Evolution of malaria virulence in cross-generation transmission through selective immune pressure
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- Case Western Reserve University
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- Manuscript
- Date:
- Received 23 June 2007 19:32 UTC; Posted 25 June 2007
- Subjects:
- Immunology, Bioinformatics, Evolutionary Biology
- Abstract:
Theoretical arguments and some mathematical models of host-parasite coevolution (e.g. [1- 6]) suggest host immunity as the driving source for the evolution of parasite virulence. Imperfect vaccines in particular, can play the role and recent work [7] sets to test these ideas experimentally, using the mouse malaria model, Plasmodium chabaudi. To this end the authors evolve parasite lines in immunized and nonimmunized (“naïve”) mice using serial passage of infected blood samples. They find parasite lines evolved in immunized mice become more virulent than those evolved in naive mice. Furthermore, this feature persisted even when the evolved strains were transmitted through mosquitoes.
Here we develop a mathematical model of parasite dynamics that qualitatively reproduces the experimental results of [7]. Our model accounts for the basic in-host processes: (i) production and depletion of red blood cells (RBC); (ii) immune-modulated parasite growth/ replication, (iii) immune stimulation and clearing of parasite. Besides we introduce multiple parasite strains with variable levels of virulence, and allow random mutations during replication process. The virulence is represented by a single parameter – immune stimulation threshold. So more virulent strains have higher “tolerance levels”, hence increased RBC depletion (anemia).
Numeric simulations with our model exhibit, as in [7] the overall evolution of virulence in serial passage of parasite strains, and its enhancement through partial (imperfect) immunization.
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- This document is licensed to the public under the Creative Commons Attribution 2.5 License
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Gurarie, David. Evolution of malaria virulence in cross-generation transmission through selective immune pressure. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2007.203.1> (2007)
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Trevor Marshall on 03 July 2007 13:47 UTC
Excellent paper.
The big variable is the immune status of the host, of course, which is tough to model because of the number of degrees of freedom (hundreds) and the inability to measure it with a specific set of reproducible parameters.
You might review the following papers. First, to get some idea of the magnitude of the number of degrees of freedom in the host innate immune response:
Brahmachary M, et al. 2007. Computational promoter analysis of mouse, rat and human antimicrobial peptide-coding genes. BMC Bioinformatics. 18;7 Suppl 5:S8
(of course, only a subset of these are active against the parasites you are modeling)
Second, evidence that microbial genomes can produce substances that directly modulate the host anti-microbial peptide response:
Marshall, Trevor. 2007. Bacterial Capnine Blocks Transcription of Human Antimicrobial Peptides. Available from Nature Precedings. doi:10.1038/npre.2007.164.1. URL http://precedings.nature.com/documents/164/version/1
This on weaknesses in using murine models where host anti-microbial response via the VDR is involved:
Marshall, Trevor. 2007. Molecular Static and Dynamic Analyses reveal Flaw in Murine Model used by US FDA to Detect Drug Carcinogenicity. Available from Nature Precedings. doi:10.1038/npre.2007.52.1. URL http://precedings.nature.com/documents/52/version/1
And finally, an early summary of our own work showing why host immunity via the Nuclear Hormone Receptors has been changing over the last half century:
Marshall TG. 2006. VDR Nuclear Receptor Competence is the Key to Recovery from Chronic Inflammatory and Autoimmune Disease. Abstract presentation, Days of Molecular Medicine 2006. Copy available from URL http://autoimmunityresearch.org/karolinska-handout.pdf
There is a comprehensive review paper on this last issue (immunomodulation due to the secosteroid we call Vitamin D) which is currently ‘in press.’ If you are interested, contact me directly for a preprint.
Overall, an excellent paper, in a field of research (modeling) which is absolutely essential to our proper understanding of the metagenomic behavior of human parasites and pathogens.