Immune modulation during infection by a secreted fungal polysaccharide

分泌的真菌多糖在感染过程中的免疫调节

• 批准号: 10180886
• 负责人: JESSICA Conrad BROWN
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-24 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10180886
• 关键词: AIDS/HIV problem; Alveolar Macrophages; Attenuated; Biogenesis; Blood; Brain; Cell physiology; Cell surface; Cells; Central Nervous System Infections; Cerebrospinal Fluid; Cessation of life; Clinical; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Data; Disease; Distal; Drug Targeting; Environment; Fungal Meningitis; Fungal Spores; Future; Generations; Genetic; Growth; Health Care Costs; Healthcare Systems; Immune; Immune mediated destruction; Immune response; Immune system; Immunocompromised Host; Immunosuppressive Agents; Infection; Infiltration; Leukocytes; Lung; Meningitis; Modeling; Molecular; Mus; Mycoses; Organ; Pathogenesis; Pathway interactions; Patients; Phagocytosis; Pharmaceutical Preparations; Play; Polymers; Polysaccharides; Process; Production; Property; Public Health; Regulation; Role; Serum; Site; Starvation; Surface; Testing; Therapeutic immunosuppression; Tissues; Treatment Side Effects; Virulence; Virulence Factors; Work; alveolar destruction; capsule; experimental study; fungus; glucuronoxylomannan; immunoregulation; monocyte; mutant; pathogen; pathogenic fungus; prevent; response; tool

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.

系统性真菌感染是一个主要的公共卫生问题，每年造成超过130万人死亡 全球和损失医疗系统数十亿美元。这些感染很难且昂贵 由于数量有限的药物和对传染性机制的理解不佳而治疗。 隐孢子虫新生虫是真菌性脑膜炎的主要原因，每年负责 全球大约有100万感染和60万人死亡。这些情况大多数是在艾滋病毒/艾滋病中 患者。感染始于肺部，但在严重的情况下传播到大脑，导致难以治疗 脑膜炎感染。 C. Neoformans产生一个大细胞表面囊，这是 这是多糖葡萄糖醛酸氧基瘤（GXM）。 GXM对于感染是必需的，促进C。 Neoformans逃避免疫细胞的吞噬作用和破坏的能力，并抑制免疫反应。 除了细胞表面GXM外，长期以来一直认为免费分泌的GXM（EXO-GXM）在 感染。自由GXM在感染期间和之后在血清和脑脊液中循环。但是，它的精确度 角色和生物发生尚不清楚。我们已经确定了该分泌途径中的第一个突变体，并将 确定分泌的GXM如何促进新梭菌的感染和传播。 我们发现，GXM在新构梭菌细胞从C. Neoformans细胞中扩散在受感染小鼠的组织中 这些组织的肺部，表明EXO-GXM有助于传播。首先，我们将分开不同 传播步骤，并确定EXO-GXM如何贡献每个。其次，我们将确定如何进行 GXM通过测试两个假设抑制感染过程中的免疫反应：1）EXO-GXM阻断免疫细胞 浸润到组织中，2）EXO-GXM防止循环白细胞的成熟或分化。最后， 我们将确定Exo-GXM生成和调控的分子机制。这些实验会 与细胞表面GXM函数单独的​​EXO-GXM函数，确定exo-gxm如何调节 感染期间哺乳动物免疫系统，并有助于确定是否可以开发出Exo-GXM 免疫抑制药物。