Defining mechanisms by which Plasmodium virulence is regulated is central to understanding the pathogenesis of human malaria. Serial blood passage of Plasmodium through rodents1,2,3, primates4 or humans5 increases parasite virulence, suggesting that vector transmission regulates Plasmodium virulence within the mammalian host. In agreement, disease severity can be modified by vector transmission6,7,8, which is assumed to ‘reset’ Plasmodium to its original character3. However, direct evidence that vector transmission regulates Plasmodium virulence is lacking. Here we use mosquito transmission of serially blood passaged (SBP) Plasmodium chabaudi chabaudi9 to interrogate regulation of parasite virulence. Analysis of SBP P. c. chabaudi before and after mosquito transmission demonstrates that vector transmission intrinsically modifies the asexual blood-stage parasite, which in turn modifies the elicited mammalian immune response, which in turn attenuates parasite growth and associated pathology. Attenuated parasite virulence associates with modified expression of the pir multi-gene family. Vector transmission of Plasmodium therefore regulates gene expression of probable variant antigens in the erythrocytic cycle, modifies the elicited mammalian immune response, and thus regulates parasite virulence. These results place the mosquito at the centre of our efforts to dissect mechanisms of protective immunity to malaria for the development of an effective vaccine.
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This work was supported by the Medical Research Council (U117584248) and the Wellcome Trust (089553 and 098051). P.J.S. is the recipient of a Leverhulme Trust Early Career Fellowship. The authors thank R. Sinden, K. Baker and M. Tunnicliff for provision of Anopheles stephensi, and Biological Services at NIMR. M. Blackman, G. Kassiotis and G. Stockinger are thanked for critical reading of the manuscript.
The authors declare no competing financial interests.
This file contains Supplementary Figures 1-12. (PDF 1913 kb)
This file contains Supplementary Tables 1-2. Supplementary Table 1 lists all genes identified as significantly upregulated in blood-stage parasites following mosquito transmission, whilst Supplementary Table 2 lists those upregulated following serial blood passage. (XLS 132 kb)
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Spence, P., Jarra, W., Lévy, P. et al. Vector transmission regulates immune control of Plasmodium virulence. Nature 498, 228–231 (2013). https://doi.org/10.1038/nature12231
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