Immune modulation during infection by a secreted fungal polysaccharide

全身性真菌感染是一个主要的公共卫生问题，每年造成130多万人死亡 全球范围内，花费数十亿美元的医疗保健系统。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的理解不足， 新型隐球菌是真菌性脑膜炎的主要原因，每年造成 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 患者感染开始在肺部，但在严重的情况下，蔓延到大脑，造成难以治疗的 脑膜炎感染C.新生儿产生一个大的细胞表面胶囊，主要组成部分， 其为多糖葡糖醛酸甘露聚糖（GXM）。GXM是感染所必需的，促进C. 新生儿逃避免疫细胞吞噬和破坏的能力，并抑制免疫反应。 除了细胞表面GXM之外，长期以来一直认为游离分泌的GXM（exo-GXM）在细胞凋亡中起作用。 感染感染期间和感染后，游离GXM在血清和脑脊液中循环。然而，其精确 作用和生物起源尚不清楚。我们已经确定了这一分泌途径的第一个突变体， 确定分泌的GXM如何促进C.新人类 我们发现GXM在C.新生细胞从 这些组织的肺，这表明exo-GXM促进传播。首先，我们将不同的 传播步骤，并确定exo-GXM如何对每个步骤做出贡献。第二，我们将确定如何外- GXM抑制感染过程中的免疫反应，通过验证两个假设：1）exo-GXM阻断免疫细胞 浸润到组织中和2）exo-GXM阻止循环白细胞的成熟或分化。最后， 我们将确定exo-GXM产生和调节的分子机制。这些实验将 将exo-GXM功能与细胞表面GXM功能分开，确定exo-GXM如何调节细胞表面GXM功能， 哺乳动物免疫系统在感染过程中，并帮助确定是否exo-GXM可以发展为一个 免疫抑制药物。

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.