title: Superinfection in malaria: Plasmodium shows its iron will.
abstract: After the bite of a malaria-infected mosquito, the Plasmodium sporozoite infects liver cells and produces thousands of merozoites, which then infect red blood cells, causing malaria. In malaria-endemic areas, several hundred infected mosquitoes can bite an individual each year, increasing the risk of superinfection. However, in infants that are yet to acquire immunity, superinfections are infrequent. We have recently shown that blood-stage parasitaemia, above a minimum threshold, impairs the growth of a subsequent sporozoite infection of liver cells. Blood-stage parasites stimulate the production of the host iron-regulatory factor hepcidin, which redistributes iron away from hepatocytes, reducing the development of the iron-dependent liver stage. This could explain why Plasmodium superinfection is not often found in young nonimmune children. Here, we discuss the impact that such protection from superinfection might have in epidemiological settings or in programmes for controlling malaria, as well as how the induction of hepcidin and redistribution of iron might influence anaemia and the outcome of non-Plasmodium co-infections.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Avenue Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Portugal
authors.forename: Hal
authors.initials: H
authors.lastname: Drakesmith
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
mesh_terms: D006790:Host-Parasite Interactions / Q000276:immunology; D006801:Humans; D007109:Immunity; D007501:Iron / Q000378:metabolism*; D008288:Malaria / Q000150:complications* / Q000469:parasitology* / Q000517:prevention & control; D010961:Plasmodium / Q000254:growth & development / Q000502:physiology*; D015163:Superinfection / Q000150:complications* / Q000469:parasitology*
chemical_list: D007501:Iron
references.citation: Annu Rev Med. 2011;62:347-60
references.pmid: 20887198
references.citation: Infect Immun. 2010 Apr;78(4):1520-7
references.pmid: 20100860
references.citation: Science. 2000 Feb 4;287(5454):845-8
references.pmid: 10657296
references.citation: Lancet. 1987 Nov 7;2(8567):1052-5
references.pmid: 2889965
references.citation: Trop Med Int Health. 2002 May;7(5):421-8
references.pmid: 12000651
references.citation: Acta Trop. 1992 Sep;52(1):59-67
references.pmid: 1359761
references.citation: Gastroenterology. 2010 Aug;139(2):393-408, 408.e1-2
references.pmid: 20542038
references.citation: Proc Soc Exp Biol Med. 1987 Feb;184(2):162-4
references.pmid: 3543939
references.citation: Lancet. 1975 Mar 22;1(7908):653-4
references.pmid: 47080
references.citation: Am J Trop Med Hyg. 2007 Oct;77(4):623-6
references.pmid: 17978060
references.citation: Nature. 2000 Feb 17;403(6771):776-81
references.pmid: 10693807
references.citation: Parasitology. 1996 Feb;112 ( Pt 2):165-8
references.pmid: 8851855
references.citation: Blood. 1996 Jun 1;87(11):4871-8
references.pmid: 8639861
references.citation: J Biol Chem. 2001 Mar 16;276(11):7811-9
references.pmid: 11113132
references.citation: Nat Genet. 2008 May;40(5):569-71
references.pmid: 18408718
references.citation: N Engl J Med. 2009 Jul 30;361(5):468-77
references.pmid: 19641203
references.citation: Food Nutr Bull. 2007 Dec;28(4 Suppl):S524-39
references.pmid: 18297891
references.citation: Blood. 2005 Aug 1;106(3):1092-7
references.pmid: 15831700
references.citation: J Parasitol. 1997 Aug;83(4):593-600
references.pmid: 9267397
references.citation: PLoS One. 2010 May 11;5(5):e10568
references.pmid: 20485496
references.citation: J Biol Chem. 2000 Jun 30;275(26):19906-12
references.pmid: 10747949
references.citation: Lancet. 2003 Feb 22;361(9358):669-73
references.pmid: 12606179
references.citation: Science. 2005 Jan 28;307(5709):528-30
references.pmid: 15681372
references.citation: J Exp Med. 2003 Jan 20;197(2):143-51
references.pmid: 12538654
references.citation: Am J Trop Med Hyg. 1982 Sep;31(5):919-22
references.pmid: 6751113
references.citation: Am J Trop Med Hyg. 1975 May;24(3):397-401
references.pmid: 808142
references.citation: Parasite. 1995 Dec;2(4):351-6
references.pmid: 8745736
references.citation: Lancet. 2011 May 21;377(9779):1770-6
references.pmid: 21514658
references.citation: AIDS. 1999 Feb 25;13(3):375-80
references.pmid: 10199228
references.citation: Blood. 1992 Jan 15;79(2):308-12
references.pmid: 1730079
references.citation: Nat Med. 2007 Sep;13(9):1096-101
references.pmid: 17721544
references.citation: Trends Parasitol. 2004 Jul;20(7):333-9
references.pmid: 15193565
references.citation: J Clin Invest. 1991 Jul;88(1):351-7
references.pmid: 2056129
references.citation: Ann Trop Med Parasitol. 1949 Apr;43(1):47-61
references.pmid: 18121270
references.citation: Trans R Soc Trop Med Hyg. 1991 Sep-Oct;85(5):578-83
references.pmid: 1780979
references.citation: Am J Trop Med Hyg. 1988 Oct;39(4):323-7
references.pmid: 3056055
references.citation: PLoS Negl Trop Dis. 2008 Jun 25;2(6):e255
references.pmid: 18575596
references.citation: Trop Med Int Health. 2003 Jan;8(1):3-11
references.pmid: 12535242
references.citation: PLoS One. 2011;6(8):e23391
references.pmid: 21858097
references.citation: Lancet. 2006 Jan 14;367(9505):133-43
references.pmid: 16413877
references.citation: J Infect Dis. 2007 Jun 15;195(12):1745-53
references.pmid: 17492589
references.citation: Clin Microbiol Rev. 2009 Jan;22(1):13-36, Table of Contents
references.pmid: 19136431
references.citation: Br J Haematol. 2009 Jun;145(5):657-64
references.pmid: 19344417
references.citation: Mol Pharmacol. 1982 Jul;22(1):140-4
references.pmid: 6811856
references.citation: J Infect Dis. 1987 Jun;155(6):1319-21
references.pmid: 3553352
references.citation: Acta Trop. 2008 Jul;107(1):8-12
references.pmid: 18468567
references.citation: Trans R Soc Trop Med Hyg. 1997 Sep-Oct;91(5):602-5
references.pmid: 9463681
references.citation: Parasitol Today. 1988 May;4(5):147-50
references.pmid: 15463072
references.citation: Drug Metab Rev. 2009;41(4):644-62
references.pmid: 19764831
references.citation: J Immunol. 2008 Dec 15;181(12):8552-8
references.pmid: 19050274
references.citation: Haematologica. 2010 Jul;95(7):1068-74
references.pmid: 20133896
references.citation: Infect Immun. 2006 May;74(5):3065-7
references.pmid: 16622252
references.citation: Am J Trop Med Hyg. 1998 Mar;58(3):358-64
references.pmid: 9546419
references.citation: Exp Parasitol. 1985 Oct;60(2):171-4
references.pmid: 4029347
references.citation: Nat Rev Microbiol. 2008 Jul;6(7):541-52
references.pmid: 18552864
references.citation: J Antimicrob Chemother. 2006 Jun;57(6):1093-9
references.pmid: 16595639
references.citation: Infect Immun. 1974 Oct;10(4):831-3
references.pmid: 4609912
references.citation: Malar J. 2009 Jan 07;8:4
references.pmid: 19128453
references.citation: Antimicrob Agents Chemother. 1993 May;37(5):1108-14
references.pmid: 8517699
references.citation: J Clin Invest. 2010 Dec;120(12):4466-77
references.pmid: 21099112
references.citation: Trans R Soc Trop Med Hyg. 1998 Mar-Apr;92(2):214-8
references.pmid: 9764337
references.citation: Nat Med. 2011 Jun;17(6):732-7
references.pmid: 21572427
references.citation: Nat Rev Microbiol. 2004 Dec;2(12):946-53
references.pmid: 15550940
references.citation: Parasite Immunol. 2006 Jan-Feb;28(1-2):51-60
references.pmid: 16438676
references.citation: Science. 2004 Dec 17;306(5704):2090-3
references.pmid: 15514116
references.citation: N Engl J Med. 1992 Nov 19;327(21):1473-7
references.pmid: 1406879
references.citation: Blood. 2011 Oct 13;118(15):4129-39
references.pmid: 21873546
references.citation: Exp Parasitol. 1999 Feb;91(2):105-14
references.pmid: 9990337
references.citation: Adv Parasitol. 2002;52:235-64
references.pmid: 12521262
references.citation: Mol Pharmacol. 1980 Sep;18(2):320-5
references.pmid: 6775184
references.citation: Am J Trop Med Hyg. 2003 Feb;68(2):169-76
references.pmid: 12641407
references.citation: Acta Haematol. 1996;95(1):70-7
references.pmid: 8604590
references.citation: Vaccine. 2009 Dec 30;27 Suppl 6:G67-71
references.pmid: 20006143
references.citation: Cell Metab. 2005 Mar;1(3):191-200
references.pmid: 16054062
references.citation: Mol Pharmacol. 1981 Jul;20(1):218-23
references.pmid: 6793844
references.citation: Blood. 2006 Oct 15;108(8):2569-77
references.pmid: 16804108
references.citation: Mol Cell. 2000 Feb;5(2):299-309
references.pmid: 10882071
references.citation: PLoS One. 2011;6(8):e23390
references.pmid: 21858096
references.citation: PLoS Med. 2011 Jan 25;8(1):e1000399
references.pmid: 21311584
references.citation: Nat Rev Microbiol. 2006 Nov;4(11):849-56
references.pmid: 17041632
references.citation: Trans R Soc Trop Med Hyg. 2000 May-Jun;94(3):310-4
references.pmid: 10975008
references.citation: Cell Microbiol. 2007 Sep;9(9):2126-40
references.pmid: 17466014
references.citation: Parasitology. 2006 Jan;132(Pt 1):13-21
references.pmid: 16393349
references.citation: Science. 2011 Feb 11;331(6018):775-8
references.pmid: 21311023
references.citation: Blood. 2007 Jul 1;110(1):18-28
references.pmid: 17341664
references.citation: Parasitology. 1988 Jun;96 ( Pt 3):607-39
references.pmid: 3043327
references.citation: J Clin Invest. 2004 May;113(9):1271-6
references.pmid: 15124018
references.citation: Antimicrob Agents Chemother. 2002 Jun;46(6):2010-3
references.pmid: 12019128
references.citation: J Infect Dis. 2009 Jan 15;199(2):253-62
references.pmid: 19032104
references.citation: Trends Parasitol. 2003 Jun;19(6):271-7
references.pmid: 12798085