The splicing factor SF3b1 is a master regulator of the innate immune response to Mycobacterium tuberculosis

 描述(申请人提供)：结核分枝杆菌，结核病的病原体，已经进化出与宿主巨噬细胞的复杂界面，以建立复制的生态位并促进感染。在感染后，结核分枝杆菌诱导宿主基因表达的变化，以下调促炎细胞因子。过去的工作已经提供了压倒性的证据，表明在感染后立即发生的宿主基因表达的变化对结核分枝杆菌确定感染是至关重要的。然而，我对基因表达变化如何在mRNA加工和成熟水平上进行调控知之甚少。我们的新工作表明，在对结核分枝杆菌的反应中，转录后对基因表达的控制是重要的，而前mRNA剪接是感染过程中的一个主要调节检查点。这里提出的研究旨在填补我们对先天免疫基因表达程序转录后调控的理解中的一个关键空白，并将阐明像结核分枝杆菌这样的人类健康病原体如何操纵宿主RNA的加工来创造有利的生态位。这些研究中产生的信息将有助于开发靶向疫苗和宿主导向疗法，旨在调节前-mRNA剪接，以增强抗菌和/或短路亲细菌基因表达程序。

 DESCRIPTION (provided by applicant): Mycobacterium tuberculosis, the causative agent of tuberculosis, has evolved a complex interface with the host macrophage in order to establish a replicative niche and promote infection. Upon infection, Mtb induces changes to host gene expression in order to down-regulate pro-inflammatory cytokines. Past work has provided overwhelming evidence that changes to host gene expression that occur in the hours immediately following infection are critical for Mtb to establish infection. However, very little i known about how gene expression changes are regulated at the level of mRNA processing and maturation. Our new work indicates that post-transcriptional control of gene expression is important during the response to Mtb and that pre- mRNA splicing is a major regulatory checkpoint during infection. The studies proposed here are intended to fill a critical void in our understanding of post-transcriptional control of the innate immune gene expression program and will shed light on how important human health pathogens like Mtb can manipulate host RNA processing in order to create a favorable niche. The information generated in these studies will contribute to the development of targeted vaccines and host-directed therapeutics aimed at modulating pre-mRNA splicing to enhance anti-bacterial and/or short circuit pro-bacterial gene expression programs.