The Structural basis of Toxoplasma gondii invasion: Micronemal protein interactions

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

The phylum Apicomplexa contains some of the most widespread protozoan parasites of humans and animals. Key members include Plasmodium spp., Eimeria spp., Neospora caninium and Toxoplasma gondii. Not only has T. gondii emerged as the principal model for the study of other apicomplexa parasites it is an important pathogen in its own right, causing severe disseminated disease. Infection by apicomplexans is established in the host by rapid and forced invasion of host cells. Proteins secreted at the first stage of this process, participate in apical attachment to host cell surfaces and the formation of a connection with the parasite actinomyosin system, thereby providing the platform from which to drive invasion - these are called microneme proteins (MICs).
We plan to investigate some fundamental aspects of how MICs assemble into surface complexes and discriminate host ligands, which will provide new information on how the parasite works at the molecular level. Our work should provide a foundation that may reveal new pathways to the development of antimicrobial strategies.

Technical Summary

Toxoplasma gondii (T. gondii) is a protozoan parasite that has been recognized as one of the most pervasive parasites known to man. Its host range is believed to encompass all warm-blooded vertebrates, including 10-90% of adult humans depending on the region, in whom it causes the life-long chronic infection Toxoplasmosis. Acute T. gondii infection during pregnancy in a nonimmune host can lead to congenital transmission and subsequent birth defects such as hydrocephalic babies. T. gondii is also an opportunistic pathogen in AIDS patients where it can awaken from a semi-dormant chronic state to produce encephalitis that is often fatal if left untreated. It therefore represents a highly underestimated public health problem that has significant economic implications. As an obligate intracellular parasite, T. gondii has the remarkable ability to invade in vitro every nucleated cell type of vertebrate origin tested. One mechanism involves the secretion of factors that are able to interact with the host cell and form a tight adhesion zone. Protein discharge from the microneme is the first step in host invasion and the key TgMIC1-TgMIC4-TgMIC6 complex binds host cells to form a ?molecular bridge? to the parasite. Despite recent attention, the fine structural details of any micronemal protein complex have yet to be elucidated. We propose to embark on an atomic resolution study of TgMIC1-TgMIC4-TgMIC6 micronemal complex from T. gondii that will address many unresolved issues. We propose to: i) Identify domains responsible for formation of TgMIC1-TgMIC4-TgMIC6 complex, ii) Determine the 3D structures of these domains from TgMIC1, TgMIC4 and TgMIC6 iii) Determine the 3D structures the TgMIC1-TgMIC4-TgMIC6 sub-complexes, and iv) Propose testable hypotheses for the architecture and function of the TgMIC1-TgMIC4-TgMIC6 complex. This work will have major impact in the basic sciences of structural biology, biochemistry and microbiology.

Publications

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Huynh MH (2015) Structural basis of Toxoplasma gondii MIC2-associated protein interaction with MIC2. in The Journal of biological chemistry

 
Description BBSRC Project Grant
Amount £350,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2009 
End 01/2011
 
Title New scripts for analysis of NMR data 
Description Software for the high through put analysis of protein NMR data 
Type Of Material Improvements to research infrastructure 
Year Produced 2009 
Provided To Others? Yes  
Impact Software download by several groups 
 
Title Protein reagents for testing in biological assays 
Description Purified protein samples 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact publications citing original work 
 
Title Structures deposited in Brookhaven PDB 
Description High resolution structures of parasite micronem proteins 
Type Of Material Biological samples 
Year Produced 2008 
Provided To Others? Yes  
Impact Citation in key reviews 
 
Title Structures published in Brookhaven PDB 
Description Structures published in Brookhaven PDB together with experiment data and access to research reagents 
Type Of Material Biological samples 
Year Produced 2016 
Provided To Others? Yes  
Impact Subsequent publicaions 
 
Description Prof Dominique Soldati-Favre 
Organisation University of Geneva
Country Switzerland 
Sector Academic/University 
PI Contribution Design of novel cellular and parasite experiment which have been carried out in collaborator Laboratory.
Collaborator Contribution Provision of reagents and peforming in vivo parasite experiments
Impact 17491595 17584164 18818666 16166092 15772760
 
Description Department event 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 100s visitor engaged with this activity

TBD
Year(s) Of Engagement Activity 2013,2017
URL http://www.centenary.mrc.ac.uk/events/science-festival/
 
Description Press release (Apicomplexan) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press release in University magazine and website

Mutilple citation to the press release
Year(s) Of Engagement Activity 2007
 
Description Press release/article (Apicomplexan) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Article on College magazine and press release

Potential collaborations identified
Year(s) Of Engagement Activity 2007