Identification and analysis of platelet polymorphisms associated with Malaria susceptibility

BRENDAN MCMORRAN (ANU) in partnership with Frank Mockenhaupt (HUB)

Human genetics is a major determinant of malaria susceptibility, although our understanding of the underlying mechanisms is poor. The McMorran lab has discovered a novel and important host protective mechanism involving platelets, and how this is influenced by host genetics factors [1,2].The experimental data of the group using mouse models of malarial infection and cultured human parasites indicates that platelets are important for host-mediated protection against malarial infection. The protective activity involves interaction (binding) between platelets and parasite-infected red cells (iRBC), platelet activation, and release of a cytotoxic platelet protein called platelet factor 4 (PF4), which kills the parasite [1,2]. Several human polymorphisms exist that determine differences in the functions of platelets and/or their responses to stimuli. In addition, genome wide association studies (GWAS)-determined malaria susceptibility alleles include those in platelet-expressed genes. The group hypothesises that platelet-expressed gene polymorphisms affect platelet-mediated protection in malaria infection and are associated with malarial susceptibility. The project aims to identify platelet-function polymorphisms in malaria patient cohorts that associate with disease susceptibility/severity, and experimentally compare the functions of platelets expressing these polymorphisms relevant to their parasite killing activity.

Interlinkages: Benedikt Beckmann (HUB), Alyssa Ingmundson (HUB), Melanie Rug (ANU), Adele Lehane (ANU), Simon Foote (ANU).

References:(1) McMorran, B. J. et al. (2009) Science 323: 797-800(2) McMorran, B. J. et al. (2012) Science 338: 1348-1351(3) Faraday, N. et al. (2011) Blood 118: 3367-3375(4) Qayyum, R. et al. (2015) BMC Genet. 16: 58(5) Timmann, C. et al., (2012) Nature 489: 443-446