The International Journal of Biochemistry & Cell Biology 43 (2011) 839–842 Contents lists available at ScienceDirect The International Journal of Biochemistry & Cell Biology journal homepage: www.elsevier.com/locate/biocel Cells in focus The Plasmodium falciparum-infected red blood cell Leann Tilley a,∗ , Matthew W.A. Dixon a , Kiaran Kirk b a Department of Biochemistry and Centre of Excellence for Coherent X-ray Science, La Trobe University, Melbourne, VIC, 3086, Australia b Research School of Biology, The Australian National University, Canberra, Australian Capital Territory 0200, Australia article info Article history: Received 18 October 2010 Received in revised form 27 February 2011 Accepted 24 March 2011 Available online 31 March 2011 Keywords: Plasmodium falciparum Red blood cell Haemoglobin Malaria parasite Antimalarial abstract Plasmodium falciparum, the most virulent of the human malaria parasites, causes up to one million deaths per year. The parasite spends part of its lifecycle inside the red blood cells (RBCs) of its host. As it grows it ingests the RBC cytoplasm, digesting it in an acidic vacuole. Free haem released during haemoglobin digestion is detoxified by conversion to inert crystals of haemozoin. Malaria pathology is evident during the blood stage of the infection and is exacerbated by adhesion of infected RBCs to blood vessel walls, which prevents splenic clearance of the infected cells. Cytoadherence is mediated by surface-exposed vir- ulence proteins that bind to endothelial cell receptors. These ‘adhesins’ are exported to the RBC surface via an exomembrane system that is established outside the parasite in the host cell cytoplasm. Antimalar- ial drugs that interfere with haem detoxification, or target other parasite-specific processes, have been effective in the treatment of malaria, but their use has been dogged by the development of resistance. Similarly, efforts to develop an effective blood vaccine are hindered by the variability of surface-exposed antigens. © 2011 Elsevier Ltd. All rights reserved. Cell facts • Plasmodium falciparum invades RBCs and develops through the ‘ring’ and ‘trophozoite’ stages, then divides to form an average of ∼20 daughter cells in the ‘schizont’ stage. • The intraerythrocytic P. falciparum parasite consumes up to 70% of the host cell haemoglobin in an acidic digestive vac- uole, generating a crystalline by-product called haemozoin. • Plasmodium-infected RBCs rely almost entirely on glycolysis for energy. • The parasite establishes an exomembrane system in the host RBC cytoplasm and this provides a pathway for trafficking proteins, including virulence determinants, to the RBC sur- face. • Adhesion of P. falciparum-infected RBCs to blood vessel walls helps avoid splenic clearance and contributes to the clinical symptoms of the disease, including fatal complications. • Quinoline antimalarials inhibit haemozoin formation leading to a build-up of toxic haematin. Abbreviations: PfEMP1, P. falciparum erythrocyte membrane protein-1; PV, par- asitophorous vacuole; PEXEL, Plasmodium export element; RBC, red blood cell; TCA, tricarboxylic acid. ∗ Corresponding author. Tel.: +61 3 94791375/83442449; fax: +61 3 94792467. E-mail addresses: L.Tilley@latrobe.edu.au, ltilley@umimelb.edu.au (L. Tilley). • Artemisinin-related antimalarials are thought to be activated by haemoglobin digestion products. • Parasites have developed resistance to quinoline antimalar- ials and there are recent reports of reduced sensitivity to artemisinin-related antimalarials. 1. Introduction The World Health Organisation recently estimated that malaria causes about 240 million bouts of illness each year and results in about 860 thousand deaths (WHO, 2010); however it is likely that these numbers under-estimate the real burden of the disease. Four species of Plasmodium – Plasmodium falciparum, P. vivax, P. ovale and P. malariae – commonly infect humans, and a fifth, P. knowlesi, has recently been identified as being responsible for a significant number of human cases in South-East Asia (Cox-Singh et al., 2008). Of these, P. falciparum causes the majority of the deaths and pro- duces the most severe clinical manifestations (Rowe et al., 2009). P. falciparum has a complex lifecycle involving stages in humans and mosquitoes, with the blood stage of the infection responsible for much of the disease pathology. During this stage the parasite undergo cycles of growth and division inside the red blood cells (RBCs) of its host. The terminally differentiated human RBC is effec- tively a “sack” of haemoglobin, tailored by evolution to perform the specialised tasks of O 2 and CO 2 transport (Klinken, 2002). The 1357-2725/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.biocel.2011.03.012