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新形梭菌感染过程中发挥了关键作用，使新形梭菌能够逃避宿主反应并在慢性感染期间持续存在。我们最近证明，在慢性感染期间，新生C.可以从光滑（SM）转变为黏液（MC）菌落变异，并表明这种转变与致命结果有关。同时，我们发现新生成的MC开关变体产生粘性荚膜多糖，导致巨噬细胞吞噬功能失调。MC感染小鼠肺部的炎症反应以强烈的巨噬细胞浸润和肺破坏为特征，而SM感染小鼠肺部则表现出有效的淋巴细胞主导的炎症反应。对开关变体之间差异表达基因的分析表明，MC开关变体中免疫原性表位下调。与这些发现一致，我们发现缺乏有效的t细胞反应和证据，不充分的吞噬和肺泡巨噬细胞的过度刺激。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。我们提出三个具体目标来检验我们的中心假设：探讨表型转换影响肺泡巨噬细胞与新生巨噬细胞相互作用的机制。目标2。)确定病原体中免疫原性表位的下调是否影响t细胞反应和Aim 3。目的：探讨巨噬细胞在宿主中的功能和病原菌表位表达对小鼠新生梭状菌感染结局的影响。如果我们的假设是正确的，这里提出的工作将具有广泛的长期意义，因为它将建立对慢性隐球菌病宿主-病原体相互作用动力学的认识。从长远来看，这将使我们能够开发出新颖的、选择性的肺保护疗法。

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.