1432-41
Carruthers, Vern B (2015) Parasites and their heterophagic appetite for disease. PLoS Pathog 11:e1004803
Roiko, Marijo S; Svezhova, Nadezhda; Carruthers, Vern B (2014) Acidification Activates Toxoplasma gondii Motility and Egress by Enhancing Protein Secretion and Cytolytic Activity. PLoS Pathog 10:e1004488

Showing the most recent 10 out of 48 publications