Our understanding of how the host immune response kills Plasmodium, the causative agent of malaria, is limited and controversial. One widely held belief is that reactive oxygen species are crucial for controlling parasite replication. One of the hallmarks of blood-stage malaria is the cyclic rupture of erythrocytes by the parasite, which releases free hemoglobin into the circulation. We propose that this free hemoglobin, as well as the hemoglobin within the erythrocyte and surrounding the parasite, effectively shields Plasmodium from reactive oxygen species well in excess of those achievable in vivo.
JensenJB, BolandMT, AkoodM.Induction of crisis forms in cultured Plasmodium falciparum with human immune serum from Sudan. Science1982;216:1230–3.
5.
Taylor-RobinsonAW, PhillipsRS, SevernA, . The role of TH1 and TH2 cells in a rodent malaria infection. Science1993;260:1931–4.
6.
GrishamMB, Jourd'HeuilD, WinkDA.Nitric oxide I. Physiological chemistry of nitric oxide and its metabolites: implications in inflammation. Am J Physiol1999;276G315–21.
7.
BredtDS, SnyderSH.Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci U S A1990;87:682–5.
8.
GreenSJ, SchellerLF, MarlettaMA, . Nitric oxide: cytokine-regulation of nitric oxide in host resistance to intracellular pathogens. Immunol Lett1994;43:87–94.
9.
PollockJS, ForstermannU, MitchellJA, . Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc Natl Acad Sci U S A1991;88:10480–4.
10.
FeelischM, StamlerJS.Methods in nitric oxide research. Chichester (UK): John Wiley and Sons; 1996.
11.
NathanC.Nitric oxide as a secretory product of mammalian cells. FASEB J1992;06:3051–64.
BogdanC.Nitric oxide and the immune response. Nat Immunol2001;02:907–16.
14.
FavreN, RyffelB, RudinW.Parasite killing in murine malaria does not require nitric oxide production. Parasitology1999;118(Pt 2):139–43.
15.
YonetoT, YoshimotoT, WangCR, . Gamma interferon production is critical for protective immunity to infection with blood-stage Plasmodium berghei XAT but neither NO production nor NK cell activation is critical. Infect Immun1999;67:2349–56.
16.
van der HeydeHC, GuY, ZhangQ, . Nitric oxide is neither necessary nor sufficient for resolution of Plasmodium chabaudi malaria in mice. J Immunol2000;165:3317–23.
17.
CavaciniLA, GuidottiM, ParkeLA, . Reassessment of the role of splenic leukocyte oxidative activity and macrophage activation in expression of immunity to malaria. Infect Immun1989;57:3677–82.
18.
SanniLA, FuS, DeanRT, . Are reactive oxygen species involved in the pathogenesis of murine cerebral malaria?. J Infect Dis1999;179:217–22.
19.
WinslowRM.aa-Crosslinked hemoglobin: was failure predicted by preclinical testing?. Vox Sang2000;79:1–20.
20.
AlayashAI.Oxygen therapeutics: can we tame haemoglobin?. Nat Rev Drug Discov2004;03:152–9.
21.
KergerH, SaltzmanDJ, MengerMD, . Systemic and subcutaneous microvascular Po2 dissociation during 4-h hemorrhagic shock in conscious hamsters. Am J Physiol1996;270H827–36.
22.
LiuX, MillerMJ, JoshiMS, . Diffusion-limited reaction of free nitric oxide with erythrocytes. J Biol Chem1998;273:18709–13.
23.
McMahonTJ, PawloskiJR, HessDT, . S-Nitrosohemoglobin is distinguished from other nitrosovasodilators by unique oxygen-dependent responses that support an allosteric mechanism of action. Blood2003;102:410–1.
24.
McMahonTJ, MoonRE, LuschingerBP, . Nitric oxide in the human respiratory cycle. Nat Med2002;08:711–7.
25.
WinterbournCC.Oxidative reactions of hemoglobin. Methods Enzymol1990;186:265–72.
26.
RomeroN, RadiR, LinaresE, . Reaction of human hemoglobin with peroxynitrite. Isomerization to nitrate and secondary formation of protein radicals. J Biol Chem2003;278:44049–57.
FaivreB, MenuP, LabrudeP, . Hemoglobin autooxidation/oxidation mechanisms and methemoglobin prevention or reduction processes in the bloodstream. Literature review and outline of autooxidation reaction. Artif Cells Blood Substit Immobil Biotechnol1998;26:17–26.
29.
NagababuE, RifkindJM.Heme degradation during autoxidation of oxyhemoglobin. Biochem Biophys Res Commun2000;273:839–45.
30.
AlayashAI, PatelRP, CashonRE.Redox reactions of hemoglobin and myoglobin: biological and toxicological implications. Antioxid Redox Signal2001;03:313–27.
Van DykeBR,SaltmanP.Hemoglobin: a mechanism for the generation of hydroxyl radicals. Free Radic Biol Med1996;20:985–9.
33.
GutteridgeJM.Iron promoters of the Fenton reaction and lipid peroxidation can be released from haemoglobin by peroxides. FEBS Lett1986;201:291–5.
34.
PuppoA, HalliwellB.Formation of hydroxyl radicals from hydrogen peroxide in the presence of iron. Is haemoglobin a biological Fenton reagent?. Biochem J1988;249:185–90.
35.
CosbyK, PartoviKS, CrawfordJH, . Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med2003;09:1498–505.
36.
NagababuE, RamasamyS, AbernethyDR, . Active nitric oxde produced in the red cell under hypoxic conditions by deoxyhemoglobin-mediated nitrite reduction. J Biol Chem2003;278:46349–56.
37.
ClarkIA, ChaudhriG, CowdenWB.Some roles of free radicals in malaria. Free Radic Biol Med1989;06:315–21.
38.
BalagopalakrishnaC, ManoharanPT, AbugoOO, . Production of superoxide from hemoglobin-bound oxygen under hypoxic conditions. Biochemistry1996;35:6393–8.
WeissL, GeduldigU, WeidanzW.Mechanisms of splenic control of murine malaria: reticular cell activation and the development of a blood-spleen barrier. Am J Anat1986;176:251–85.
42.
NalwayaN, DeenWM.Analysis of the effects of nitric oxide and oxygen on nitric oxide production by macrophages. J Theor Biol2004;226:409–19.
43.
KuchanMJ, FrangosJA.Role of calcium and calmodulin in flow-induced nitric oxide production in endothelial cells. Am J Physiol1994;266C628–36.
44.
KharitonovVG, SundquistAR, SharmaVS.Kinetics of nitric oxide autoxidation in aqueous solution. J Biol Chem1994;269:5881–3.
45.
BishopJJ, NancePR, PopelAS, . Erythrocyte margination and sedimentation in skeletal muscle venules. Am J Physiol Heart Circ Physiol2001;281H951–8.
46.
VaughnMW, KuoL, LiaoJC.Estimation of nitric oxide production and reaction rates in tissue by use of a mathematical model. Am J Physiol1998;274H2163–76.
47.
NalwayaN, DeenWM.Peroxynitrite exposure of cells cocultured with macrophages. Ann Biomed Eng2004;32:664–76.
48.
PradaJ, GraningerW, LehmanLG, . Upregulation of ICAM-1, IL-1 and reactive oxygen intermediates (ROI) by exogenous antigens from Plasmodium falciparum parasites in vitro, and of sICAM-1 in the acute phase of malaria. J Chemother1995;07:424–6.
49.
ChiwakataCB, HemmerCJ, DietrichM.High levels of inducible nitric oxide synthase mRNA are associated with increased monocyte counts in blood and have a beneficial role in Plasmodium falciparum malaria. Infect Immun2000;68:394–9.
50.
GoldringJP,NemaoraniS.Antimalarial drugs modulate the expression of monocyte receptors. Int J Immunopharmacol1999;21:599–607.
KunJF, MordmullerB, LellB, . Polymorphism in promoter region of inducible nitric oxide synthase gene and protection against malaria. Lancet1998;351:265–6.
HobbsMR, UdhayakumarV, LevesqueMC, . A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children. Lancet2002;360:1468–75.
55.
OhashiJ, NakaI, PatarapotikulJ, . Significant association of longer forms of CCTTT microsatellite repeat in the inducible nitric oxide synthase promoter with severe malaria in Thailand. J Infect Dis2002;186:578–81.
56.
LevesqueMC, HobbsMR, AnsteyNM, . Nitric oxide synthase type 2 promoter polymorphisms, nitric oxide production, and disease severity in Tanzanian children with malaria. J Infect Dis1999;180:1994–2002.
57.
MomboLE, NtoumiF, BisseyeC, . Human genetic polymorphisms and asymptomatic Plasmodium falciparum malaria in Gabonese schoolchildren. Am J Trop Med Hyg2003;68:186–90.
58.
BoutlisCS, TjitraE, ManiboeyH, . Nitric oxide production and mononuclear cell nitric oxide synthase activity in malaria-tolerant Papuan adults. Infect Immun2003;71:3682–9.
59.
SeriromS, RaharjoWH, ChotivanichK, . Anti-adhesive effect of nitric oxide on Plasmodium falciparum cytoadherence under flow. Am J Pathol2003;162:1651–60.
GyanB, Troye-BlombergM, PerlmannP, . Human monocytes cultured with and without interferon-gamma inhibit Plasmodium falciparum parasite growth in vitro via secretion of reactive nitrogen intermediates. Parasite Immunol1994;16:371–5.
62.
RockettKA, AwburnMM, CowdenWB, . Killing of Plasmodium falciparum in vitro by nitric oxide derivatives. Infect Immun1991;59:3280–3.
63.
OckenhouseCF, SchulmanS, ShearHL.Oxidative killing of malaria parasites by mononuclear phagocytes. Prog Clin Biol Res1984;155:93–108.
64.
OckenhouseCF, SchulmanS, ShearHL.Induction of crisis forms in the human malaria parasite Plasmodium falciparum by gamma-interferon-activated, monocyte-derived macrophages. J Immunol1984;133:1601–8.
65.
FritscheG, LarcherC, SchennachH, . Regulatory interactions between iron and nitric oxide metabolism for immune defense against Plasmodium falciparum infection. J Infect Dis2001;183:1388–94.
66.
van der HeydeHC, EllosoMM, vandeWJ, . Use of hydroethidine and flow cytometry to assess the effects of leukocytes on the malarial parasite Plasmodium falciparum. Clin Diagn Lab Immunol1995;02:417–25.
67.
GillmanBM, BatchelderJ, FlahertyP, . Suppression of Plasmodium chabaudi parasitemia is independent of the action of reactive oxygen intermediates and/or nitric oxide. Infect Immun2004;72:6359–66.
68.
JacobsP, RadziochD, StevensonMM.Nitric oxide expression in the spleen, but not in the liver, correlates with resistance to blood-stage malaria in mice. J Immunol1995;155:5306–13.
69.
SchofieldL, HackettF.Signal transduction in host cells by a glycosylphosphatidylinositol toxin of malaria parasites. J Exp Med1993;177:145–53.
70.
KrishnegowdaG, HajjarAM, ZhuJ, . Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols (GPIs) of Plasmodium falciparum: cell signaling receptors, GPI structural requirement, and regulation of GPI activity. J Biol Chem2005;289:8606–16.
71.
JaramilloM, PlanteI, OuelletN, . Hemozoin-inducible proinflammatory events in vivo: potential role in malaria infection. J Immunol2004;172:3101–10.
72.
PostmaNS, MommersEC, ElingWM, . Oxidative stress in malaria; implications for prevention and therapy. Pharm World Sci1996;18:121–9.
73.
ErelO, VuralH, AksoyN, . Oxidative stress of platelets and thrombocytopenia in patients with vivax malaria. Clin Biochem2001;34:341–4.
74.
SobolewskiP, GramagliaI, FrangosJA, . Plasmodium berghei resist reactive oxygen species killing and exhibit intrinsic defense mechanisms. Infect Immun 2005;in review:341–4.
75.
Troye-BlombergM, WeidanzWP,van der HeydeHC. Immunity to malaria. In:WahlgrenM, PerlmannP, editors. Malaria : molecular and clinical aspects. Chur (Switzerland): Charwood Academic Publishers; 1999. p.403–38.
76.
McDevittMA, XieJ, GordeukV, . The anemia of malaria infection: role of inflammatory cytokines. Curr Hematol Rep2004;03:97–106.
77.
WinkDA, MirandaKM, EspeyMG, . Mechanisms of the antioxidant effects of nitric oxide. Antioxid Redox Signal2001;03:203–13.
