Antibody differentially alters Histoplasma extracellular vesicles

抗体差异改变组织胞浆菌细胞外囊泡

基本信息

批准号：
9136369
负责人：
JOSHUA D NOSANCHUK
金额：
$ 29.47万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-15 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9136369
关键词：
Acquired Immunodeficiency Syndrome Affect Anti-Retroviral Agents Antibodies Antifungal Agents Area Behavior Binding Biological Markers Biology Brazil Cause of Death Cell Wall Cell surface Cells Cellular Metabolic Process Cessation of life Chaperonin 60 Country Cryptococcus neoformans Disease Effector Cell Electron Microscopy Foundations French Guiana Gene Expression Glucans Goals Guatemala HIV Health Histoplasma Histoplasma capsulatum Histoplasmosis Human Image Immune response Incidence Individual Investigation Laboratories Latin American Life Lipid Bilayers Lipids Macrophage Activation Mass Spectrum Analysis Measurement Mediating Melanins Metabolism Methodology Monoclonal Antibodies Morbidity - disease rate Mycoses Opportunistic Infections Outcome Pathogenesis Patients Phagocytosis Phagosomes Pneumonia Poison Polysaccharides Process Production Proteins Proteome Recording of previous events Regimen Research Serum Staging Surface Testing Therapeutic Monoclonal Antibodies Translating Vaccines Vesicle Virulence Virulence Factors Work Yeasts base capsule combat crosslink dimorphism extracellular vesicles falls fungus immunogenic insight light scattering mortality novel novel therapeutic intervention pathogen protective effect public health relevance response vesicular release zeta potential

项目摘要

DESCRIPTION (provided by applicant): The ability of the HIV-associated fungal pathogen Histoplasma capsulatum (Hc) to cause severe invasive disease is attributed to the fungus' ability to efficiently subvert host responses. For example, the capacity of the fungus to impair phagosome maturation and the presence of melanin in the fungal cell wall contribute to intracellular survival through avoidance of host surveillance as well as blocking the effects of host effector responses. We have shown that Hc produces extracellular vesicles containing biologically active molecules. However, many questions on disease pathogenesis arise from this process of vesiculogenesis. In the first Aim, we will explore how protective and non-protective antibodies (Abs) regulate the production and release of extracellular vesicles from Hc. We are pursuing this work based on our findings that protective Abs to Hc alter gene expression and that cross-linking by Abs changes the outcome of interactions with host effector cells. Using a pair of protective and non-protective monoclonal antibodies (mAbs) that bind to the same region on heat shock protein 60 expressed on the Hc cell surface, we will determine (Aim 1) the mAbs' capacity to alter the formation and secretion of these bilayered vesicles as well as (Aim 2) their impact on the protein and lipid cargo within the vesicles. We are pursuing this work based on our observations that the vesicles can alter the behavior of host cells and that the cargo within the vesicles includes compounds that are immunomodulatory. The results of the studies in this R21 will provide new insights into the basic biology of Hc, elucidate new activities of Abs, and serve as a potential foundation for new therapeutic approaches to combat this important fungus as well as other eukaryotic pathogens.

描述（由适用提供）：与HIV相关的真菌病原体组织囊肿（HC）引起严重侵入性疾病的能力归因于真菌有效颠覆宿主反应的能力。例如，真菌损害吞噬体成熟的能力和真菌细胞壁中黑色素的存在通过避免宿主监测以及阻止宿主效应子反应的影响，从而有助于细胞内存活。我们已经表明，HC产生含有生物活性分子的细胞外蔬菜。然而，许多有关疾病发病机理的问题来自这种囊泡的过程。在第一个目标中，我们将探讨如何受保护和非保护抗体（ABS）调节HC细胞外蔬菜的产生和释放。我们正在基于保护ABS对HC的发现改变基因表达的发现，而ABS的交联改变了与宿主效应细胞的相互作用的结果。使用在HC细胞表面表达的热休克蛋白60上与同一区域结合的一对受保护和非保护的单克隆抗体（MAB），我们将确定（AIM 1）MABS的能力，改变了这些双层蔬菜的形成和分泌的能力，以及（AIM 2）它们对蛋白质和脂肪量的影响。我们是根据我们的观察结果来追求这项工作的，即蔬菜可以改变宿主细胞的行为，并且蔬菜中的货物包括免疫调节的化合物。在本R21中的研究结果将为HC的基本生物学，阐明ABS的新活动提供新的见解，并为应对这种重要的真菌以及其他真核生物病原体的新治疗方法的潜在基础。