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（NOS II）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 （TGF- 1）通过调控NOS - 1的重要作用，调节宿主对疟原虫（疟疾的病原体）等病原体的反应。高水平的NO似乎通过s -亚硝化激活潜伏的TGF- 1，并随后使内源性TGF- 1中和剂（潜伏相关肽，LAP）失活，而在某些疾病状态下释放的强效促氧化剂游离血红素为激活潜伏的TGF- 1提供了另一种机制。在无脊椎动物中，按蚊通过诱导合成主要局限于中肠的一氧化氮来限制疟疾寄生虫的发育。斯氏按蚊NOS （AsNOS）与脊椎动物NOS基因具有显著的保守性；然而，人们对AsNOS是如何调控的知之甚少。我们的初步研究表明，人类TGF¿1被斯蒂芬假体摄入并在中肠激活，可调节AsNOS和疟原虫的发育。我们还鉴定出一种蚊子TGF-¿同源物As60A，其在中肠诱导表达并与寄生虫感染相关，表明与脊椎动物TGF-¿1一样，As60A是宿主对寄生虫感染反应的标记物。因此，按蚊的吸血行为在中肠环境中建立了包括AsNOS、NO、TGF-¿1和As60A在内的脊椎动物和无脊椎动物免疫因子之间的功能接口。我们推测，在蚊子中肠中，(1)哺乳动物TGF-¿1被血液消化过程中释放的血红素激活，诱导蚊子NO； (2) TGF-¿1和As60A激活交叉信号通路，调节靶基因表达和寄生虫发育。在基本水平上，本文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，这些生物在超过5亿年的进化中分离。在更广泛的应用层面上，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.