Cross-talk among mosquito and mammalian immune factors

描述(由申请人提供)：诱导型一氧化氮合酶(NOSII)是哺乳动物和无脊椎动物细胞抗病原体武器库中的重要武器。在哺乳动物中，转化生长因子-1(转化生长因子-1)通过对一氧化氮合酶LI的显著调节作用，调节宿主对疟疾病原体如疟疾病原体的反应。高水平的NO似乎通过S亚硝化和随后内源性转化生长因子-β1(潜伏期相关肽，LAP)的失活来激活潜伏的转化生长因子β1，而在某些疾病状态下释放的有效促氧化剂游离血红素为潜在转化生长因子-1的激活提供了另一种机制。在无脊椎动物中，按蚊通过主要位于中肠的NO的诱导合成来限制疟疾寄生虫的发展。斯氏按蚊(Anopheles stephensi NOS，AsNOS)与脊椎动物的NOS基因具有显著的保守性；然而，关于AsNOS是如何调控的，人们知之甚少。我们的初步研究表明，被斯氏疟原虫摄取并在中肠激活的人转化生长因子1调节AsNOS和疟原虫的发育。我们还鉴定了蚊子转化生长因子-β同源基因As60A，它在中肠中被诱导表达，并与寄生虫感染相关，表明与脊椎动物的转化生长因子-β1一样，As60A是宿主对寄生虫感染反应的标志。因此，按蚊的取血行为在脊椎动物和无脊椎动物的免疫因子之间建立了一个功能界面，包括中肠环境中的AsNOS、NO、转化生长因子β1和As60A。我们假设，在蚊子中肠中，(1)哺乳动物的转化生长因子β1被血液消化过程中释放的血红素激活，并诱导蚊子产生一氧化氮；(2)转化生长因子β1和As60A激活交叉的信号通路，调节靶基因的表达和寄生虫的发育。在基础水平上，这里提出的研究将确定细胞因子控制是否是免疫基因调控的保守特征，这些生物之间的进化间隔超过5亿年。在更实用的层面上，拟议的研究可能会对疟疾的控制产生影响。

DESCRIPTION (provided by the applicant): Inducible nitric oxide synthase (NOS II) is a vital weapon in the anti-pathogen arsenal of both mammalian and invertebrate cells. In mammals, transforming growth factor-¿1 (TGF-¿1) modulates the host response to pathogens such as Plasmodium, the causative agent of malaria, via a prominent role in the regulation of NOS lI. High levels of NO appear to activate latent TGF¿1 by S-nitrosation and subsequent inactivation of the endogenous neutralizer of TGF-¿1 (the latency-associated peptide, LAP), while free heme, a potent pro-oxidant released in certain disease states, provides an additional mechanism for activation of latent TGF-¿1. Among invertebrates, Anopheles mosquitoes limit malaria parasite development with an inducible synthesis of NO that is localized principally to the midgut. Anopheles stephensi NOS (AsNOS) shows remarkable conservation with vertebrate NOS genes; however, little is known about how AsNOS is regulated. Our Preliminary Studies reveal that human TGF¿1, ingested by A. stephensi and activated in the midgut, regulates AsNOS and Plasmodium development. We have also identified a mosquito TGF-¿ homolog, As60A, whose expression is induced in the midgut and correlated with parasite infection, indicating that like its vertebrate counterpart TGF-¿1, As60A is a marker of the host response to parasite infection. The act of blood feeding by Anopheles, therefore, creates a functional interface among vertebrate and invertebrate immune factors including AsNOS, NO, TGF-¿1, and As60A in the midgut environment. We hypothesize that, in the mosquito midgut, (1) mammalian TGF-¿1 is activated by heme released during blood digestion and induced mosquito NO and (2) that TGF-¿1 and As60A activate intersecting signaling pathways to regulate target gene expression and parasite development. At a basic level, the studies proposed herein will establish whether cytokine control is a conserved feature of immune gene regulation among organisms that are separated by more than 500 million years of evolution. At a more applied level, the proposed research will likely have implications for the control of malaria.