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J Theor Biol. 2013 Oct 7;334:173-86. doi: 10.1016/j.jtbi.2013.05.028. Epub 2013 Jun 11.

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

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Department of Mathematics, University of Pittsburgh, Pittsburgh, PA 15260, USA.


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.


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

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