In vivo, in vitro, and in silico studies suggest a conserved immune module that regulates malaria parasite transmission from mammals to mosquitoes

JOURNAL OF THEORETICAL BIOLOGY

卷:334

Article

Price, Ian¹  Ermentrout, Bard^1,3  Zamora, Ruben^2,3  Wang, Bo⁴  Azhar, Nabil^2,3,5  Mi, Qi^3,6  Constantine, Gregory^1,3  Faeder, James R.^3,5  Luckhart, Shirley⁴  Vodovotz, Yoram^2,3 

[1] Univ Pittsburgh, Dept Math, Pittsburgh, PA 15260 USA

[2] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15213 USA

[3] Univ Pittsburgh, McGowan Inst Regenerat Med, Ctr Inflammat & Regenerat Modeling, Pittsburgh, PA 15219 USA

[4] Univ Calif Davis, Dept Med Microbiol & Immunol, Davis, CA 95616 USA

[5] Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA 15260 USA

[6] Univ Pittsburgh, Dept Sports Med & Nutr, Pittsburgh, PA 15260 USA

关键词: Malaria;    Mathematical model;    Transforming growth Factor-beta 1;    Nitric oxide;    Mitogen-activated protein kinase;   

DOI  :  10.1016/j.jtbi.2013.05.028

来源: Elsevier

【 摘 要 】

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-beta 1 (TGF-beta 1). In mammals, TGF-beta 1 regulates inducible nitric oxide (NO) synthase (iNOS) both positively and negatively. In some settings, high levels of NO activate latent TGF-beta 1, which in turn suppresses iNOS expression. In the mosquito, ingested TGF-beta 1 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 ERR. Computational models linking TGF-beta 1, 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-beta 1. An ordinary differential equation (ODE) model further supported the hypothesis of TGF-beta 1-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-beta 1 in the mosquito midgut. Ingested TGF-beta 1, however, did not exhibit this behavior. Accordingly, we hypothesized and experimentally verified that ingested TGF-beta 1 induces the expression of the endogenous mosquito TGF-beta superfamily ligand As60A. Computational simulation of these complex, cross-species interactions suggested that TG-beta 1 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. (C) 2013 Elsevier Ltd. All rights reserved.

【 授权许可】

Free