Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Vector transmission regulates immune control of Plasmodium virulence



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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Mosquito transmission of P. c. chabaudi AS attenuates virulence.
Figure 2: Mosquito transmission of P. c. chabaudi AS transforms the elicited mammalian immune response.
Figure 3: Transformed innate and adaptive immune responses attenuate P. c. chabaudi AS virulence.
Figure 4: Mosquito transmission of P. c. chabaudi AS modifies parasite gene expression in the erythrocytic cycle.

Accession codes



Data deposits

RNA-seq datasets have been deposited in ArrayExpress with accession number E-ERAD-95.


  1. Dearsly, A. L., Sinden, R. E. & Self, I. A. Sexual development in malarial parasites: gametocyte production, fertility and infectivity to the mosquito vector. Parasitology 100, 359–368 (1990)

    Article  Google Scholar 

  2. Mackinnon, M. J. & Read, A. F. Selection for high and low virulence in the malaria parasite Plasmodium chabaudi. Proc. R. Soc. Lond. B 266, 741–748 (1999)

    CAS  Article  Google Scholar 

  3. Yoeli, M., Hargreaves, B., Carter, R. & Walliker, D. Sudden increase in virulence in a strain of Plasmodium berghei yoelii. Ann. Trop. Med. Parasitol. 69, 173–178 (1975)

    CAS  Article  Google Scholar 

  4. Hartley, E. G. Increased virulence of Plasmodium cynomolgi bastianellii in the rhesus monkey. Trans. R. Soc. Trop. Med. Hyg. 63, 411–412 (1969)

    CAS  Article  Google Scholar 

  5. Chin, W., Contacos, P. G., Collins, W. E., Jeter, M. H. & Alpert, E. Experimental mosquito-transmission of Plasmodium knowlesi to man and monkey. Am. J. Trop. Med. Hyg. 17, 355–358 (1968)

    CAS  Article  Google Scholar 

  6. Alger, N. E., Branton, M., Harant, J. & Silverman, P. H. Plasmodium berghei NK65 in the inbred A-J mouse: variations in virulence of P. berghei demes. J. Protozool. 18, 598–601 (1971)

    CAS  Article  Google Scholar 

  7. Knowles, G. & Walliker, D. Variable expression of virulence in the rodent malaria parasite Plasmodium yoelii yoelii. Parasitology 81, 211–219 (1980)

    CAS  Article  Google Scholar 

  8. Mackinnon, M. J., Bell, A. & Read, A. F. The effects of mosquito transmission and population bottlenecking on virulence, multiplication rate and rosetting in rodent malaria. Int. J. Parasitol. 35, 145–153 (2005)

    CAS  Article  Google Scholar 

  9. Spence, P. J., Jarra, W., Lévy, P., Nahrendorf, W. & Langhorne, J. Mosquito transmission of the rodent malaria parasite Plasmodium chabaudi. Malar. J. 11, 407 (2012)

    Article  Google Scholar 

  10. Glynn, J. R., Collins, W. E., Jeffery, G. M. & Bradley, D. J. Infecting dose and severity of falciparum malaria. Trans. R. Soc. Trop. Med. Hyg. 89, 281–283 (1995)

    CAS  Article  Google Scholar 

  11. Langhorne, J., Ndungu, F. M., Sponaas, A. M. & Marsh, K. Immunity to malaria: more questions than answers. Nature Immunol. 9, 725–732 (2008)

    CAS  Article  Google Scholar 

  12. Stephens, R., Culleton, R. L. & Lamb, T. J. The contribution of Plasmodium chabaudi to our understanding of malaria. Trends Parasitol. 28, 73–82 (2012)

    Article  Google Scholar 

  13. Spence, P. J. & Langhorne, J. T cell control of malaria pathogenesis. Curr. Opin. Immunol. 24, 444–448 (2012)

    CAS  Article  Google Scholar 

  14. del Portillo, H. A. et al. The role of the spleen in malaria. Cell. Microbiol. 14, 343–355 (2012)

    CAS  Article  Google Scholar 

  15. Sponaas, A. M. et al. Malaria infection changes the ability of splenic dendritic cell populations to stimulate antigen-specific T cells. J. Exp. Med. 203, 1427–1433 (2006)

    CAS  Article  Google Scholar 

  16. Jain, V. et al. Plasma IP-10, apoptotic and angiogenic factors associated with fatal cerebral malaria in India. Malar. J. 7, 83 (2008)

    Article  Google Scholar 

  17. Lawton, J. et al. Characterization and gene expression analysis of the cir multi-gene family of Plasmodium chabaudi chabaudi (AS). BMC Genomics 13, 125 (2012)

    CAS  Article  Google Scholar 

  18. Cunningham, D., Lawton, J., Jarra, W., Preiser, P. & Langhorne, J. The pir multigene family of Plasmodium: antigenic variation and beyond. Mol. Biochem. Parasitol. 170, 65–73 (2010)

    CAS  Article  Google Scholar 

  19. Brannan, L. R., McLean, S. A. & Phillips, R. S. Antigenic variants of Plasmodium chabaudi chabaudi AS and the effects of mosquito transmission. Parasite Immunol. 15, 135–141 (1993)

    CAS  Article  Google Scholar 

  20. McLean, S. A., Phillips, R. S., Pearson, C. D. & Walliker, D. The effect of mosquito transmission of antigenic variants of Plasmodium chabaudi. Parasitology 94, 443–449 (1987)

    Article  Google Scholar 

  21. Manske, M. et al. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing. Nature 487, 375–379 (2012)

    ADS  CAS  Article  Google Scholar 

  22. Peters, J. et al. High diversity and rapid changeover of expressed var genes during the acute phase of Plasmodium falciparum infections in human volunteers. Proc. Natl Acad. Sci. USA 99, 10689–10694 (2002)

    ADS  CAS  Article  Google Scholar 

  23. Madsen, L. et al. Mice lacking all conventional MHC class II genes. Proc. Natl Acad. Sci. USA 96, 10338–10343 (1999)

    ADS  CAS  Article  Google Scholar 

  24. Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992)

    CAS  Article  Google Scholar 

  25. Chomczynski, P. & Sacchi, N. The single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: twenty-something years on. Nature Protocols 1, 581–585 (2006)

    CAS  Article  Google Scholar 

  26. Kyes, S., Pinches, R. & Newbold, C. A simple RNA analysis method shows var and rif multigene family expression patterns in Plasmodium falciparum. Mol. Biochem. Parasitol. 105, 311–315 (2000)

    CAS  Article  Google Scholar 

  27. Kozarewa, I. et al. Amplification-free Illumina sequencing-library preparation facilitates improved mapping and assembly of (G+C)-biased genomes. Nature Methods 6, 291–295 (2009)

    CAS  Article  Google Scholar 

  28. Trapnell, C., Pachter, L. & Salzberg, S. L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009)

    CAS  Article  Google Scholar 

  29. Anders, S. & Huber, W. Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010)

    CAS  Article  Google Scholar 

  30. Sargeant, T. J. et al. Lineage-specific expansion of proteins exported to erythrocytes in malaria parasites. Genome Biol. 7, R12 (2006)

    Article  Google Scholar 

  31. Alexa, A., Rahnenfuhrer, J. & Lengauer, T. Improved scoring of functional groups from gene expression data by decorrelating GO graph structure. Bioinformatics 22, 1600–1607 (2006)

    CAS  Article  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



P.J.S., W.J. and J.L. designed the study. P.J.S., W.J., P.L., L.C. and T.B. performed the experiments. P.J.S. and A.J.R. analysed the data. M.S. and M.B. provided project management. P.J.S. wrote the manuscript.

Corresponding author

Correspondence to Jean Langhorne.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figure

This file contains Supplementary Figures 1-12. (PDF 1913 kb)

Supplementary Tables

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)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Spence, P., Jarra, W., Lévy, P. et al. Vector transmission regulates immune control of Plasmodium virulence. Nature 498, 228–231 (2013).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing