title: In vivo, in vitro, and in silico studies suggest a conserved immune module that regulates malaria parasite transmission from mammals to mosquitoes.
abstract: Human malaria can be caused by the parasite Plasmodium falciparum that is transmitted by female Anopheles mosquitoes. "Immunological crosstalk" between the mammalian and anopheline hosts for Plasmodium functions to control parasite numbers. Key to this process is the mammalian cytokine transforming growth factor-β1 (TGF-β1). In mammals, TGF-β1 regulates inducible nitric oxide (NO) synthase (iNOS) both positively and negatively. In some settings, high levels of NO activate latent TGF-β1, which in turn suppresses iNOS expression. In the mosquito, ingested TGF-β1 induces A. stephensi NOS (AsNOS), which limits parasite development and which in turn is suppressed by activation of the mosquito homolog of the mitogen-activated protein kinases MEK and ERK. Computational models linking TGF-β1, AsNOS, and MEK/ERK were developed to provide insights into this complex biology. An initial Boolean model suggested that, as occurs in mammalian cells, MEK/ERK and AsNOS would oscillate upon ingestion of TGF-β1. An ordinary differential equation (ODE) model further supported the hypothesis of TGF-β1-induced multiphasic behavior of MEK/ERK and AsNOS. To achieve this multiphasic behavior, the ODE model was predicated on the presence of constant levels of TGF-β1 in the mosquito midgut. Ingested TGF-β1, however, did not exhibit this behavior. Accordingly, we hypothesized and experimentally verified that ingested TGF-β1 induces the expression of the endogenous mosquito TGF-β superfamily ligand As60A. Computational simulation of these complex, cross-species interactions suggested that TGF-β1 and NO-mediated induction of As60A expression together may act to maintain multiphasic AsNOS expression via MEK/ERK-dependent signaling. We hypothesize that multiphasic behavior as represented in this model allows the mosquito to balance the conflicting demands of parasite killing and metabolic homeostasis in the face of damaging inflammation.
authors.affiliation: Department of Mathematics, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Price
authors.forename: Bard
authors.initials: B
authors.lastname: Ermentrout
authors.forename: Ruben
authors.initials: R
authors.lastname: Zamora
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Nabil
authors.initials: N
authors.lastname: Azhar
authors.forename: Qi
authors.initials: Q
authors.lastname: Mi
authors.forename: Gregory
authors.initials: G
authors.lastname: Constantine
authors.forename: James R
authors.initials: JR
authors.lastname: Faeder
authors.forename: Shirley
authors.initials: S
authors.lastname: Luckhart
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
mesh_terms: D000818:Animals; D000852:Anopheles / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D019295:Computational Biology / Q000379:methods; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D005260:Female; D006790:Host-Parasite Interactions / Q000276:immunology; D006801:Humans; D019476:Insect Proteins / Q000276:immunology / Q000378:metabolism; D007303:Insect Vectors / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D020935:MAP Kinase Signaling System / Q000276:immunology; D016778:Malaria, Falciparum / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D018448:Models, Immunological; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000276:immunology / Q000378:metabolism; D010963:Plasmodium falciparum / Q000276:immunology* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism
chemical_list: C424084:As60A protein, Anopheles stephensi; D019476:Insect Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Anopheles stephensi 60A; Anopheles stephensi NOS; As60A; AsNOS; ERK; ERK kinase kinase; JNK; Jun N-terminal kinase; MAPK; MAPK of 38 kilo Dalton molecular weight; MEK; Malaria; Mathematical model; Mitogen-activated protein kinase; NO; NOS; Nitric oxide; ODE; PBS; RNS; TGF-β1; Transforming growth Factor-β1; extracellular signal-regulated kinase; iNOS; mammalian inducible NOS; mitogen-activated protein kinase; nitric oxide; nitric oxide synthase; ordinary differential equation; p38 MAPK; phosphate-buffered saline; reactive nitric oxide species; transforming growth factor-β1