Abstract
What determines the dynamics of parasite and anaemia during acute primary malaria infections? Why do some strains of malaria reach higher densities and cause greater anaemia than others? The conventional view is that the fastest replicating parasites reach the highest densities and cause the greatest loss of red blood cells (RBCs). Other current hypotheses suggest that the maximum parasite density is achieved by strains that either elicit the weakest immune responses or infect the youngest RBCs (reticulocytes). Yet another hypothesis is a simple resource limitation model where the peak parasite density and the maximum anaemia (percentage loss of RBCs) during the acute phase of infection equal the fraction of RBCs that the malaria parasite can infect. We discriminate between these hypotheses by developing a mathematical model of acute malaria infections and confronting it with experimental data from the rodent malaria parasite Plasmodium chabaudi. We show that the resource limitation model can explain the initial dynamics of infection of mice with different strains of this parasite. We further test the model by showing that without modification it closely reproduces the dynamics of competing strains in mixed infections of mice with these strains of P. chabaudi. Our results suggest that a simple resource limitation is capable of capturing the basic features of the dynamics of both parasite and RBC loss during acute malaria infections of mice with P. chabaudi, suggesting that it might be worth exploring if similar results might hold for other acute malaria infections, including those of humans.
References
-
Anderson R.M, May R.M& Gupta S . 1989 Non-linear phenomena in host–parasite interactions. Parasitology. 99, Suppl., S59–S79. Crossref, PubMed, Web of Science, Google Scholar -
Antia R, Levin B.R& May R.M . 1994 Within-host population dynamics and the evolution and maintenance of microparasite virulence. Am. Nat. 144, 457–472.doi:10.1086/285686. . Crossref, Web of Science, Google Scholar -
Baccam P, Beauchemin C, Macken C.A, Hayden F.G& Perelson A.S . 2006 Kinetics of influenza A virus infection in humans. J. Virol. 80, 7590–7599.doi:10.1128/JVI.01623-05. . Crossref, PubMed, Web of Science, Google Scholar -
Bannerman, R. M. 1983 Hematology. In The mouse in biomedical research, vol. III, ch.12. Normative biology, immunology, and husbandry (eds J. D. Small, H. L. Foster & J. G. Fox), pp. 301–304. London, UK: Academic Press. Google Scholar
-
Bell A.S, de Roode J.C, Sim D& Read A.F . 2006 Within-host competition in genetically diverse malaria infections: parasite virulence and competitive success. Evol. Int. J. Org. Evol. 60, 1358–1371. Crossref, PubMed, Web of Science, Google Scholar -
Bruce M.C& Day K.P . 2002 Cross-species regulation of malaria parasitaemia in the human host. Curr. Opin. Microbiol. 5, 431–437.doi:10.1016/S1369-5274(02)00348-X. . Crossref, PubMed, Web of Science, Google Scholar -
Bruce M.C, Donnelly C.A, Alpers M.P, Galinski M.R, Barnwell J.W, Walliker D& Day K.P . 2000 Cross-species interactions between malaria parasites in humans. Science. 287, 845–848.doi:10.1126/science.287.5454.845. . Crossref, PubMed, Web of Science, Google Scholar -
Chotivanich K, Udomsangpetch R, Simpson J.A, Newton P, Pukrittayakamee S, Looareesuwan S& White N.J . 2000 Parasite multiplication potential and the severity of falciparum malaria. J. Infect. Dis. 181, 1206–1209.doi:10.1086/315353. . Crossref, PubMed, Web of Science, Google Scholar -
Chotivanich K, Udomsangpetch R, Pattanapanyasat K, Chierakul W, Simpson J, Looareesuwan S& White N . 2002 Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P. falciparum malaria. Blood. 100, 1172–1176. Crossref, PubMed, Web of Science, Google Scholar -
Cox, F. E. G. 1988 Major animal models in malaria research: rodent In Malaria: principles and practice of malariology (eds W. H. Wernsdorfer & I. McGregor), ch. 49, 1503–1543. London, UK: Churchill Livingstone. Google Scholar
-
Cromer D, Evans K.J, Schofield L& Davenport M.P . 2006 Preferential invasion of reticulocytes during late-stage Plasmodium berghei infection accounts for reduced circulating reticulocyte levels. Int. J. Parasitol. 36, 1389–1397.doi:10.1016/j.ijpara.2006.07.009. . Crossref, PubMed, Web of Science, Google Scholar -
de Roode, J. C. 2005 Within-host competition and the evolution of malaria parasites. PhD thesis, University of Edinburgh. Google Scholar
-
de Roode J.C, Culleton R, Cheesman S.J, Carter R& Read A.F . 2004 Host heterogeneity is a determinant of competitive exclusion or coexistence in genetically diverse malaria infections. Proc. R. Soc. B. 271, 1073–1080.doi:10.1098/rspb.2004.2695. . Link, Web of Science, Google Scholar -
de Roode J.C, Virulence and competitive ability in genetically diverse malaria infections. Proc. Natl Acad. Sci. USA. 102, 2005a 7624–7628.doi:10.1073/pnas.0500078102. . Crossref, PubMed, Web of Science, Google Scholar -
de Roode J.C, Helinski M.E.H, Anwar M.A& Read A.F Dynamics of multiple infection and within-host competition in genetically diverse malaria infections. Am. Nat. 166, 2005b 531–542.doi:10.1086/491659. . Crossref, PubMed, Web of Science, Google Scholar -
Dietz K, Raddatz G& Molineaux L . 2006 Mathematical model of the first wave of Plasmodium falciparum asexual parasitemia in non-immune and vaccinated individuals. Am. J. Trop. Med. Hyg. 75, 46–55. Crossref, PubMed, Web of Science, Google Scholar -
Duraisingh M.T, Maier A.G, Triglia T& Cowman A.F . 2003 Erythrocyte-binding antigen 175 mediates invasion in Plasmodium falciparum utilizing sialic acid-dependent and -independent pathways. Proc. Natl Acad. Sci. USA. 100, 4796–4801.doi:10.1073/pnas.0730883100. . Crossref, PubMed, Web of Science, Google Scholar -
Field J.W . 1949 Blood examination and prognosis in acute falciparum malaria. Trans. R. Soc. Trop. Med. Hyg. 43, 33–48.doi:10.1016/0035-9203(49)90022-X. . Crossref, PubMed, Web of Science, Google Scholar -
Field J.W& Niven J.C . 1937 A note on prognosis in relation to parasite counts in acute subtertian malaria. Trans. R. Soc. Trop. Med. Hyg. 6, 569–574.doi:10.1016/S0035-9203(37)90070-1. . Crossref, Google Scholar -
Frank S.A . 1999 A model for the sequential dominance of antigenic variants in African trypanosome infections. Proc. R. Soc. B. 266, 1397–1401.doi:10.1098/rspb.1999.0793. . Link, Web of Science, Google Scholar -
Gandon S, Mackinnon M.J, Nee S& Read A.F . 2001 Imperfect vaccines and the evolution of pathogen virulence. Nature. 414, 751–776.doi:10.1038/414751a. . Crossref, PubMed, Web of Science, Google Scholar -
Garnham P.C.C Malaria parasites and other haemosporidia. 1966 London, UK:Blackwell Scientific Publishers. Google Scholar -
Gravenor M.B, McLean A.R& Kwiatkowski D . 1995 The regulation of malaria parasitaemia: parameter estimates for a population model. Parasitology. 110, Pt 2, 115–122. Crossref, PubMed, Web of Science, Google Scholar -
Haydon D.T, Matthews L, Timms R& Colegrave N . 2003 Top-down or bottom-up regulation of intra-host blood-stage malaria: do malaria parasites most resemble the dynamics of prey or predator?. Proc. R. Soc. B. 270, 289–298.doi:10.1098/rspb.2002.2203. . Link, Web of Science, Google Scholar -
Hellriegel B . 1992 Modelling the immune response to malaria with ecological concepts: short-term behaviour against long-term equilibrium. Proc. R. Soc. B. 250, 249–256.doi:10.1098/rspb.1992.0156. . Link, Web of Science, Google Scholar -
Hetzel C& Anderson R.M . 1996 The within-host cellular dynamics of bloodstage malaria—theoretical and experimental studies. Parasitology. 113, 25–38. Crossref, PubMed, Web of Science, Google Scholar -
Hutagalung R, Wilairatana P, Looareesuwan S, Brittenham G.M, Aikawa H& Gordeuk V.R . 1999 Influence of hemoglobin E trait on the severity of falciparum malaria. J. Infect. Dis. 179, 283–286.doi:10.1086/314561. . Crossref, PubMed, Web of Science, Google Scholar -
Jakeman G.N, Saul A, Hogarth W.L& Collins W.E . 1999 Anaemia of acute malaria infections in non-immune patients primarily results from destruction of uninfected erythrocytes. Parasitology. 119, Pt 2, 127–133.doi:10.1017/S0031182099004564. . Crossref, PubMed, Web of Science, Google Scholar -
Kitchen S.F Falciparum malaria. Malariology& Boyd M.F . 1949app. 995–1016. Eds. London, UK:Saunders. Google Scholar -
Kitchen S.F Symptomatology: general considerations. Malariology& Boyd M.F . 1949bpp. 966–994. Eds. London, UK:Saunders. Google Scholar -
Mackey M.C Mathematical models of hematopoietic cell replication and control. The art of mathematical modeling: case studies in ecology, physiology and biofluids, Othmer H.G, Adler F.R, Lewis M.A& Dallon J.C . 1996pp. 149–178. Eds. New York, NY:Prentice-Hall. Google Scholar -
Mackinnon M.J& Read A.F . 2004 Virulence in malaria: an evolutionary viewpoint. Phil. Trans. R. Soc. B. 359, 965–986.doi:10.1098/rstb.2003.1414. . Link, Web of Science, Google Scholar -
Mary J.Y, Valleron A.J, Croizat H& Frindel E . 1980 Mathematical analysis of bone marrow erythropoiesis: application to C3H mouse data. Blood Cells. 6, 241–262. PubMed, Google Scholar -
Mason D.P, McKenzie F.E& Bossert W.H . 1999 The blood-stage dynamics of mixed Plasmodium malariae–Plasmodium falciparum infections. J. Theor. Biol. 198, 549–566.doi:10.1006/jtbi.1999.0932. . Crossref, PubMed, Web of Science, Google Scholar -
McQueen P.G& McKenzie F.E . 2004 Age-structured red blood cell susceptibility and the dynamics of malaria infections. Proc. Natl Acad. Sci USA. 101, 9161–9166.doi:10.1073/pnas.0308256101. . Crossref, PubMed, Web of Science, Google Scholar -
McQueen P.G& McKenzie F.E . 2006 Competition for red blood cells can enhance Plasmodium vivax parasitemia in mixed-species malaria infections. Am. J. Trop. Med. Hyg. 75, 112–125. Crossref, PubMed, Web of Science, Google Scholar -
Menendez C, Fleming A.F& Alonso P.L . 2000 Malaria-related anaemia. Parasitol. Today. 16, 469–476.doi:10.1016/S0169-4758(00)01774-9. . Crossref, PubMed, Google Scholar -
Miller L.H, Baruch D.I, Marsh K& Doumbo O.K . 2002 The pathogenic basis of malaria. Nature. 415, 673–679.doi:10.1038/415673a. . Crossref, PubMed, Web of Science, Google Scholar -
Molineaux L, Diebner H.H, Eichner M, Collins W.E, Jeffery G.M& Dietz K . 2001 Plasmodium falciparum parasitaemia described by a new mathematical model. Parasitology. 122, 379–391.doi:10.1017/S0031182001007533. . Crossref, PubMed, Web of Science, Google Scholar -
Mota M.M, Brown K.N, Holder A.A& Jarra W . 1998 Acute Plasmodium chabaudi chabaudi malaria infection induces antibodies which bind to the surfaces of parasitized erythrocytes and promote their phagocytosis by macrophages in vitro. Infect. Immun. 66, 4080–4086. Crossref, PubMed, Web of Science, Google Scholar -
Perelson A.S . 2002 Modelling viral and immune system dynamics. Nat. Rev. Immunol. 2, 28–36.doi:10.1038/nri700. . Crossref, PubMed, Web of Science, Google Scholar -
Phillips A.N . 1996 Reduction of HIV concentration during acute infection: independence from a specific immune response. Science. 271, 497–499.doi:10.1126/science.271.5248.497. . Crossref, PubMed, Web of Science, Google Scholar -
Phillips R.S, Brannan L.R, Balmer P& Neuville P . 1997 Antigenic variation during malaria infection—the contribution from the murine parasite Plasmodium chabaudi. Parasite Immunol. 19, 427–434.doi:10.1046/j.1365-3024.1997.d01-239.x. . Crossref, PubMed, Web of Science, Google Scholar -
Recker M, Nee S, Bull P.C, Kinyanjui S, Marsh K, Newbold C& Gupta S . 2004 Transient cross-reactive immune responses can orchestrate antigenic variation in malaria. Nature. 429, 555–558.doi:10.1038/nature02486. . Crossref, PubMed, Web of Science, Google Scholar -
Regoes R.R, Antia R, Garber D.A, Silvestri G, Feinberg M.B& Staprans S.I . 2004 Roles of target cells and virus-specific cellular immunity in primary simian immunodeficiency virus infection. J. Virol. 78, 4866–4875.doi:10.1128/JVI.78.9.4866-4875.2004. . Crossref, PubMed, Web of Science, Google Scholar -
Simpson J.A, Silamut K, Chotivanich K, Pukrittayakamee S& White N.J . 1999 Red cell selectivity in malaria: a study of multiple-infected erythrocytes. Trans. R. Soc. Trop. Med. Hyg. 93, 165–168.doi:10.1016/S0035-9203(99)90295-X. . Crossref, PubMed, Web of Science, Google Scholar -
Suzuki M, Ohneda K, Hosoya-Ohmura S, Tsukamoto S, Ohneda O, Philipsen S& Yamamoto M . 2006 Real-time monitoring of stress erythropoiesis in vivo using Gata1- and beta-globin LCR-luciferase transgenic mice. Blood. 108, 726–733.doi:10.1182/blood-2005-10-4064. . Crossref, PubMed, Web of Science, Google Scholar