Immune modulation during infection by a secreted fungal polysaccharide

系统性真菌感染是一个主要的公共卫生问题，每年导致130多万人死亡 在全球范围内，并花费医疗保健系统数十亿美元。这些感染是困难和昂贵的 由于药物数量有限和对感染机制了解不足而导致的治疗。 新生隐球菌是引起真菌性脑膜炎的主要原因，每年 全球约有100万人感染，60万人死亡。这些病例大多数是艾滋病毒/艾滋病。 病人。感染开始于肺部，但在严重的情况下会扩散到大脑，导致难以治疗的 脑膜炎感染。新生革兰氏杆菌产生一个大的细胞表面被膜，这是 即葡糖醛酸木甘露聚糖(GXM)。GXM是感染所必需的，促进C。 新生杆菌能够逃避免疫细胞的吞噬和破坏，并抑制免疫反应。 除了细胞表面的GXM，自由分泌的GXM(exo-GXM)长期以来一直被认为在 感染。在感染期间和感染后，血清和脑脊液中有游离的GXM循环。然而，它的精确度 角色和生物发生还不清楚。我们已经在这个分泌途径中发现了第一个突变体，并将 确定分泌的GXM如何促进新生葡萄球菌的感染和传播。 我们发现GXM在感染小鼠的组织中蓄积，然后新生葡萄球菌细胞从 肺到这些组织，这表明外源GXM有助于扩散。首先，我们将分开不同的 传播步骤，并确定外源GXM对每个步骤的贡献。其次，我们将确定外部环境如何- GXM通过检验两个假设来抑制感染过程中的免疫反应：1)外源性GXM阻断免疫细胞 渗入组织和2)外源性GXM阻止循环中白细胞的成熟或分化。最后， 我们将确定外源GXM的产生和调控的分子机制。这些实验将 将exo-GXM函数从细胞表面GXM函数中分离出来，确定exo-GXM如何调制 哺乳动物在感染过程中的免疫系统，并帮助确定外源GXM是否可以发展为 免疫抑制药。

Systemic fungal infections are a major public health concern, annually causing over 1.3 million deaths worldwide and costing healthcare systems billions of dollars. These infections are difficult and expensive to treat due to a limited number of drugs and poor understanding of infectious mechanisms. Cryptococcus neoformans is the major cause of fungal meningitis, annually responsible for approximately 1 million infections and 600,000 deaths worldwide. The majority of these cases are in HIV/AIDS patients. Infections begin in the lungs but in severe cases spread to the brain, causing a difficult-to-treat meningitis infection. C. neoformans produces a large cell surface capsule, the predominant component of which is the polysaccharide glucuronoxylomannan (GXM). GXM is necessary for infection, facilitates C. neoformans's ability to evade phagocytosis and destruction by immune cells, and inhibits immune responses. In addition to cell surface GXM, free secreted GXM (exo-GXM) has been long thought to play a role in infection. Free GXM circulates in serum and cerebrospinal fluid during and after infection. However, its precise role and biogenesis are not understood. We have identified the first mutants in this secretion pathway and will determine how secreted GXM facilitates infection and dissemination of C. neoformans. We find that GXM accumulates in the tissue of infected mice before C. neoformans cells spread from the lungs to those tissues, suggesting that exo-GXM facilitates dissemination. First, we will separate different steps of dissemination and determine how exo-GXM contributes to each. Second, we will determine how exo- GXM inhibits the immune response during infection by testing two hypotheses: 1) exo-GXM blocks immune cell infiltration into tissue and 2) exo-GXM prevents maturation or differentiation of circulating leukocytes. Finally, we will determine the molecular mechanisms of exo-GXM generation and regulation. These experiments will separate exo-GXM function from cell surface GXM function, determine how exo-GXM modulates the mammalian immune system during infection, and help determine whether exo-GXM could be developed as an immunosuppressive drug.