Abstract
The pathology associated with malaria infection is largely due to the ability of infected human RBCs to adhere to a number of receptors on endothelial cells within tissues and organs. This phenomenon is driven by the export of parasite-encoded proteins to the host cell, the exact function of many of which is still unknown. Here we inactivate the function of one of these exported proteins, PFA66, a member of the J-domain protein family. Although parasites lacking this protein were still able to grow in cell culture, we observed severe defects in normal host cell modification, including aberrant morphology of surface knobs, disrupted presentation of the cytoadherence molecule PfEMP1, and a total lack of cytoadherence, despite the presence of the knob associated protein KAHRP. Complementation assays demonstrate that an intact J-domain is required for recovery to a wild-type phenotype and suggest that PFA66 functions in concert with a HSP70 to carry out host cell modification. Strikingly, this HSP70 is likely to be of host origin. ATPase assays on recombinant protein verify a functional interaction between PFA66 and residual host cell HSP70. Taken together, our data reveal a role for PFA66 in host cell modification, strongly implicate human HSP70s as being essential in this process and uncover a new KAHRP-independent molecular factor required for correct knob biogenesis.
Highlights
Plasmodium falciparum causes the most severe form of malaria in humans, malaria tropica, responsible for over 200 million clinical cases and 400,000 deaths per annum, mainly in children under the age of 5 and mostly in sub-Saharan Africa [1]
We have studied which factors from both parasite and host cell are required for this renovation process, and discover that human chaperone proteins, referred to as HSP70, are required
We find that inactivation of PFA66 function leads to dramatic aberrations in host cell modification, especially in knob morphology, capacity for cytoadherence and surface exposure of the virulence factor PfEMP1
Summary
Plasmodium falciparum causes the most severe form of malaria in humans, malaria tropica, responsible for over 200 million clinical cases and 400,000 deaths per annum, mainly in children under the age of 5 and mostly in sub-Saharan Africa [1]. The pathology associated with malaria infection is largely due to the ability of infected human RBCs (red blood cells, RBC) to adhere to a number of receptors on endothelial cells within tissues and organs [2] This cytoadherence results in reduced blood flow in the affected areas, hypoxia and (in cerebral malaria) increased intracranial pressure [2,3]. The phenomenon of cytoadherence results from parasite-induced host cell modification in which parasite-encoded proteins are transported to and exposed at the surface of the infected host cell, where they mediate endothelial binding and antigenic variation [4,5,6] In addition to these surface proteins, parasites encode, express, and export a large number of other proteins to the infected RBC [7,8,9,10,11]. Many of these proteins are specific to P. falciparum, and their function is still not well understood, partly due to limitations in reverse genetic systems [9,12,13]
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