title: Innate immunity induced by Plasmodium liver infection inhibits malaria reinfections.
abstract: Following transmission through a mosquito bite to the mammalian host, Plasmodium parasites first invade and replicate inside hepatocytes before infecting erythrocytes and causing malaria. The mechanisms limiting Plasmodium reinfections in humans living in regions of malaria endemicity have mainly been explored by studying the resistance induced by the blood stage of infection. However, epidemiologic studies have suggested that in high-transmission areas, preerythrocytic stages also activate host resistance to reinfection. This, along with the recent discovery that liver infections trigger a specific and effective type I interferon (IFN) response, prompted us to hypothesize that this pre-erythrocyte-stage-induced resistance is linked to liver innate immunity. Here, we combined experimental approaches and mathematical modeling to recapitulate field studies and understand the molecular basis behind such resistance. We present a newly established mouse reinfection model and demonstrate that rodent malaria liver-stage infection inhibits reinfection. This protection relies on the activation of innate immunity and involves the type I IFN response and the antimicrobial cytokine gamma IFN (IFN-γ). Importantly, mathematical simulations indicate that the predictions based on our experimental murine reinfection model fit available epidemiological data. Overall, our study revealed that liver-stage-induced innate immunity may contribute to the preerythrocytic resistance observed in humans in regions of malaria hyperendemicity.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal pliehl@medicina.ulisboa.pt mprudencio@medicina.ulisboa.pt.
authors.forename: Peter
authors.initials: P
authors.lastname: Liehl
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Meireles
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Inês S
authors.initials: IS
authors.lastname: Albuquerque
authors.affiliation: Centre for Vascular Research, UNSW Australia, Sydney, NSW, Australia.
authors.forename: Mykola
authors.initials: M
authors.lastname: Pinkevych
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Baptista
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Maria M
authors.identifier: http://orcid.org/0000-0002-2858-1041
authors.initials: MM
authors.lastname: Mota
authors.affiliation: Centre for Vascular Research, UNSW Australia, Sydney, NSW, Australia.
authors.forename: Miles P
authors.initials: MP
authors.lastname: Davenport
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal pliehl@medicina.ulisboa.pt mprudencio@medicina.ulisboa.pt.
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
mesh_terms: D056704:Adaptive Immunity; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000852:Anopheles / Q000469:parasitology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007113:Immunity, Innate; D007156:Immunologic Memory; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000276:immunology* / Q000469:parasitology; D008288:Malaria / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015233:Models, Statistical; D059208:Parasite Load; D010962:Plasmodium berghei / Q000254:growth & development / Q000276:immunology*; D011506:Proteins / Q000235:genetics / Q000276:immunology; D016601:RNA-Binding Proteins; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D034101:Sporozoites / Q000254:growth & development / Q000276:immunology*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C092573:Ifit1 protein, mouse; C087697:Ifit3 protein, mouse; C508032:Ifnar1 protein, mouse; D050839:Interferon Regulatory Factor-7; D047908:Intracellular Signaling Peptides and Proteins; C494235:Irf7 protein, mouse; D011506:Proteins; D016601:RNA-Binding Proteins; D049452:Green Fluorescent Proteins; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma; C118306:Usp18 protein, mouse; D043222:Ubiquitin Thiolesterase