Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
mBio. 2013 Jan 15;4(1):e00522-12. doi: 10.1128/mBio.00522-12.
Infectious microorganisms often play a role in modulating the immune responses of their infected hosts. We demonstrate that Cryptococcus neoformans signals through the Rim101 transcription factor to regulate cell wall composition and the host-pathogen interface. In the absence of Rim101, C. neoformans exhibits an altered cell surface in response to host signals, generating an excessive and ineffective immune response that results in accelerated host death. This host immune response to the rim101Δ mutant strain is characterized by increased neutrophil influx into the infected lungs and an altered pattern of host cytokine expression compared to the response to wild-type cryptococcal infection. To identify genes associated with the observed phenotypes, we performed whole-genome RNA sequencing experiments under capsule-inducing conditions. We defined the downstream regulon of the Rim101 transcription factor and determined potential cell wall processes involved in the capsule attachment defects and altered mechanisms of virulence in the rim101Δ mutant. The cell wall generates structural stability for the cell and allows the attachment of surface molecules such as capsule polysaccharides. In turn, the capsule provides an effective mask for the immunogenic cell wall, shielding it from recognition by the host immune system.
Cryptococcus neoformans is an opportunistic human pathogen that is a significant cause of death in immunocompromised individuals. There are two major causes of death due to this pathogen: meningitis due to uncontrolled fungal proliferation in the brain in the face of a weakened immune system and immune reconstitution inflammatory syndrome characterized by an overactive immune response to subclinical levels of the pathogen. In this study, we examined how C. neoformans uses the conserved Rim101 transcription factor to specifically remodel the host-pathogen interface, thus regulating the host immune response. These studies explored the complex ways in which successful microbial pathogens induce phenotypes that ensure their own survival while simultaneously controlling the nature and degree of the associated host response.
感染性微生物通常在调节其感染宿主的免疫反应方面发挥作用。我们证明，新生隐球菌通过 Rim101 转录因子发出信号，以调节细胞壁组成和宿主-病原体界面。在没有 Rim101 的情况下，新生隐球菌对宿主信号的反应会改变其细胞表面，产生过度且无效的免疫反应，导致宿主死亡加速。与野生型新生隐球菌感染相比，宿主对 rim101Δ 突变菌株的这种免疫反应的特征是感染肺部的中性粒细胞 influx 增加，以及宿主细胞因子表达模式的改变。为了鉴定与观察到的表型相关的基因，我们在诱导荚膜形成的条件下进行了全基因组 RNA 测序实验。我们定义了 Rim101 转录因子的下游调控子，并确定了参与荚膜附着缺陷和 rim101Δ 突变体中改变的毒力机制的潜在细胞壁过程。细胞壁为细胞提供结构稳定性，并允许表面分子（如荚膜多糖）附着。反过来，荚膜为免疫原性细胞壁提供了有效的屏蔽，使其免受宿主免疫系统的识别。
新生隐球菌是一种机会性人类病原体，是免疫功能低下个体死亡的主要原因之一。由该病原体引起的死亡有两个主要原因：由于免疫系统减弱，真菌在大脑中不受控制地增殖导致的脑膜炎，以及以亚临床水平的病原体引起的过度活跃的免疫反应为特征的免疫重建炎症综合征。在这项研究中，我们研究了新生隐球菌如何使用保守的 Rim101 转录因子专门重塑宿主-病原体界面，从而调节宿主免疫反应。这些研究探讨了成功的微生物病原体诱导表型的复杂方式，这些表型确保了它们自身的生存，同时控制了相关宿主反应的性质和程度。
