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The lipid phosphatidylserine (PS) is usually confined to the inner leaflet of the red blood cell membrane (RBC) bilayer; however, some studies suggest that infection with the intracellular parasite results in the presence of this lipid in the RBC membrane outer leaflet, where it could act as a recognition signal to phagocytes. Here, we used fluorescent lipid analogues and probes to investigate the enzymatic reactions responsible for maintaining asymmetry between membrane leaflets, and found that in parasitised RBCs the maintenance of membrane asymmetry was partly disrupted, and PS was increased in the outer leaflet. We examined the underlying causes for the differences between uninfected and infected RBCs using fluorescent dyes and probes, and found that calcium levels increased in the infected RBC cytoplasm, whereas membrane cholesterol was depleted from the erythrocyte plasma membrane. We explored the resulting effect of PS exposure on enhanced phagocytosis by monocytes, and show that infected RBCs must expend energy to limit phagocyte recognition, and provide experimental evidence that PS exposure contributes to phagocytic recognition of <jats:italic>P<\/jats:italic>. <jats:italic>falciparum<\/jats:italic>-infected RBCs. Together, these findings underscore the pivotal role for PS exposure on the surface of <jats:italic>Plasmodium falciparum<\/jats:italic>-infected erythrocytes for <jats:italic>in vivo<\/jats:italic> interactions with the host immune system, and provide a rationale for targeted antimalarial drug design.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009259","type":"journal-article","created":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T18:45:33Z","timestamp":1613673933000},"page":"e1009259","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":30,"title":["Breakdown in membrane asymmetry regulation leads to monocyte recognition of P. falciparum-infected red blood cells"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9983-1474","authenticated-orcid":true,"given":"Merryn","family":"Fraser","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6747-6076","authenticated-orcid":true,"given":"Weidong","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8040-1634","authenticated-orcid":true,"given":"Stefan","family":"Br\u00f6er","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3807-473X","authenticated-orcid":true,"given":"Florian","family":"Kurth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0476-9947","authenticated-orcid":true,"given":"Leif-Erik","family":"Sander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6147-8591","authenticated-orcid":true,"given":"Kai","family":"Matuschewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7369-1058","authenticated-orcid":true,"given":"Alexander G.","family":"Maier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,2,18]]},"reference":[{"issue":"6","key":"ppat.1009259.ref001","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.pt.2018.11.010","article-title":"Plasmodium falciparum","volume":"35","author":"AG Maier","year":"2019","journal-title":"Trends Parasitol."},{"issue":"3","key":"ppat.1009259.ref002","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.cell.2016.07.055","article-title":"Malaria: Biology and disease","volume":"167","author":"AF Cowman","year":"2016","journal-title":"Cell"},{"issue":"8","key":"ppat.1009259.ref003","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/nrmicro.2016.79","article-title":"Plasmodium species: master renovators of their host cells","volume":"14","author":"TF de Koning-Ward","year":"2016","journal-title":"Nat Rev Microbiol."},{"issue":"5","key":"ppat.1009259.ref004","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/nrmicro2110","article-title":"Malaria parasite proteins that remodel the host erythrocyte","volume":"7","author":"AG Maier","year":"2009","journal-title":"Nat Rev Microbiol."},{"issue":"2","key":"ppat.1009259.ref005","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1182\/blood-2010-04-202911","article-title":"The pathogenesis of Plasmodium falciparum malaria in humans: insights from splenic physiology","volume":"117","author":"PA Buffet","year":"2011","journal-title":"Blood."},{"issue":"1444","key":"ppat.1009259.ref006","first-page":"1","article-title":"Sticking for a cause: The falciparum malaria parasites cytoadherence paradigm","volume":"10","author":"WC Lee","year":"2019","journal-title":"Front Immunol"},{"issue":"1","key":"ppat.1009259.ref007","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20131007","article-title":"Membrane transport in the malaria parasite and its host erythrocyte","volume":"457","author":"K Kirk","year":"2014","journal-title":"Biochem J."},{"issue":"61","key":"ppat.1009259.ref008","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/newbio236011a0","article-title":"Asymmetrical lipid bilayer structure for biological membranes","volume":"236","author":"MS Bretscher","year":"1972","journal-title":"Nat New Biol."},{"issue":"8","key":"ppat.1009259.ref009","doi-asserted-by":"crossref","first-page":"R386","DOI":"10.1016\/j.cub.2018.01.007","article-title":"Transbilayer lipid asymmetry","volume":"28","author":"T Kobayashi","year":"2018","journal-title":"Curr Biol."},{"issue":"10","key":"ppat.1009259.ref010","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.tcb.2006.08.009","article-title":"Biophysical properties of lipids and dynamic membranes","volume":"16","author":"PA Janmey","year":"2006","journal-title":"Trends Cell 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Commun."},{"key":"ppat.1009259.ref014","doi-asserted-by":"crossref","first-page":"2399","DOI":"10.1016\/S0021-9258(17)41959-4","article-title":"Exposure of phosphatidylserine in the outer leaflet of human red blood cells. Relationship to cell density, cell age, and clearance by mononuclear cells","volume":"269","author":"J Connor","year":"1994","journal-title":"J Biol Chem."},{"issue":"1","key":"ppat.1009259.ref015","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1146\/annurev-immunol-042617-053010","article-title":"Apoptosis and clearance of apoptotic cells","volume":"36","author":"S Nagata","year":"2018","journal-title":"Annu Rev Immunol."},{"issue":"8","key":"ppat.1009259.ref016","doi-asserted-by":"crossref","first-page":"5131","DOI":"10.1016\/S0021-9258(18)89189-X","article-title":"In vivo recognition and clearance of red blood cells containing phosphatidylserine in their plasma membranes","volume":"260","author":"AJ Schroit","year":"1985","journal-title":"J Biol Chem."},{"issue":"6","key":"ppat.1009259.ref017","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1172\/JCI111913","article-title":"Increased adherence of sickled and phosphatidylserine-enriched human erythrocytes to 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hemolytic anemia","volume":"101","author":"N Arashiki","year":"2016","journal-title":"Haematologica."},{"issue":"17","key":"ppat.1009259.ref024","doi-asserted-by":"crossref","first-page":"6809","DOI":"10.1074\/jbc.RA118.007270","article-title":"Identification and functional analyses of disease-associated P4-ATPase phospholipid flippase variants in red blood cells","volume":"294","author":"AY Liou","year":"2019","journal-title":"J Biol Chem."},{"issue":"8","key":"ppat.1009259.ref025","doi-asserted-by":"crossref","first-page":"2752","DOI":"10.1021\/acs.jproteome.7b00025","article-title":"Quantitative analysis of human red blood cell proteome","volume":"16","author":"AH Bryk","year":"2017","journal-title":"J Proteome Res."},{"issue":"3","key":"ppat.1009259.ref026","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.bbalip.2012.10.006","article-title":"Mammalian P4-ATPases and ABC transporters and their role in phospholipid transport","volume":"1831","author":"JA Coleman","year":"2013","journal-title":"Biochim Biophys Acta\u2014Mol Cell Biol Lipids."},{"issue":"1","key":"ppat.1009259.ref027","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0005-2736(98)00049-2","article-title":"Evidence for a role of the multidrug resistance protein (MRP) in the outward translocation of NBD-phospholipids in the erythrocyte membrane","volume":"1372","author":"D Kamp","year":"1998","journal-title":"Biochim Biophys Acta\u2014Biomembr"},{"issue":"1","key":"ppat.1009259.ref028","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.abb.2007.04.002","article-title":"Phospholipid scramblases: An overview","volume":"462","author":"SK Sahu","year":"2007","journal-title":"Arch Biochem Biophys."},{"issue":"3","key":"ppat.1009259.ref029","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1097\/MOH.0b013e3282f97af7","article-title":"Regulation of phospholipid asymmetry in the erythrocyte membrane","volume":"15","author":"DL Daleke","year":"2008","journal-title":"Curr Opin Hematol."},{"issue":"8","key":"ppat.1009259.ref030","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.bbalip.2015.12.020","article-title":"On the molecular mechanism of flippase- and scramblase-mediated phospholipid transport","volume":"1861","author":"C Montigny","year":"2016","journal-title":"Biochim Biophys Acta\u2014Mol Cell Biol Lipids."},{"key":"ppat.1009259.ref031","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1097\/MOH.0000000000000326","article-title":"Maintenance and regulation of asymmetric phospholipid distribution in human erythrocyte membranes: Implications for erythrocyte functions","volume":"24","author":"N Arashiki","year":"2017","journal-title":"Curr Opin Hematol."},{"issue":"13","key":"ppat.1009259.ref032","doi-asserted-by":"crossref","first-page":"2724","DOI":"10.1016\/j.febslet.2010.03.020","article-title":"Phospholipid scramblase: An update","volume":"584","author":"EM Bevers","year":"2010","journal-title":"FEBS Lett."},{"issue":"S1","key":"ppat.1009259.ref033","first-page":"41","article-title":"Phospholipid scramblases","volume":"8","author":"P Williamson","year":"2015","journal-title":"Lipid Insights."},{"issue":"2","key":"ppat.1009259.ref034","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1182\/blood.V69.2.401.401","article-title":"Altered plasma membrane phospholipid organization in Plasmodium falciparum-infected human erythrocytes","volume":"69","author":"RS Schwartz","year":"1987","journal-title":"Blood."},{"issue":"2","key":"ppat.1009259.ref035","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1111\/j.1365-2141.1988.tb06198.x","article-title":"Abnormal membrane phospholipid organization in Plasmodium falciparum-infected human erythrocytes","volume":"68","author":"P Joshi","year":"1988","journal-title":"Br J Haematol."},{"key":"ppat.1009259.ref036","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1139\/o90-083","article-title":"Phospholipid asymmetry in the plasma membrane of malaria infected erythrocytes","volume":"68","author":"GN Moll","year":"1990","journal-title":"Biochem Cell Biol."},{"issue":"2","key":"ppat.1009259.ref037","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1017\/S0031182000062466","article-title":"Alterations in erythrocyte membrane phospholipid organization due to the intracellular growth of the human malaria parasite, Plasmodium falciparum","volume":"102","author":"PA Maguire","year":"1991","journal-title":"Parasitology."},{"issue":"6","key":"ppat.1009259.ref038","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/S0169-4758(97)85284-2","article-title":"Altered membrane phospholipid asymmetry in Plasmodium falciparum-infected erythrocytes","volume":"13","author":"I Sherman","year":"1997","journal-title":"Parasitol Today."},{"issue":"5\u20136","key":"ppat.1009259.ref039","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1159\/000067908","article-title":"Cytoadherence of malaria-infected red blood cells involves exposure of phosphatidylserine","volume":"12","author":"S Eda","year":"2002","journal-title":"Cell Physiol Biochem."},{"issue":"8","key":"ppat.1009259.ref040","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/0169-4758(95)80044-1","article-title":"Malaria: Phosphatidylserine expression is not increased on the surface of parasitized erythrocytes","volume":"11","author":"J Taverne","year":"1995","journal-title":"Parasitol Today."},{"issue":"6","key":"ppat.1009259.ref041","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1002\/cyto.b.20141","article-title":"Cytoadherence between endothelial cells and P. falciparum infected and noninfected normal and thalassemic red blood cells","volume":"70B","author":"P Butthep","year":"2006","journal-title":"Cytom Part B Clin Cytom."},{"issue":"15022","key":"ppat.1009259.ref042","first-page":"1","article-title":"Febrile temperature elevates the expression of phosphatidylserine on Plasmodium falciparum (FCR3CSA) infected red blood cell surface leading to increased cytoadhesion","volume":"8","author":"R Zhang","year":"2018","journal-title":"Sci Rep."},{"issue":"6","key":"ppat.1009259.ref043","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1159\/000075122","article-title":"Dependence of Plasmodium falciparum in vitro growth on the cation permeability of the human host erythrocyte","volume":"13","author":"V Brand","year":"2003","journal-title":"Cell Physiol Biochem."},{"issue":"5\u20136","key":"ppat.1009259.ref044","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1159\/000257529","article-title":"Accelerated clearance of Plasmodium-infected erythrocytes in sickle cell trait and Annexin-A7 deficiency","volume":"24","author":"PA Lang","year":"2009","journal-title":"Cell Physiol 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falciparum in vitro","volume":"4","author":"D Engelbrecht","year":"2013","journal-title":"Cell Death Dis."},{"key":"ppat.1009259.ref048","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.parint.2016.07.007","article-title":"Plasmodium falciparum exhibits markers of regulated cell death at high population density in vitro","volume":"65","author":"D Engelbrecht","year":"2016","journal-title":"Parasitol Int."},{"issue":"50","key":"ppat.1009259.ref049","doi-asserted-by":"crossref","first-page":"E5455","DOI":"10.1073\/pnas.1414221111","article-title":"(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium","volume":"111","author":"MB Jim\u00e9nez-D\u00edaz","year":"2014","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"1","key":"ppat.1009259.ref050","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/0169-4758(92)90305-L","article-title":"Lipid compartmentalization in erythrocytes parasitized by Plasmodium spp","volume":"8","author":"AP Sim\u00f5es","year":"1992","journal-title":"Parasitol Today."},{"key":"ppat.1009259.ref051","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/978-3-662-05181-8_15","volume-title":"Red Cell Membrane Transport in Health and Disease","author":"T Tiffert","year":"2003"},{"key":"ppat.1009259.ref052","doi-asserted-by":"crossref","first-page":"9848","DOI":"10.3390\/ijms14059848","article-title":"Calcium in red blood cells\u2014a perilous balance","volume":"14","author":"A Bogdanova","year":"2013","journal-title":"Int J Mol Sci."},{"issue":"8","key":"ppat.1009259.ref053","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1007\/BF00931087","article-title":"Role of calcium and erythrocyte cytoskeleton phosphorylation in the invasion of Plasmodium falciparum","volume":"76","author":"M Wasserman","year":"1990","journal-title":"Parasitol 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