Toxoplasma gondii attachment and invasion: architecture, assembly and recognition of microneme protein complexes

A parasite colonises and grows in a different organism and while it is not a benefit to the host, it can often cause disease. The protozoan parasite Toxoplasma gondii (T. gondii) is both a single-celled and animal-like organism. It is a major cause of congenital birth defects, as well as being often associated with immuno-compromised patients (e.g. AIDS) and an important veterinary pathogen. As one of the most common parasitic infections of man and animals, infecting more than 500 million people worldwide, T. gondii has a large socio-economic impact. Current treatments have toxic side effects with low efficacy and a vaccine has yet to be developed, therefore T. gondii represents a highly underestimated public health problem. We propose to study the mechanisms by which T. gondii are able colonise and invade hosts from the atomic standpoint, which will provide guidance for the rational design of drugs and vaccines.

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 and it infects more than 500 million people worldwide. Acute T. gondii infection during pregnancy can lead to congenital transmission and subsequent birth defects. T. gondii is also an opportunistic pathogen in immunocomprised individuals, such as AIDS and cancer patients, where it can awaken from a semi-dormant chronic state to produce encephalitis that is often fatal if left untreated. T. gondii represents a highly underestimated public health problem that has significant economic impact. Unlike other pathogens that hijack existing host cell uptake pathways, Toxoplasma and other apicomplexan parasites including Plasmodium actively force entry into host cells, where they gain respite from the host defense mechanisms. This conserved process relies on the regulated release of factors from novel organelles, namely micronemes, rhoptrys and dense granules. Protein complexes secreted from the microneme organelles (microneme proteins or MICs) play roles in colonising the host, gliding motility, apical attachment and subsequent invasion. Three heteromeric complexes (MIC2-M2AP, MIC1-4-6, and MIC3-8), have been described in T. gondii , however despite advances in their identification and importance to parasite survival, fundamental aspects of MIC architecture, assembly and interactions with cellular targets remain poorly understood. In this new proposal we aim to build on our previous MRC-funded work and develop more sophisticated structural analyses of functional complexes. These timely studies will reveal new functional and mechanistic insights but also suggest strategies for therapeutic intervention.