Multiple Infections, Immune Dynamics, and the Evolution of Virulence

Samuel Alizon and Minus van Baalen
The American Naturalist
Vol. 172, No. 4 (October 2008), pp. E150-E168
DOI: 10.1086/590958
Stable URL:
Page Count: 19
  • Download PDF
  • Cite this Item

You are not currently logged in.

Access your personal account or get JSTOR access through your library or other institution:


Log in to your personal account or through your institution.

Multiple Infections, Immune Dynamics, and the Evolution of Virulence
We're having trouble loading this content. Download PDF instead.


Abstract: Understanding the effect of multiple infections is essential for the prediction (and eventual control) of virulence evolution. Some theoretical studies have considered the possibility that several strains coexist in the same host (coinfection), but few have taken their within‐host dynamics explicitly into account. Here, we develop a nested approach based on a simple model for the interaction of parasite strains with their host’s immune system. We study virulence evolution by linking the within‐host dynamics to an epidemiological framework that incorporates multiple infections. Our model suggests that antigenically similar parasite strains cannot coexist in the long term inside a host. We also find that the optimal level of virulence increases with the efficiency of multiple infections. Finally, we notice that coinfections create heterogeneity in the host population (with susceptible hosts and infected hosts), which can lead to evolutionary branching in the parasite population and the emergence of a hypervirulent parasite strategy. We interpret this result as a parasite specialization to the infectious state of the hosts. Our study has experimental and theoretical implications in a virulence management perspective.

Notes and References

This item contains 77 references.

Literature Cited
  • ['Alizon, S. 2008. Decreased overall virulence in coinfected hosts leads to the persistence of virulent parasites. American Naturalist 172:E67–E79.']
  • ['Alizon, S., and M. van Baalen. 2005. Emergence of a convex trade‐off between transmission and virulence. American Naturalist 165:E155–E167.']
  • ['Anderson, R. M., and R. M. May. 1982. Coevolution of hosts and parasites. Parasitology 85:411–426.']
  • ['André, J.‐B., and B. Godelle. 2006. Within‐host evolution and virulence in microparasites. Journal of Theoretical Biology 241:402–409.']
  • ['André, J.‐B., J.‐B. Ferdy, and B. Godelle. 2003. Within‐host parasite dynamics, emerging trade‐off, and evolution of virulence with immune system. Evolution 57:1489–1497.']
  • ['Andreasen, V., J. Lin, and S. A. Levin. 1997. The dynamics of cocirculating inluenza strains conferring partial cross‐immunity. Journal of Mathematical Biology 35:825–842.']
  • ['Bell, A. S., J. C. de Roode, D. Sim, and A. F. Read. 2006. Within‐host competition in genetically diverse malaria infections: parasite virulence and competitive success. Evolution 60:1358–1371.']
  • ['Boldin, B., and O. Diekmann. 2008. Superinfections can induce evolutionarily stable coexistence of pathogens. Journal of Mathematical Biology 56:635–672.']
  • ['Bonhoeffer, S., and M. A. Nowak. 1994. Intra‐host versus inter‐host selection: viral strategies of immune function impairment. Proceedings of the National Academy of Sciences of the USA 91:8062–8066.']
  • ['Bremermann, H. J., and J. Pickering. 1983. A game‐theoretical model of parasite virulence. Journal of Theoretical Biology 100:411–426.']
  • ['Brown, S. P. 2001. Collective action in RNA virus. Journal of Evolutionary Biology 14:821–828.']
  • ['Brown, S. P., and B. T. Grenfell. 2001. An unlikely partnership: parasites, concomitant immunity and host defence. Proceedings of the Royal Society B: Biological Sciences 268:2543–2549.']
  • ['Brown, S. P., and R. Johnstone. 2001. Cooperation in the dark: signalling and collective action in quorum‐sensing bacteria. Proceedings of the Royal Society B: Biological Sciences 268:961–965.']
  • ['Brown, S. P., M. E. Hochberg, and B. T. Grenfell. 2002. Does multiple infection select for raised virulence? Trends in Microbiology 10:401–405.']
  • ['Chao, L., K. A. Hanley, C. L. Burch, C. Dahlberg, and P. E. Turner. 2000. Kin selection and parasite evolution: higher and lower virulence with hard and soft selection. Quarterly Review of Biology 75:261–275.']
  • ['Cooper, T. F., and J. A. Heinemann. 2005. Selection for plasmid post‐segregational killing depends on multiple infection: evidence for the selection of more virulent parasites through parasite‐level competition. Proceedings of the Royal Society B: Biological Sciences 272:403–410.']
  • ['Cox, F. E. G. 2001. Concomitant infections, parasites and immune responses. Parasitology 122:S23–S38.']
  • ['Davies, C. M., E. F. Fairbrother, and J. P. Webster. 2002. Mixed strain schistosome infection of snails and the evolution of parasite virulence. Parasitology 124:31–38.']
  • ['Day, K. P., F. Karamalis, J. Thompson, D. A. Barnes, C. Peterson, H. Brown, G. V. Brown, and D. J. Kemp. 1993. Genes necessary for expression of a virulence determinant and for transmission of Plasmodium falciparum are located on a 0.3‐megabase region of chromosome 9. Proceedings of the National Academy of Sciences of the USA 90:8292–8296.']
  • ['Day, T., and S. R. Proulx. 2004. A general theory for the evolutionary dynamics of virulence. American Naturalist 163:E40–E63.']
  • ['De Boer, R. J., and A. S. Perelson. 1995. Towards general function describing T‐cell proliferation. Journal of Theoretical Biology 175:567–576.']
  • ['de Roode, J. C., R. Culleton, S. J. Cheesman, R. Carter, and A. F. Read. 2004. Host heterogeneity is a determinant of competitive exclusion or coexistence in genetically diverse malaria infections. Proceedings of the Royal Society B: Biological Sciences 271:1073–1080.']
  • ['de Roode, J. C., M. E. H. Helinski, M. A. Anwar, and A. F. Read. 2005a. Dynamics of multiple infection and within‐host competition in genetically diverse malaria infections. American Naturalist 166:531–542.']
  • ['de Roode, J. C., R. Pansini, S. J. Cheesman, M. E. H. Helinski, S. Huijben, A. R. Wargo, A. S. Bell, B. H. K. Chan, D. Walliker, and A. F. Read. 2005b. Virulence and competitive ability in genetically diverse malaria infections. Proceedings of the National Academy of Sciences of the USA 102:7624–7628.']
  • ['Ebert, D., and K. Mangin. 1997. The influence of host demography on the evolution of virulence of microsporidian gut parasite. Evolution 51:1828–1837.']
  • ['Escriu, F., A. Fraile, and F. García‐Arenal. 2000. Evolution of virulence in natural populations of the satellite RNA of cucumber mosaic virus. Phytopathology 90:480–485.']
  • ['Ewald, P. W. 1983. Host‐parasite relations, vectors, and the evolution of disease severity. Annual Review of Ecology and Systematics 14:465–485.']
  • ['Frank, S. A. 1996. Models of parasite virulence. Quarterly Review of Biology 71:37–78.']
  • ['———. 2002. Immunology and evolution of infectious disease. Princeton University Press, Princeton, NJ.']
  • ['Gandon, S. 2004. Evolution of multihost parasites. Evolution 58:455–469.']
  • ['Gandon, S., V. A. A. Jansen, and M. van Baalen. 2001. Host life‐history and the evolution of parasite virulence. Evolution 55:1056–1062.']
  • ['Gandon, S., M. van Baalen, and V. A. A. Jansen. 2002. The evolution of parasite virulence, superinfection, and host resistance. American Naturalist 159:658–669.']
  • ['Ganusov, V. V., C. T. Bergstrom, and R. Antia. 2002. Within‐host population dynamics and the evolution of microparasites in a heterogeneous host population. Evolution 52:213–223.']
  • ['Geritz, S. A. H., J. A. J. Metz, E. Kisdi, and G. Meszéna. 1997. Dynamics of adaptation and evolutionary branching. Physical Review Letters 78:2024–2027.']
  • ['Gilbert, S. C., M. Plebanski, S. Gupta, J. Morris, M. Cox, M. Aidoo, D. Kwiatkowski, B. M. Greenwood, H. C. Whittle, and A. V. S. Hill. 1998. Association of malaria parasite population structure, HLA, and immunological antagonism. Science 279:1173–1177.']
  • ['Gilchrist, M. A., and D. Coombs. 2006. Evolution of virulence: interdependence, constraints, and selection using nested models. Theoretical Population Biology 69:145–153.']
  • ['Gilchrist, M. A., and A. Sasaki. 2002. Modeling host‐parasite coevolution: a nested approach based on mechanistic models. Journal of Theoretical Biology 218:289–308.']
  • ['Gog, J. R., and B. T. Grenfell. 2002. Dynamics and selection of many‐strain pathogens. Proceedings of the National Academy of Sciences of the USA 99:17209–17214.']
  • ['Gomulkiewicz, R., and R. D. Holt. 1995. When does evolution by natural selection prevent extinction? Evolution 49:201–207.']
  • ['Gower, C. M., and J. P. Webster. 2005. Intraspecific competition and the evolution of virulence in a parasitic trematode. Evolution 59:544–553.']
  • ['Griffin, A. S., S. A. West, and A. Buckling. 2004. Cooperation and competition in pathogenic bacteria. Nature 430:1024–1027.']
  • ['Gupta, S., K. Trenholme, R. M. Anderson, and K. P. Day. 1994. Antigenic diversity and the transmission dynamics of Plasmodium falciparum. Science 263:961–963.']
  • ['Hamilton, W. D. 1972. Altruism and related phenomena, mainly in social insects. Annual Review of Ecology and Systematics 3:193–232.']
  • ['Harrison, F., L. E. Browning, M. Vos, and A. Buckling. 2006. Cooperation and virulence in acute Pseudomonas aeruginosa infections. BMC Biology 4:21.']
  • ['Hellriegel, B. 1992. Modelling the immune response to malaria with ecological concepts: short‐term behaviour against long‐term equilibrium. Proceedings of the Royal Society B: Biological Sciences 250:249–256.']
  • ['Hodgson, D. J., R. B. Hitchman, A. J. Vanbergen, R. S. Hails, R. D. Possee, and J. S. Cory. 2004. Host ecology determines the relative fitness of virus genotypes in mixed‐genotype nucleopolyhedrovirus infections. Journal of Evolutionary Biology 17:1018–1025.']
  • ['Holt, R. D. 1977. Predation, apparent competition, and the structure of prey communities. Theoretical Population Biology 12:197–229.']
  • ['Hood, M. E. 2003. Dynamics of multiple infection and within‐host competition by the anther‐smut pathogen. American Naturalist 162:122–133.']
  • ['James, L. C., P. Roversi, and S. Tawfik. 2003. Antibody multispecificity mediated by conformational diversity. Science 299:1362–1367.']
  • ['Jansen, V. A. A., and G. S. E. E. Mulder. 1999. Evolving biodiversity. Ecology Letters 2:379–386.']
  • ['Korthals Altes, H., and V. A. A. Jansen. 2000. Intra‐host competition between nef‐defective escape mutants and wildtype human immunodeficiency virus type 1. Proceedings of the Royal Society B: Biological Sciences 267:183–189.']
  • ['Levin, S., and D. Pimentel. 1981. Selection of intermediate rates of increase in parasite‐host systems. American Naturalist 117:308–315.']
  • ['López‐Ferber, M., O. Simon, T. Williams, and P. Caballero. 2003. Defective or effective? mutualistic interactions between virus genotypes. Proceedings of the Royal Society B: Biological Sciences 270:2249–2255.']
  • ['Lord, C. C., B. Barnard, K. Day, J. W. Hargrove, J. J. McNamara, R. E. L. Paul, K. Trenholme, and M. E. J. Woolhouse. 1999. Aggregation and distribution of strains in micro‐parasites. Philosophical Transactions of the Royal Society B: Biological Sciences 354:799–807.']
  • ['Mackinnon, M. J., and A. F. Read. 1999. Genetic relationships between parasite virulence and transmission in the rodent malaria Plasmodium chabaudi. Evolution 53:689–703.']
  • ['Maynard Smith, J. 1982. Evolution and the theory of games. Cambridge University Press, Cambridge.']
  • ['McLean, A. R., and M. A. Nowak. 1992. Models of interactions between HIV and other pathogens. Journal of Theoretical Biology 155:69–86.']
  • ['Metz, J. A. J., and O. Diekmann. 1986. The dynamics of physiologically structured populations. Lecture notes in biomathematics. Vol. 68. Springer, Berlin.']
  • ['Mosquera, J., and F. R. Adler. 1998. Evolution of virulence: a unified framework for coinfection and superinfection. Journal of Theoretical Biology 195:293–313.']
  • ['Nowak, M. A., and R. M. May. 1994. Superinfection and the evolution of parasite virulence. Proceedings of the Royal Society B: Biological Sciences 255:81–89.']
  • ['Nowak, M. A., R. M. May, and R. M. Anderson. 1990. The evolutionary dynamics of HIV‐1 quasispecies and the development of immunodeficiency disease. AIDS 4:1095–1103.']
  • ['Paine, R. T. 1969. A note on trophic complexity and community stability. American Naturalist 103:91–93.']
  • ['Paul, R. E. L., T. Lafond, C. D. M. Müller‐Graf, S. Nithiuthai, P. T. Brey, and J. C. Koella. 2004. Experimental evaluation of the relationship between lethal or non‐lethal virulence and transmission success in malaria parasite infections. BMC Evolutionary Biology 4:30.']
  • ['Petney, T. N., and R. H. Andrews. 1998. Multiparasite communities in animals and humans: frequency, structure and pathogenic significance. International Journal of Parasitology 28:377–393.']
  • ['Pradeu, T., and E. Carosella. 2006. On the definition of a criterion of immunogenicity. Proceedings of the National Academy of Sciences of the USA 103:17858–17861.']
  • ['Råberg, L., J. C. de Roode, A. S. Bell, P. Stamou, D. Gray, and A. F. Read. 2006. The role of immune‐mediated apparent competition in genetically diverse malaria infections. American Naturalist 168:41–53.']
  • ['Read, A. F., and L. H. Taylor. 2001. The ecology of genetically diverse infections. Science 292:1099–1102.']
  • ['Read, A. F., M. J. Mackinnon, M. A. Anwar, and L. H. Taylor. 2002. Kin‐selection models as evolutionary explanations of malaria. Pages 165–178 in U. Dieckmann, J. A. J. Metz, M. W. Sabelis, and K. Sigmund, eds. Adaptive dynamics of infectious diseases: in pursuit of virulence management. Cambridge University Press, Cambridge.']
  • ['Regoes, R. R., M. A. Nowak, and S. Bonhoeffer. 2000. Evolution of virulence in a heterogeneous host population. Evolution 54:64–71.']
  • ['Stollenwerk, N., and V. A. A. Jansen. 2003. Meningitis, pathogenicity near criticality: the epidemiology of meningococcal disease as a model for accidental pathogens. Journal of Theoretical Biology 222:347–359.']
  • ['Turner, P. E., and L. Chao. 1999. Prisoner’s Dilemma in an RNA virus. Nature 398:441–443.']
  • ['———. 2003. Escape from Prisoner’s Dilemma in RNA phage \n\\documentclass{aastex}\n\\usepackage{amsbsy}\n\\usepackage{amsfonts}\n\\usepackage{amssymb}\n\\usepackage{bm}\n\\usepackage{mathrsfs}\n\\usepackage{pifont}\n\\usepackage{stmaryrd}\n\\usepackage{textcomp}\n\\usepackage{portland,xspace}\n\\usepackage{amsmath,amsxtra}\n\\usepackage[OT2,OT1]{fontenc}\n\\newcommand\\cyr{\n\\renewcommand\\rmdefault{wncyr}\n\\renewcommand\\sfdefault{wncyss}\n\\renewcommand\\encodingdefault{OT2}\n\\normalfont\n\\selectfont}\n\\DeclareTextFontCommand{\\textcyr}{\\cyr}\n\\pagestyle{empty}\n\\DeclareMathSizes{10}{9}{7}{6}\n\\begin{document}\n\\landscape\n$\\Phi 6$\n\\end{document}\n. American Naturalist 161:497–505.']
  • ['van Baalen, M., and M. W. Sabelis. 1995a. The dynamics of multiple infection and the evolution of virulence. American Naturalist 146:881–910.']
  • ['———. 1995b. The milker‐killer dilemma in spatially structured predator‐prey interactions. Oikos 74:391–400.']
  • ['Vignuzzi, M., J. K. Stone, J. J. Arnold, C. E. Cameron, and R. Andino. 2006. Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population. Nature 439:344–348.']
  • ['Vizoso, D. B. V., and D. V. Ebert. 2005. Mixed inoculations of a microsporidian parasite with horizontal and vertical infections. Oecologia (Berlin) 143:157–166.']
  • ['Yoshida, T., L. E. Jones, S. P. Ellner, G. F. Fussmann, and N. G. Hairston Jr. 2003. Rapid evolution drives ecological dynamics in a predator‐prey system. Nature 424:303–306.']