response to phenotypic switch variants to C. neoformans

描述（由申请人提供）：越来越多的证据表明，微生物微进化在慢性丙型肝炎中起着关键作用。neoformans感染作为一种机制，这使得C.新生儿逃避宿主反应，并在慢性感染期间持续存在。我们最近证明了C。在慢性感染过程中，新生儿可以从光滑（SM）菌落转变为粘液样（MC）菌落变体，并表明这种转变与致死结果相关。同时，我们发现新产生的MC开关变体产生粘性荚膜多糖，这导致巨噬细胞吞噬功能障碍。MC感染小鼠的肺中的炎症反应的特征在于强烈的巨噬细胞浸润和肺破坏，而SM感染小鼠的肺表现出有效的淋巴细胞主导的炎症反应。开关变体之间差异表达基因的分析表明，免疫原性表位在MC开关变体中下调。与这些发现一致，我们发现缺乏有效的T细胞反应和证据不足的吞噬作用和过度刺激肺泡巨噬细胞。在这里，我们将研究表型转换对炎症免疫反应和生存的影响。我们提出了三个具体的目标来测试我们的中心假设：1。探讨表型转换影响肺泡巨噬细胞与C.新人类目标2）确定病原体中免疫原性表位的下调是否影响T细胞应答和目的3。研究宿主巨噬细胞功能和病原体抗原表位表达对C.小鼠中的新形线虫感染。如果我们的假设是正确的，这里提出的工作将具有广泛的意义，从长远来看，因为它将建立洞察慢性隐球菌病的宿主-病原体相互作用的动力学。从长远来看，这将使我们能够开发新的选择性肺保护疗法。

DESCRIPTION (provided by applicant): Increasing evidence points to a critical role of microbial microevolution during chronic C. neoformans infection as a mechanism, which allows C. neoformans to escape host response and persist during chronic infection. We recently demonstrated that C. neoformans can switch from a smooth (SM) to a mucoid (MC) colony variant during chronic infection and showed that this switch is associated with lethal outcome. Simultaneously we showed that the newly generated MC switch variant produces a viscous capsular polysaccharide, which leads to dysfunctional phagocytosis by macrophages. The inflammatory response in the lung of MC infected mice is characterized by intense macrophage infiltration and lung destruction, whereas lungs of SM infected mice exhibit an effective lymphocyte dominated inflammatory response. Analysis of differentially expressed genes between the switch variants demonstrated that an immunogenic epitope is downregulated in the MC switch variant. Consistent with these findings we find a lack of effective T-cell response and evidence for inadequate phagocytosis and overstimulation of alveolar macrophages. Here we will examine the effects of phenotypic switching on the inflammatory immune response and survival. We propose three specific Aims to test our central hypothesis: 1.) To explore mechanisms by which phenotypic switching affects interactions of alveolar macrophages with C. neoformans. Aim 2.) To determine if down regulation of an immunogenic epitope in the pathogen affects T-cell response and Aim 3.) To examine the effects of macrophage function in the host and epitope expression in the pathogen on outcome of C. neoformans infection in mice. If our hypothesis is correct, the work proposed here will have broad significance in the long-term, because it will establish insight into the dynamics of host-pathogen interaction in chronic cryptococcosis. This should in the long-term enable us to develop novel, selective lung-protective therapies.