University of Cambridge
Tennis Court Road
The protozoan phylum Apicomplexa is arguably the most important group of parasitic pathogens responsible for human and animal disease. According to recent WHO figures, malaria (Plasmodium spp.) alone produces global morbidity and mortality figures into the hundreds-of-millions affected people each year. The encephalitis caused by Toxoplasma gondii infection kills an estimated 15-20% of all AIDS patients. Livestock losses and the implementation of control measures for avian coccidiosis (Eimeria spp.), costs the poultry industry millions of pounds annually. Despite decades of effort, there has been little progress in the prevention and treatment of apicomplexan diseases.
We are continuing to generate and employ T. gondii genome sequence information to investigate basic properties of the host-parasite interaction. In collaboration with the Pathogen Sequencing Unit at the Sanger Centre, T. gondii RH (type I lineage) chromosome Ia and Ib has been sequenced and annotated. Whole genome shotgun sequence of the ME49 B7 (type II lineage) isolate has been completed at TIGR. Comparsion of ChrIa between the two strains has revealed that the chromosome is identical. This is a surprising result given the high level of SNP polymorphism on ChrIb between the two strains. This observation is consistent with a prediction in our earlier work that some genes/chromosomal regions/chromosomes must be completely conserved between the type lineages and likely carry information essential for clonal growth/infection between intermediate hosts (1,4). Moreover, it appears as though the relationship between the clonal lineages may be explained by a very few number of crosses between ancestral parents (2). This suggests that a genetic crosses are rare but have been critical to the evolution and global population expansion of toxoplasma.
In anticipation of complete genome sequence for T.gondii, we have initiated a microarray project using cDNA clones from the EST effort (5) to study changes in gene expression during infection and growth within the host cell. In collaboration with the Boothroyd lab at Stanford, this microarray analysis has helped identify a key virulence factor that is secreted direcly into the host cell upon invasion (3). Further investigation into his novel mechanism will allow us a greater understanding of how the parasite modulates the host immune response. It is also possible to monitor host cell changes simultaneously with mouse oligonucleotide based microarrays. In addition, we are using NMR and GC-MS metabolomic data to monitor host cell changes, integrating these data with microarray data. These methods and the data generated represent a major step towards understanding the host-parasite interaction and will has applications ranging from defining genes involved with pathogenesis to investigating drug action in vitro.
- Graduate Students:
Russell Brown, Lalitha Sundaram
- Khan A, Taylor S, Ajioka JW, Rosenthal BM, Sibley LD (2009) Selection at a single locus leads to widespread expansion of Toxoplasma gondii lineages that are virulent in mice. PLoS Genet. 5(3):e1000404. Epub 2009 Mar 6
- Hermes G, Ajioka JW, Kelly KA, Mui E, Roberts F, Kasza K, Mayr T, Kirisits MJ, Wollmann R, Ferguson DJ, Roberts CW, Hwang JH, Trendler T, Kennan RP, Suzuki Y, Reardon C, Hickey WF, Chen L, McLeod R. (2008) Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection. J Neuroinflammation. 2008 Oct 23; 5:48.
- Sibley LD, Ajioka JW (2008) Population structure of Toxoplasma gondii: clonal expansion driven by infrequent recombination and selective sweeps. Annu Rev Microbiol. 62: 329-51
- Khan, A., Bohme, U. Kelly, K.A. Ajioka, J.W. (2006) Common inheritance of chromosome Ia associated with clonal expansion of Toxoplasma gondii. Genome Res. 16: 1119-25.
- Boyle JP, Rajasekar B, Saeij JP, Ajioka JW, Berriman M, Paulsen I, Roos DS, Sibley LD, White MW, Boothroyd JC. (2006) Just one cross appears capable of dramatically altering the population biology of a eukaryotic pathogen like Toxoplasma gondii. Proc Natl Acad Sci U S A. 103: 10514-9
- Saeij JP, Boyle JP, Coller S, Taylor S, Sibley LD, Brooke-Powell ET, Ajioka JW, Boothroyd, J. (2006) Polymorphic secreted kinases are key virulence factors in toxoplasmosis. Science 314: 1780-1783.
- Su, C., Evans, D., Cole, R.H., Kissinger, J.C., Ajioka, J.W., Sibley, L.D. (2003) Recent expansion of Toxoplasma through enhanced oral transmission. Science 299: 414-416
- Ajioka, J.W., Boothroyd, J.C., Brunk, B.P., Hehl, A., Hiller, L., Manger, I.D., Overton, G.C., Marrra, M., Roos, D., Wan, K-L., Waterston, R. and Sibley, L.D. (1998) Gene discovery by EST sequencing in Toxoplasma gondii reveals sequences restricted to the Apicomplexa. Genome Res. 8: 18-28. Jim Ajioka