Villegas-Mendez A., Stafford N., Haley M.J., Pravitasari N.E., Baudoin F., Ali A., Asih P.B.S., Siregar J.E., Baena E., Syafruddin D., Couper K.N., Oceandy D.
The Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom; Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, M13 9PT, United Kingdom; Eijkman Institute for Molecular Biology, Jakarta, 10430, Indonesia; Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Manchester, SK10 4TG, United Kingdom; Division of Cancer Sciences, The University of Manchester, Manchester, United Kingdom
Background: Recent genome wide analysis studies have identified a strong association between single nucleotide variations within the human ATP2B4 gene and susceptibility to severe malaria. The ATP2B4 gene encodes the plasma membrane calcium ATPase 4 (PMCA4), which is responsible for controlling the physiological level of intracellular calcium in many cell types, including red blood cells (RBCs). It is, therefore, postulated that genetic differences in the activity or expression level of PMCA4 alters intracellular Ca2+ levels and affects RBC hydration, modulating the invasion and growth of the Plasmodium parasite within its target host cell. Methods: In this study the course of three different Plasmodium spp. infections were examined in mice with systemic knockout of Pmca4 expression. Results: Ablation of PMCA4 reduced the size of RBCs and their haemoglobin content but did not affect RBC maturation and reticulocyte count. Surprisingly, knockout of PMCA4 did not significantly alter peripheral parasite burdens or the dynamics of blood stage Plasmodium chabaudi infection or reticulocyte-restricted Plasmodium yoelii infection. Interestingly, although ablation of PMCA4 did not affect peripheral parasite levels during Plasmodium berghei infection, it did promote slight protection against experimental cerebral malaria, associated with a minor reduction in antigen-experienced T cell accumulation in the brain. Conclusions: The finding suggests that PMCA4 may play a minor role in the development of severe malarial complications, but that this appears independent of direct effects on parasite invasion, growth or survival within RBCs. © 2021, The Author(s).
Cerebral malaria; Knockout mice; Malaria; Plasmodium; PMCA4; Red blood cell
Publisher: BioMed Central Ltd
Volume 20, Issue 1, Art No 297, Page – , Page Count
Journal Link: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85109194609&doi=10.1186%2fs12936-021-03832-w&partnerID=40&md5=2eb8ee0eee29cff7aad5fb0fe0341097
Type: All Open Access, Gold, Green
(2020) World malaria report 2020, , World Health Organization, Geneva; Feachem, R.G.A., Chen, I., Akbari, O., Bertozzi-Villa, A., Bhatt, S., Binka, F., Malaria eradication within a generation: ambitious, achievable, and necessary (2019) Lancet, 394, pp. 1056-1112. , PID: 31511196; Imwong, M., Dhorda, M., Myo Tun, K., Thu, A.M., Phyo, A.P., Proux, S., Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study (2020) Lancet Infect Dis, 20, pp. 1470-1480. , COI: 1:CAS:528:DC%2BB3cXhtl2qs7jO, PID: 32679084; Ndila, C.M., Uyoga, S., Macharia, A.W., Nyutu, G., Peshu, N., Ojal, J., Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study (2018) Lancet Haematol, 5, pp. e333-e345. , PID: 30033078; Reappraisal of known malaria resistance loci in a large multicenter study (2014) Nat Genet, 46, pp. 1197-1204. , COI: 1:CAS:528:DC%2BC2cXhs1ehsrzN, PID: 4617542; Timmann, C., Thye, T., Vens, M., Evans, J., May, J., Ehmen, C., Genome-wide association study indicates two novel resistance loci for severe malaria (2012) Nature, 489, pp. 443-446. , COI: 1:CAS:528:DC%2BC38XhtF2ru7bI, PID: 22895189; Stafford, N., Wilson, C., Oceandy, D., Neyses, L., Cartwright, E.J., The plasma membrane calcium ATPases and their role as major new players in human disease (2017) Physiol Rev, 97, pp. 1089-1125. , COI: 1:CAS:528:DC%2BC1cXltlCgu7g%3D, PID: 28566538; Strehler, E.E., Zacharias, D.A., Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps (2001) Physiol Rev, 81, pp. 21-50. , COI: 1:CAS:528:DC%2BD3MXitV2kt7Y%3D, PID: 11152753; de Jong, K., Kuypers, F.A., Flow cytometric determination of PMCA-mediated Ca2+-extrusion in individual red blood cells (2007) Cytometry A, 71, pp. 693-699. , PID: 17598186, COI: 1:CAS:528:DC%2BD2sXhtlGrtLfK; Lew, V.L., Daw, N., Perdomo, D., Etzion, Z., Bookchin, R.M., Tiffert, T., Distribution of plasma membrane Ca2+ pump activity in normal human red blood cells (2003) Blood, 102, pp. 4206-4213. , COI: 1:CAS:528:DC%2BD3sXpsFalsLk%3D, PID: 12920020; Garcia-Sancho, J., Lew, V.L., Detection and separation of human red cells with different calcium contents following uniform calcium permeabilization (1988) J Physiol, 407, pp. 505-522. , COI: 1:CAS:528:DyaL1MXitVOmtA%3D%3D, PID: 3151493; Gardos, G., The function of calcium in the potassium permeability of human erythrocytes (1958) Biochim Biophys Acta, 30, pp. 653-654. , COI: 1:CAS:528:DyaG1MXks1antw%3D%3D, PID: 13618284; Tiffert, T., Lew, V.L., Ginsburg, H., Krugliak, M., Croisille, L., Mohandas, N., The hydration state of human red blood cells and their susceptibility to invasion by Plasmodium falciparum (2005) Blood, 105, pp. 4853-4860. , COI: 1:CAS:528:DC%2BD2MXlsVWis78%3D, PID: 15728121; Schuh, K., Cartwright, E.J., Jankevics, E., Bundschu, K., Liebermann, J., Williams, J.C., Plasma membrane Ca2+ ATPase 4 is required for sperm motility and male fertility (2004) J Biol Chem, 279, pp. 28220-28226. , COI: 1:CAS:528:DC%2BD2cXlt1Cltbo%3D, PID: 15078889; Mohamed, T.M.A., Abou-Leisa, R., Stafford, N., Maqsood, A., Zi, M., Prehar, S., The plasma membrane calcium ATPase 4 signalling in cardiac fibroblasts mediates cardiomyocyte hypertrophy (2016) Nat Commun, 7, p. 11074. , COI: 1:CAS:528:DC%2BC28Xlt1GisbY%3D, PID: 27020607; Elased, K., De Souza, J.B., Playfair, J.H., Blood-stage malaria infection in diabetic mice (1995) Clin Exp Immunol, 99, pp. 440-444. , COI: 1:CAS:528:DyaK2MXls1Gqtro%3D, PID: 7882567; De Souza, J.B., Williamson, K.H., Otani, T., Playfair, J.H., Early gamma interferon responses in lethal and nonlethal murine blood-stage malaria (1997) Infect Immun, 65, pp. 1593-1598. , PID: 9125535; Lin, J.W., Annoura, T., Sajid, M., Chevalley-Maurel, S., Ramesar, J., Klop, O., A novel ‘gene insertion/marker out’ (GIMO) method for transgene expression and gene complementation in rodent malaria parasites (2011) PLoS One., 6. , COI: 1:CAS:528:DC%2BC38Xms1Cisw%3D%3D, PID: 22216235; Villegas-Mendez, A., Greig, R., Shaw, T.N., de Souza, J.B., Gwyer Findlay, E., Stumhofer, J.S., IFN-gamma-producing CD4+ T cells promote experimental cerebral malaria by modulating CD8+ T cell accumulation within the brain (2012) J Immunol, 189, pp. 968-979. , COI: 1:CAS:528:DC%2BC38XpvFentbo%3D, PID: 22723523; Ovchynnikova, E., Aglialoro, F., von Lindern, M., van den Akker, E., The shape shifting story of reticulocyte maturation (2018) Front Physiol, 9, p. 829. , PID: 30050448; Huang, B.W., Pearman, E., Kim, C.C., Mouse models of uncomplicated and fatal malaria (2015) Bio Protoc., 5. , PID: 26236758; Langhorne, J., Quin, S.J., Sanni, L.A., Mouse models of blood-stage malaria infections: immune responses and cytokines involved in protection and pathology (2002) Chem Immunol, 80, pp. 204-228. , COI: 1:CAS:528:DC%2BD38XksFyntrc%3D, PID: 12058640; Lin, J.W., Spaccapelo, R., Schwarzer, E., Sajid, M., Annoura, T., Deroost, K., Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance (2015) J Exp Med, 212, pp. 893-903. , COI: 1:CAS:528:DC%2BC2MXhtVOgsb3N, PID: 25941254; de Haro, C., de Herreros, A.G., Ochoa, S., Protein phosphorylation and translational control in reticulocytes: activation of the heme-controlled translational inhibitor by calcium ions and phospholipid (1985) Curr Top Cell Regul, 27, pp. 63-81. , PID: 4092499; Couper, K.N., Blount, D.G., Hafalla, J.C., van Rooijen, N., de Souza, J.B., Riley, E.M., Macrophage-mediated but gamma interferon-independent innate immune responses control the primary wave of Plasmodium yoelii parasitemia (2007) Infect Immun, 75, pp. 5806-5818. , COI: 1:CAS:528:DC%2BD2sXhsVWit7jN, PID: 17923512; Dondorp, A.M., Desakorn, V., Pongtavornpinyo, W., Sahassananda, D., Silamut, K., Chotivanich, K., Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2 (2005) PLoS Med., 2. , PID: 16104831, COI: 1:CAS:528:DC%2BD2MXhtFWlsLnO; Belnoue, E., Kayibanda, M., Vigario, A.M., Deschemin, J.C., van Rooijen, N., Viguier, M., On the pathogenic role of brain-sequestered alphabeta CD8+ T cells in experimental cerebral malaria (2002) J Immunol, 169, pp. 6369-6375. , COI: 1:CAS:528:DC%2BD38Xpt1Klsrk%3D, PID: 12444144; deWalick, S., Amante, F.H., McSweeney, K.A., Randall, L.M., Stanley, A.C., Haque, A., Cutting edge: conventional dendritic cells are the critical APC required for the induction of experimental cerebral malaria (2007) J Immunol, 178, pp. 6033-6037. , COI: 1:CAS:528:DC%2BD2sXksl2nt7o%3D, PID: 17475826; Haque, A., Best, S.E., Unosson, K., Amante, F.H., de Labastida, F., Anstey, N.M., Granzyme B expression by CD8+ T cells is required for the development of experimental cerebral malaria (2011) J Immunol, 186, pp. 6148-6156. , COI: 1:CAS:528:DC%2BC3MXmtlyksLo%3D, PID: 21525386; Howland, S.W., Poh, C.M., Renia, L., Activated brain endothelial cells cross-present malaria antigen (2015) PLoS Pathog., 11. , PID: 26046849, COI: 1:CAS:528:DC%2BC2MXhtVGnsLjJ; Butler, N.S., Moebius, J., Pewe, L.L., Traore, B., Doumbo, O.K., Tygrett, L.T., Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection (2011) Nat Immunol, 13, pp. 188-195. , PID: 22157630, COI: 1:CAS:528:DC%2BC3MXhs1eitr3J; Villegas-Mendez, A., Shaw, T.N., Inkson, C.A., Strangward, P., de Souza, J.B., Couper, K.N., Parasite-specific CD4+ IFN-gamma+ IL-10+ T cells distribute within both lymphoid and nonlymphoid compartments and are controlled systemically by interleukin-27 and ICOS during blood-stage malaria infection (2016) Infect Immun, 84, pp. 34-46. , COI: 1:CAS:528:DC%2BC28Xos1eisLk%3D, PID: 26459508; Lessard, S., Gatof, E.S., Beaudoin, M., Schupp, P.G., Sher, F., Ali, A., An erythroid-specific ATP2B4 enhancer mediates red blood cell hydration and malaria susceptibility (2017) J Clin Invest, 127, pp. 3065-3074. , PID: 28714864; Hillringhaus, S., Dasanna, A.K., Gompper, G., Fedosov, D.A., Importance of erythrocyte deformability for the alignment of malaria parasite upon invasion (2019) Biophys J, 117, pp. 1202-1214. , COI: 1:CAS:528:DC%2BC1MXhslyisLzI, PID: 31540708; Bogdanova, A., Makhro, A., Wang, J., Lipp, P., Kaestner, L., Calcium in red blood cells-a perilous balance (2013) Int J Mol Sci, 14, pp. 9848-9872. , PID: 23698771, COI: 1:CAS:528:DC%2BC3sXhtVSktLvM; Fowkes, F.J., Allen, S.J., Allen, A., Alpers, M.P., Weatherall, D.J., Day, K.P., Increased microerythrocyte count in homozygous alpha(+)-thalassaemia contributes to protection against severe malarial anaemia (2008) PLoS Med., 5. , PID: 18351796, COI: 1:CAS:528:DC%2BD1cXmvVSlt7Y%3D; Krause, M.A., Diakite, S.A., Lopera-Mesa, T.M., Amaratunga, C., Arie, T., Traore, K., alpha-Thalassemia impairs the cytoadherence of Plasmodium falciparum-infected erythrocytes (2012) PLoS One., 7. , COI: 1:CAS:528:DC%2BC38XnvFSmtb0%3D, PID: 22623996; Gros, R., Afroze, T., You, X.M., Kabir, G., Van Wert, R., Kalair, W., Plasma membrane calcium ATPase overexpression in arterial smooth muscle increases vasomotor responsiveness and blood pressure (2003) Circ Res, 93, pp. 614-621. , COI: 1:CAS:528:DC%2BD3sXnsFSgsrY%3D, PID: 12933703; Mohamed, T.M., Oceandy, D., Prehar, S., Alatwi, N., Hegab, Z., Baudoin, F.M., Specific role of neuronal nitric-oxide synthase when tethered to the plasma membrane calcium pump in regulating the beta-adrenergic signal in the myocardium (2009) J Biol Chem, 284, pp. 12091-12098. , COI: 1:CAS:528:DC%2BD1MXltVCmtbc%3D, PID: 19278978; Oceandy, D., Cartwright, E.J., Emerson, M., Prehar, S., Baudoin, F.M., Zi, M., Neuronal nitric oxide synthase signaling in the heart is regulated by the sarcolemmal calcium pump 4b (2007) Circulation, 115, pp. 483-492. , COI: 1:CAS:528:DC%2BD2sXnvF2mtQ%3D%3D, PID: 17242280; Baggott, R.R., Alfranca, A., Lopez-Maderuelo, D., Mohamed, T.M., Escolano, A., Oller, J., Plasma membrane calcium ATPase isoform 4 inhibits vascular endothelial growth factor-mediated angiogenesis through interaction with calcineurin (2014) Arterioscler Thromb Vasc Biol, 34, pp. 2310-2320. , COI: 1:CAS:528:DC%2BC2cXhsFKnsLvE, PID: 25147342; Ono, K., Wang, X., Han, J., Resistance to tumor necrosis factor-induced cell death mediated by PMCA4 deficiency (2001) Mol Cell Biol, 21, pp. 8276-8288. , COI: 1:CAS:528:DC%2BD3MXovVegs7k%3D, PID: 11713265; Supper, V., Schiller, H.B., Paster, W., Forster, F., Boulegue, C., Mitulovic, G., Association of CD147 and calcium exporter PMCA4 uncouples IL-2 expression from early TCR signaling (2016) J Immunol, 196, pp. 1387-1399. , COI: 1:CAS:528:DC%2BC28Xht1aitb8%3D, PID: 26729804; Campanella, G.S., Tager, A.M., El Khoury, J.K., Thomas, S.Y., Abrazinski, T.A., Manice, L.A., Chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 are required for the development of murine cerebral malaria (2008) Proc Natl Acad Sci USA, 105, pp. 4814-4819. , COI: 1:CAS:528:DC%2BD1cXktlSrt7s%3D, PID: 18347328; Howland, S.W., Poh, C.M., Gun, S.Y., Claser, C., Malleret, B., Shastri, N., Brain microvessel cross-presentation is a hallmark of experimental cerebral malaria (2013) EMBO Mol Med, 5, pp. 984-999. , PID: 23681698, COI: 1:CAS:528:DC%2BC3sXhtVCgs7vM; Sorensen, E.W., Lian, J., Ozga, A.J., Miyabe, Y., Ji, S.W., Bromley, S.K., CXCL10 stabilizes T cell-brain endothelial cell adhesion leading to the induction of cerebral malaria (2018) JCI Insight., 3. , PID: 5931132; Strangward, P., Haley, M.J., Shaw, T.N., Schwartz, J.M., Greig, R., Mironov, A., A quantitative brain map of experimental cerebral malaria pathology (2017) PLoS Pathog., 13. , PID: 28273147, COI: 1:CAS:528:DC%2BC2sXhvFCgsLjE
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