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• W2607175114 abstract "In malaria, CD36 plays several roles, including mediating parasite sequestration to host organs, phagocytic clearance of parasites, and regulation of immunity. Although the functions of CD36 in parasite sequestration and phagocytosis have been clearly defined, less is known about its role in malaria immunity. Here, to understand the function of CD36 in malaria immunity, we studied parasite growth, innate and adaptive immune responses, and host survival in WT and Cd36−/− mice infected with a non-lethal strain of Plasmodium yoelii. Compared with Cd36−/− mice, WT mice had lower parasitemias and were resistant to death. At early but not at later stages of infection, WT mice had higher circulatory proinflammatory cytokines and lower anti-inflammatory cytokines than Cd36−/− mice. WT mice showed higher frequencies of proinflammatory cytokine-producing and lower frequencies of anti-inflammatory cytokine-producing dendritic cells (DCs) and natural killer cells than Cd36−/− mice. Cytokines produced by co-cultures of DCs from infected mice and ovalbumin-specific, MHC class II-restricted α/β (OT-II) T cells reflected CD36-dependent DC function. WT mice also showed increased Th1 and reduced Th2 responses compared with Cd36−/− mice, mainly at early stages of infection. Furthermore, in infected WT mice, macrophages and neutrophils expressed higher levels of phagocytic receptors and showed enhanced phagocytosis of parasite-infected erythrocytes than those in Cd36−/− mice in an IFN-γ-dependent manner. However, there were no differences in malaria-induced humoral responses between WT and Cd36−/− mice. Overall, the results show that CD36 plays a significant role in controlling parasite burden by contributing to proinflammatory cytokine responses by DCs and natural killer cells, Th1 development, phagocytic receptor expression, and phagocytic activity. In malaria, CD36 plays several roles, including mediating parasite sequestration to host organs, phagocytic clearance of parasites, and regulation of immunity. Although the functions of CD36 in parasite sequestration and phagocytosis have been clearly defined, less is known about its role in malaria immunity. Here, to understand the function of CD36 in malaria immunity, we studied parasite growth, innate and adaptive immune responses, and host survival in WT and Cd36−/− mice infected with a non-lethal strain of Plasmodium yoelii. Compared with Cd36−/− mice, WT mice had lower parasitemias and were resistant to death. At early but not at later stages of infection, WT mice had higher circulatory proinflammatory cytokines and lower anti-inflammatory cytokines than Cd36−/− mice. WT mice showed higher frequencies of proinflammatory cytokine-producing and lower frequencies of anti-inflammatory cytokine-producing dendritic cells (DCs) and natural killer cells than Cd36−/− mice. Cytokines produced by co-cultures of DCs from infected mice and ovalbumin-specific, MHC class II-restricted α/β (OT-II) T cells reflected CD36-dependent DC function. WT mice also showed increased Th1 and reduced Th2 responses compared with Cd36−/− mice, mainly at early stages of infection. Furthermore, in infected WT mice, macrophages and neutrophils expressed higher levels of phagocytic receptors and showed enhanced phagocytosis of parasite-infected erythrocytes than those in Cd36−/− mice in an IFN-γ-dependent manner. However, there were no differences in malaria-induced humoral responses between WT and Cd36−/− mice. Overall, the results show that CD36 plays a significant role in controlling parasite burden by contributing to proinflammatory cytokine responses by DCs and natural killer cells, Th1 development, phagocytic receptor expression, and phagocytic activity. Malaria is a major public health problem in many countries around the world, causing about ∼0.5 million deaths annually (1World Health Organization World Malaria Report 2015. World Health Organization, Geneva2015Crossref Google Scholar, 2Murray C.J. Rosenfeld L.C. Lim S.S. Andrews K.G. Foreman K.J. Haring D. Fullman N. Naghavi M. Lozano R. Lopez A.D. Global malaria mortality between 1980 and 2010: a systematic analysis.Lancet. 2012; 379: 413-431Abstract Full Text Full Text PDF PubMed Scopus (1102) Google Scholar). The disease is caused primarily by Plasmodium falciparum and Plasmodium vivax, which are the most prevalent malaria parasites in endemic regions (3Battle K.E. Guerra C.A. Golding N. Duda K.A. Cameron E. Howes R.E. Elyazar I.R. Baird J.K. Reiner Jr., R.C. Gething P.W. Smith D.L. Hay S.I. Global database of matched Plasmodium falciparum and P. vivax incidence and prevalence records from 1985–2013.Sci. Data. 2015; 2150012Crossref PubMed Scopus (21) Google Scholar, 4Howes R.E. Battle K.E. Mendis K.N. Smith D.L. Cibulskis R.E. Baird J.K. Hay S.I. Global epidemiology of Plasmodium vivax.Am. J. Trop. Med. Hyg. 2016; 95: 15-34Crossref PubMed Scopus (237) Google Scholar). Thus far, antimalarial drugs have been the only mode of treatment for malaria infections; however, in recent years, parasites have developed resistance, including to the more recently introduced artemisinins (5Baird J.K. Resistance to therapies for infection by Plasmodium vivax.Clin. Microbiol. Rev. 2009; 22: 508-534Crossref PubMed Scopus (221) Google Scholar, 6Ashley E.A. Dhorda M. Fairhurst R.M. Amaratunga C. Lim P. Suon S. Sreng S. Anderson J.M. Mao S. Sam B. Sopha C. Chuor C.M. Nguon C. Sovannaroth S. Pukrittayakamee S. et al.Spread of artemisinin resistance in Plasmodium falciparum malaria.N. Engl. J. Med. 2014; 371: 411-423Crossref PubMed Scopus (1442) Google Scholar, 7Faway E. Musset L. Pelleau S. Volney B. Casteras J. Caro V. Menard D. Briolant S. Legrand E. Plasmodium vivax multidrug resistance-1 gene polymorphism in French Guiana.Malar. J. 2016; 15: 540Crossref PubMed Scopus (15) Google Scholar). Given that parasites are likely to develop resistance to newly introduced drugs, alternative strategies are required to treat malaria infections. Mass vaccination would be a better strategy, but an effective vaccine is not available, and its development remains challenging (8Stanisic D.I. Good M.F. Whole organism blood stage vaccines against malaria.Vaccine. 2015; 33: 7469-7475Crossref PubMed Scopus (25) Google Scholar, 9Neafsey D.E. Juraska M. Bedford T. Benkeser D. Valim C. Griggs A. Lievens M. Abdulla S. Adjei S. Agbenyega T. Agnandji S.T. Aide P. Anderson S. Ansong D. Aponte J.J. et al.Genetic diversity and protective efficacy of the RTS,S/AS01 malaria vaccine.N. Engl. J. Med. 2015; 373: 2025-2037Crossref PubMed Scopus (231) Google Scholar). Gaining insight into the molecular and cellular processes involved in protective immunity and pathogenesis may help in the design of an efficacious vaccine and/or immunomodulation agents to treat malaria (10Stevenson M.M. Riley E.M. Innate immunity to malaria.Nat. Rev. Immunol. 2004; 4: 169-180Crossref PubMed Scopus (482) Google Scholar, 11Augustine A.D. Hall B.F. Leitner W.W. Mo A.X. Wali T.M. Fauci A.S. NIAID workshop on immunity to malaria: addressing immunological challenges.Nat. Immunol. 2009; 10: 673-678Crossref PubMed Scopus (18) Google Scholar). Innate immunity plays crucial roles in the outcome of malaria (10Stevenson M.M. Riley E.M. Innate immunity to malaria.Nat. Rev. Immunol. 2004; 4: 169-180Crossref PubMed Scopus (482) Google Scholar, 12Schofield L. Grau G.E. Immunological processes in malaria pathogenesis.Nat. Rev. Immunol. 2005; 5: 722-735Crossref PubMed Scopus (499) Google Scholar, 13Gazzinelli R.T. Kalantari P. Fitzgerald K.A. Golenbock D.T. Innate sensing of malaria parasites.Nat. Rev. Immunol. 2014; 14: 744-757Crossref PubMed Scopus (182) Google Scholar). It functions as the first line of defense in controlling infection through phagocytic clearance of parasites and regulates the development of adaptive immunity. Dendritic cells (DCs) 5The abbreviations used are: DCdendritic cellIRBCinfected red blood cellPfEMP1P. falciparum erythrocyte membrane protein-1MϕmacrophagePMNpolymorphonuclear neutrophilBMDMM-CSF-differentiated mouse bone marrow cellCR1/CR2complement receptors 1 and 2pipostinfectionCFSEcarboxyfluorescein succinimidyl esterOVAovalbuminNKnatural killerTCRT cell receptorOT-II T cellOVA-specific, MHC class II-restricted α/β T cellFcRFc receptorThT helper cellTbetT-box transcription factor encoded by Tbx21PEphycoerythrinAPCallophycocyaninBVBrilliant VioletPerCPperidinin-chlorophyll protein complex. and macrophages (Mϕs) are important early responders of the innate immune system. In malaria, Mϕs are primarily involved in parasitemia control through phagocytic uptake of parasites (14Smith T.G. Serghides L. Patel S.N. Febbraio M. Silverstein R.L. Kain K.C. CD36-mediated nonopsonic phagocytosis of erythrocytes infected with stage I and IIA gametocytes of Plasmodium falciparum.Infect. Immun. 2003; 71: 393-400Crossref PubMed Scopus (56) Google Scholar, 15Patel S.N. Serghides L. Smith T.G. Febbraio M. Silverstein R.L. Kurtz T.W. Pravenec M. Kain K.C. CD36 mediates the phagocytosis of Plasmodium falciparum-infected erythrocytes by rodent macrophages.J. Infect. Dis. 2004; 189: 204-213Crossref PubMed Scopus (103) Google Scholar, 16Cabrera A. Neculai D. Kain K.C. CD36 and malaria: friends or foes? A decade of data provides some answers.Trends Parasitol. 2014; 30: 436-444Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar), whereas DCs efficiently produce proinflammatory cytokines, such as TNF-α and IL-12, and present antigens. IL-12, a Th1-polariazing cytokine, activates NK cells to induce the secretion of IFN-γ, another Th1-promoting cytokine. IFN-γ, TNF-α, and IL-1 prime phagocytic cells to enhance phagocytic activity (17Mandell G.L. Cytokines, phagocytes, and pentoxifylline.J. Cardiovasc. Pharmacol. 1995; 25: S20-S22Crossref PubMed Scopus (71) Google Scholar). The initial cytokines produced by DCs modulate T and B cell functions, contributing to the development of parasite-specific cellular and humoral immunity. dendritic cell infected red blood cell P. falciparum erythrocyte membrane protein-1 macrophage polymorphonuclear neutrophil M-CSF-differentiated mouse bone marrow cell complement receptors 1 and 2 postinfection carboxyfluorescein succinimidyl ester ovalbumin natural killer T cell receptor OVA-specific, MHC class II-restricted α/β T cell Fc receptor T helper cell T-box transcription factor encoded by Tbx21 phycoerythrin allophycocyanin Brilliant Violet peridinin-chlorophyll protein complex. CD36 is a multifunctional class B scavenger receptor that also functions as a pattern recognition receptor in innate immune cells (18Febbraio M. Hajjar D.P. Silverstein R.L. CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism.J. Clin. Investig. 2001; 108: 785-791Crossref PubMed Scopus (932) Google Scholar, 19Silverstein R.L. Febbraio M. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior.Sci. Signal. 2009; 2: re3Crossref PubMed Scopus (714) Google Scholar). CD36 not only interacts with diverse ligands, including thrombospondin-1, long-chain fatty acids, certain oxidized lipids, types I and IV collagen, and β-amyloid, but also binds and mediates uptake of pathogens and apoptotic cells (18Febbraio M. Hajjar D.P. Silverstein R.L. CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism.J. Clin. Investig. 2001; 108: 785-791Crossref PubMed Scopus (932) Google Scholar, 19Silverstein R.L. Febbraio M. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior.Sci. Signal. 2009; 2: re3Crossref PubMed Scopus (714) Google Scholar). Many cell types, including platelets, Mϕs, DCs, adipocytes, and endothelial, epithelial, and muscle cells, express CD36 (18Febbraio M. Hajjar D.P. Silverstein R.L. CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism.J. Clin. Investig. 2001; 108: 785-791Crossref PubMed Scopus (932) Google Scholar, 19Silverstein R.L. Febbraio M. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior.Sci. Signal. 2009; 2: re3Crossref PubMed Scopus (714) Google Scholar). The CD36-dependent internalization of pathogens and endogenous pathogenic molecules, such as oxidized low-density lipoprotein and β-amyloid protein, activate Src/Syk family non-receptor tyrosine kinases, ERK and Jun members of the MAPK signaling pathways, and NF-κB transcription factors, resulting in the production of proinflammatory mediators (16Cabrera A. Neculai D. Kain K.C. CD36 and malaria: friends or foes? A decade of data provides some answers.Trends Parasitol. 2014; 30: 436-444Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 19Silverstein R.L. Febbraio M. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior.Sci. Signal. 2009; 2: re3Crossref PubMed Scopus (714) Google Scholar, 20Stewart C.R. Stuart L.M. Wilkinson K. van Gils J.M. Deng J. Halle A. Rayner K.J. Boyer L. Zhong R. Frazier W.A. Lacy-Hulbert A. El Khoury J. Golenbock D.T. Moore K.J. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer.Nat. Immunol. 2010; 11: 155-161Crossref PubMed Scopus (1092) Google Scholar). Thus, CD36 is involved in several physiological and pathological processes, including immunity, lipid absorption, storage and metabolism, inflammation, and cardiovascular and Alzheimer's diseases (18Febbraio M. Hajjar D.P. Silverstein R.L. CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism.J. Clin. Investig. 2001; 108: 785-791Crossref PubMed Scopus (932) Google Scholar, 19Silverstein R.L. Febbraio M. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior.Sci. Signal. 2009; 2: re3Crossref PubMed Scopus (714) Google Scholar). CD36 plays several important roles in malaria, including parasite sequestration in microvascular capillaries of various organs; in phagocytic clearance of parasites through uptake of infected erythrocytes; and in immune responses (20Stewart C.R. Stuart L.M. Wilkinson K. van Gils J.M. Deng J. Halle A. Rayner K.J. Boyer L. Zhong R. Frazier W.A. Lacy-Hulbert A. El Khoury J. Golenbock D.T. Moore K.J. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer.Nat. Immunol. 2010; 11: 155-161Crossref PubMed Scopus (1092) Google Scholar, 21Pasloske B.L. Howard R.J. Malaria, the red cell, and the endothelium.Annu. Rev. Med. 1994; 45: 283-295Crossref PubMed Scopus (81) Google Scholar, 22Day K.P. Hayward R.E. Smith D. Culvenor J.G. CD36-dependent adhesion and knob expression of the transmission stages of Plasmodium falciparum is stage specific.Mol. Biochem. Parasitol. 1998; 93: 167-177Crossref PubMed Scopus (62) Google Scholar, 23Weatherall D.J. Miller L.H. Baruch D.I. Marsh K. Doumbo O.K. Casals-Pascual C. Roberts D.J. Malaria and the red cell.Hematology Am. Soc. Hematol. Educ. Program. 2002; 2002: 35-57Crossref Scopus (144) Google Scholar, 24Hoebe K. Georgel P. Rutschmann S. Du X. Mudd S. Crozat K. Sovath S. Shamel L. Hartung T. Zähringer U. Beutler B. CD36 is a sensor of diacylglycerides.Nature. 2005; 433: 523-527Crossref PubMed Scopus (706) Google Scholar, 25Patel S.N. Lu Z. Ayi K. Serghides L. Gowda D.C. Kain K.C. Disruption of CD36 impairs cytokine response to Plasmodium falciparum glycosylphosphatidylinositol and confers susceptibility to severe and fatal malaria in vivo.J. Immunol. 2007; 178: 3954-3961Crossref PubMed Scopus (63) Google Scholar, 26Erdman L.K. Cosio G. Helmers A.J. Gowda D.C. Grinstein S. Kain K.C. CD36 and TLR interactions in inflammation and phagocytosis: implications for malaria.J. Immunol. 2009; 183: 6452-6459Crossref PubMed Scopus (82) Google Scholar, 27Urban B.C. Willcox N. Roberts D.J. A role for CD36 in the regulation of dendritic cell function.Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 8750-8755Crossref PubMed Scopus (257) Google Scholar). Of these, it is best known for functioning as a receptor for several members of the P. falciparum erythrocyte membrane protein-1 (PfEMP1) family of variant proteins, which are expressed on the infected red blood cell (IRBC) surface (28Baruch D.I. Gormely J.A. Ma C. Howard R.J. Pasloske B.L. Plasmodium falciparum erythrocyte membrane protein 1 is a parasitized erythrocyte receptor for adherence to CD36, thrombospondin, and intercellular adhesion molecule 1.Proc. Natl. Acad. Sci. U.S.A. 1996; 93: 3497-3502Crossref PubMed Scopus (339) Google Scholar, 29Hsieh F.L. Turner L. Bolla J.R. Robinson C.V. Lavstsen T. Higgins M.K. The structural basis for CD36 binding by the malaria parasite.Nat. Commun. 2016; 712837Crossref PubMed Scopus (113) Google Scholar, 30Smith J.D. Chitnis C.E. Craig A.G. Roberts D.J. Hudson-Taylor D.E. Peterson D.S. Pinches R. Newbold C.I. Miller L.H. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes.Cell. 1995; 82: 101-110Abstract Full Text PDF PubMed Scopus (820) Google Scholar). This interaction mediates the adherence of IRBCs to microvascular endothelia, enabling parasites to be sequestered in host organs and avoid clearance from the circulation. When immunity against an adherent PfEMP1 is present in the host, parasites expressing other PfEMP1 variants having different adherent specificity are sequestered in the host organs. The parasites multiply and accumulate in large numbers in organs, contributing to severe malaria pathogenesis (31Ochola L.B. Siddondo B.R. Ocholla H. Nkya S. Kimani E.N. Williams T.N. Makale J.O. Liljander A. Urban B.C. Bull P.C. Szestak T. Marsh K. Craig A.G. Specific receptor usage in Plasmodium falciparum cytoadherence is associated with disease outcome.PLoS One. 2011; 6e14741Crossref PubMed Scopus (96) Google Scholar, 32Bernabeu M. Danziger S.A. Avril M. Vaz M. Babar P.H. Brazier A.J. Herricks T. Maki J.N. Pereira L. Mascarenhas A. Gomes E. Chery L. Aitchison J.D. Rathod P.K. Smith J.D. Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass.Proc. Natl. Acad. Sci. U.S.A. 2016; 113: E3270-E3279Crossref PubMed Scopus (72) Google Scholar, 33Jespersen J.S. Wang C.W. Mkumbaye S.I. Minja D.T. Petersen B. Turner L. Petersen J.E. Lusingu J.P. Theander T.G. Lavstsen T. Plasmodium falciparum var genes expressed in children with severe malaria encode CIDRα1 domains.EMBO Mol. Med. 2016; 8: 839-850Crossref PubMed Scopus (65) Google Scholar, 34Magistrado P.A. Staalsoe T. Theander T.G. Hviid L. Jensen A.T. CD36 selection of 3D7 Plasmodium falciparum associated with severe childhood malaria results in reduced VAR4 expression.Malar. J. 2008; 7: 204Crossref PubMed Scopus (5) Google Scholar). Murine CD36 has ∼85% identity to human CD36 at the amino acid level. Although murine parasites do not express PfEMP1 orthologs, CD36 mediates the sequestration of Plasmodium berghei Antwerpen-Kasapa (ANKA), a cytoadherent murine malaria parasite strain, to lungs and adipose tissue of infected mice, presumably by interacting with unidentified structure(s) on the IRBC surface (35Franke-Fayard B. Janse C.J. Cunha-Rodrigues M. Ramesar J. Büscher P. Que I. Löwik C. Voshol P.J. den Boer M.A. van Duinen S.G. Febbraio M. Mota M.M. Waters A.P. Murine malaria parasite sequestration: CD36 is the major receptor, but cerebral pathology is unlinked to sequestration.Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 11468-11473Crossref PubMed Scopus (247) Google Scholar). Recent studies have shown that CD36-mediated sequestration of P. berghei ANKA strain causes acute liver injury (36Lagassé H.A. Anidi I.U. Craig J.M. Limjunyawong N. Poupore A.K. Mitzner W. Scott A.L. Recruited monocytes modulate malaria-induced lung injury through CD36-mediated clearance of sequestered infected erythrocytes.J. Leukoc. Biol. 2016; 99: 659-671Crossref PubMed Scopus (28) Google Scholar, 37Brugat T. Editorial: CD36: Russian roulette of host and parasites during malaria infection.J. Leukoc. Biol. 2016; 99: 643-645Crossref PubMed Scopus (1) Google Scholar). Furthermore, both in human and mouse malaria, CD36 controls parasitemia through phagocytic uptake of IRBCs by Mϕs and polymorphonuclear neutrophils (PMNs) (14Smith T.G. Serghides L. Patel S.N. Febbraio M. Silverstein R.L. Kain K.C. CD36-mediated nonopsonic phagocytosis of erythrocytes infected with stage I and IIA gametocytes of Plasmodium falciparum.Infect. Immun. 2003; 71: 393-400Crossref PubMed Scopus (56) Google Scholar, 16Cabrera A. Neculai D. Kain K.C. CD36 and malaria: friends or foes? A decade of data provides some answers.Trends Parasitol. 2014; 30: 436-444Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Additionally, CD36 has been shown to regulate MAPK signaling and modulate TNF-α responses in mouse malaria infection and to modulate parasite glycosylphosphatidylinositol-induced cytokine responses by mouse Mϕs and human blood DCs (16Cabrera A. Neculai D. Kain K.C. CD36 and malaria: friends or foes? A decade of data provides some answers.Trends Parasitol. 2014; 30: 436-444Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 27Urban B.C. Willcox N. Roberts D.J. A role for CD36 in the regulation of dendritic cell function.Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 8750-8755Crossref PubMed Scopus (257) Google Scholar, 38Gowda N.M. Wu X. Kumar S. Febbraio M. Gowda D.C. CD36 contributes to malaria parasite-induced pro-inflammatory cytokine production and NK and T cell activation by dendritic cells.PLoS One. 2013; 8e77604Crossref PubMed Scopus (24) Google Scholar). In P. falciparum-endemic regions, single-nucleotide polymorphisms in the Cd36 gene have been linked to protection against cerebral and other severe malaria (39Pain A. Urban B.C. Kai O. Casals-Pascual C. Shafi J. Marsh K. Roberts D.J. A non-sense mutation in Cd36 gene is associated with protection from severe malaria.Lancet. 2001; 357: 1502-1503Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 40Omi K. Ohashi J. Patarapotikul J. Hananantachai H. Naka I. Looareesuwan S. Tokunaga K. CD36 polymorphism is associated with protection from cerebral malaria.Am. J. Hum. Genet. 2003; 72: 364-374Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar), although another study has implicated mutations in Cd36 to susceptibility to malaria (41Aitman T.J. Cooper L.D. Norsworthy P.J. Wahid F.N. Gray J.K. Curtis B.R. McKeigue P.M. Kwiatkowski D. Greenwood B.M. Snow R.W. Hill A.V. Scott J. Malaria susceptibility and CD36 mutation.Nature. 2000; 405: 1015-1016Crossref PubMed Scopus (190) Google Scholar). Thus, CD36 plays an important role in immune responses to malaria, but insight into CD36-mediated regulation of immune responses to malaria remains less understood. Therefore, the main objective of this study was to determine the contribution of CD36 in malaria-induced immune responses and dissect the associated cellular mechanisms. To this end, we analyzed immune responses and assessed parasite growth kinetics and host survival in WT and Cd36−/− mice infected with a non-lethal, non-sequestering Plasmodium yoelii strain, which allows assessment of immune responses during the course of innate and adaptive immunity development. The results showed that CD36 significantly contributes to the production of proinflammatory cytokines by the cells of the innate immune system and Th1 development. CD36 also contributes to the suppression of anti-inflammatory cytokine production and Th2 development. Additionally, the CD36-dependent immune responses contribute to the expression of other phagocytic receptors and phagocytic activity, thereby significantly reducing parasite burden and malarial mortality. Overall, our results define the role of CD36 in malaria immunity, revealing the associated cellular mechanisms. In this study, we investigated the role of CD36 in immunity to blood stage malaria and in clinical outcomes by infecting WT and Cd36−/− mice with a non-sequestering P. yoelii 17XNL strain and analyzing various responses during the course of innate and adaptive immunity development. In mice infected with P. yoelii 17XNL strain, parasitemias reach a peak of 30–40% by about 20 days, and mice generally survive by clearing infection (42Butler N.S. Moebius J. Pewe L.L. Traore B. Doumbo O.K. Tygrett L.T. Waldschmidt T.J. Crompton P.D. Harty J.T. Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection.Nat. Immunol. 2011; 13: 188-195Crossref PubMed Scopus (365) Google Scholar, 43Stegmann K.A. De Souza J.B. Riley E.M. IL-18-induced expression of high-affinity IL-2R on murine NK cells is essential for NK-cell IFN-γ production during murine Plasmodium yoelii infection.Eur. J. Immunol. 2015; 45: 3431-3440Crossref PubMed Scopus (30) Google Scholar, 44Sebina I. James K.R. Soon M.S. Fogg L.G. Best S.E. Labastida Rivera F. Montes de Oca M. Amante F.H. Thomas B.S. Beattie L. Souza-Fonseca-Guimaraes F. Smyth M.J. Hertzog P.J. Hill G.R. Hutloff A. et al.IFNαR1-signalling obstructs ICOS-mediated humoral immunity during non-lethal blood-stage Plasmodium infection.PLoS Pathog. 2016; 12e1005999Crossref PubMed Scopus (41) Google Scholar). In contrast, mice infected with the sequestering, lethal P. yoelii 17XL strain die at 6–10 days postinfection (pi), exhibiting peak parasitemias of 60–80% (pi) (45Imai T. Shen J. Chou B. Duan X. Tu L. Tetsutani K. Moriya C. Ishida H. Hamano S. Shimokawa C. Hisaeda H. Himeno K. Involvement of CD8+ T cells in protective immunity against murine blood-stage infection with Plasmodium yoelii 17XL strain.Eur. J. Immunol. 2010; 40: 1053-1061Crossref PubMed Scopus (81) Google Scholar, 46Couper K.N. Blount D.G. Hafalla J.C. van Rooijen N. de Souza J.B. Riley E.M. Macrophage-mediated but γ interferon-independent innate immune responses control the primary wave of Plasmodium yoelii parasitemia.Infect. Immun. 2007; 75: 5806-5818Crossref PubMed Scopus (63) Google Scholar, 47Kaul D.K. Nagel R.L. Llena J.F. Shear H.L. Cerebral malaria in mice: demonstration of cytoadherence of infected red blood cells and microrheologic correlates.Am. J. Trop. Med. Hyg. 1994; 50: 512-521Crossref PubMed Scopus (45) Google Scholar). Survival analysis showed that 90% of WT mice infected with P. yoelii 17XNL survived, whereas the majority of infected Cd36−/− mice died between 17 and 24 days pi (Fig. 1A). Analysis of parasite growth kinetics showed, in both WT and Cd36−/− mice, slow parasite growth during the 1st week of infection and then a rapid increase, reaching peak parasitemias at 20–22 days pi (Fig. 1B). After this period, parasitemias were markedly decreased to basal levels in surviving mice. These observations agree with the previously reported growth pattern of P. yoelii 17XNL (42Butler N.S. Moebius J. Pewe L.L. Traore B. Doumbo O.K. Tygrett L.T. Waldschmidt T.J. Crompton P.D. Harty J.T. Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection.Nat. Immunol. 2011; 13: 188-195Crossref PubMed Scopus (365) Google Scholar, 43Stegmann K.A. De Souza J.B. Riley E.M. IL-18-induced expression of high-affinity IL-2R on murine NK cells is essential for NK-cell IFN-γ production during murine Plasmodium yoelii infection.Eur. J. Immunol. 2015; 45: 3431-3440Crossref PubMed Scopus (30) Google Scholar, 44Sebina I. James K.R. Soon M.S. Fogg L.G. Best S.E. Labastida Rivera F. Montes de Oca M. Amante F.H. Thomas B.S. Beattie L. Souza-Fonseca-Guimaraes F. Smyth M.J. Hertzog P.J. Hill G.R. Hutloff A. et al.IFNαR1-signalling obstructs ICOS-mediated humoral immunity during non-lethal blood-stage Plasmodium infection.PLoS Pathog. 2016; 12e1005999Crossref PubMed Scopus (41) Google Scholar). Throughout the infection period, parasitemias were significantly higher in Cd36−/− mice than in WT mice. Although parasitemias were relatively low in both WT and Cd36−/− mice up to 10–12 days pi, the parasitemias in Cd36−/− mice were 57–125% higher than those in WT mice (Fig. 1C). The CD36-depedent control of parasitemia is consistent with the reported results that CD36 is efficiently expressed by Mϕs and contributes to parasitemia control in mice infected with Plasmodium chabaudi (25Patel S.N. Lu Z. Ayi K. Serghides L. Gowda D.C. Kain K.C. Disruption of CD36 impairs cytokine response to Plasmodium falciparum glycosylphosphatidylinositol and confers susceptibility to severe and fatal malaria in vivo.J. Immunol. 2007; 178: 3954-3961Crossref PubMed Scopus (63) Google Scholar). Because CD36 functions both as a scavenger and pattern recognition receptor, it is not surprising that P. yoelii IRBCs are recognized by CD36 on Mϕs likely through relatively weak interactions and phagocytosed. Thus, the above data demonstrated that CD36 contributes to parasitemia control and resistance against malarial fatality. Based on the results presented in Fig. 1, we predicted that CD36 contributes to malaria-induced immune responses that are involved in parasitemia control and resistance to disease severity. Proinflammatory cytokine responses induced at early stages of infection play important roles in either pathogenesis or resistance to malaria depending on whether or not parasites are sequestered in host organs (10Stevenson M.M. Riley E.M. Innate immunity to malaria.Nat. Rev. Immunol. 2004; 4: 169-180Crossref PubMed Scopus (482) Google Scholar, 12Schofield L. Grau G.E. Immunological processes in malaria pathogenesis.Nat. Rev. Immunol. 2005; 5: 722-735Crossref PubMed Scopus (499) Google Scholar, 23Weatherall D.J. Miller L.H. Baruch D.I. Marsh K. Doumbo O.K. Casals-Pascual C. Roberts D.J. Malaria and the red cell.Hematology Am. Soc. Hematol. Educ. Program. 2002; 2002: 35-57Crossref Scopus (144) Google Scholar). High levels of proi" @default.
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• W2607175114 date "2017-06-01" @default.
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• W2607175114 title "CD36 receptor regulates malaria-induced immune responses primarily at early blood stage infection contributing to parasitemia control and resistance to mortality" @default.
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