Blair Bailey A, Bragdon Emma, Dhillon Gursimran, Baker Nnamdi, Stasiak Lena, Muthig Mya, Miramon Pedro, Lorenz Michael C, Wheeler Robert T
Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA.
mBio. 2025 May 14;16(5):e0052925. doi: 10.1128/mbio.00529-25. Epub 2025 Apr 2.
is one of the most frequent causes of bloodstream infections, and our first line of defense against these invasive infections is the innate immune system. The early immune response is critical in controlling infection, but has several strategies to evade host immune attack. Phagocytosis of blocks hyphal growth, limiting host damage and virulence, but how limits early recruitment and phagocytosis in vertebrate infection is poorly understood. To study innate immune evasion by intravital imaging, we utilized the transparent larval zebrafish infection model to screen 131 . mutants for altered virulence and phagocyte response. Infections with each of the seven hypovirulent mutants led to altered phagocyte recruitment and/or phagocytosis, falling into four categories. Of particular interest among these is , a predicted β-importin and newly identified virulence factor. The ∆/∆ mutant fails to limit phagocytosis, and its virulence defects are eliminated when phagocyte activity is compromised, suggesting that its role in virulence is limited to immune evasion. These quantitative intravital imaging experiments are the first to document altered -phagocyte interactions for several additional mutants and clearly distinguish recruitment from phagocytic uptake, suggesting that modulates both events. This initial large-scale screen of individual mutants in a vertebrate, coupled with high-resolution imaging of -phagocyte interactions, provides a more nuanced view of how diverse mutations can lead to more effective phagocytosis, a key immune process that blocks germination and drives anti-fungal immunity.
is part of the human microbial community and is a dangerous opportunistic pathogen, able to prevent its elimination by the host immune system. Although avoids immune attack through several strategies, we still understand little about how it regulates when immune phagocytes get recruited to the infection site and when they engulf fungal cells. We tested over 130 selected mutants for their ability to cause lethal infection and found several hypovirulent mutants, which provoked altered innate immune responses, resulting in lower overall inflammation and greater host survival. Of particular interest is , which acts to limit fungal phagocytosis and is predicted to regulate the activity of stress-associated transcription factors. Our high-content screening was enabled by modeling infection in transparent vertebrate zebrafish larva. Our findings help us understand how survives immune attack during commensal and pathogenic growth, and may eventually inform new strategies for controlling disease.
是血流感染最常见的原因之一，而我们抵御这些侵袭性感染的第一道防线是先天免疫系统。早期免疫反应对于控制感染至关重要，但有几种策略来逃避宿主免疫攻击。对的吞噬作用会阻止菌丝生长，限制宿主损伤和毒力，但在脊椎动物感染中如何限制早期募集和吞噬作用却知之甚少。为了通过活体成像研究先天免疫逃避，我们利用透明的斑马鱼幼体感染模型筛选了131个突变体的毒力和吞噬细胞反应变化。七种低毒力突变体中的每一种感染都会导致吞噬细胞募集和/或吞噬作用改变，分为四类。其中特别有趣的是，一种预测的β-输入蛋白和新鉴定的毒力因子。Δ/Δ突变体无法限制吞噬作用，当吞噬细胞活性受损时其毒力缺陷被消除，这表明其在毒力中的作用仅限于免疫逃避。这些定量活体成像实验首次记录了几种其他突变体的-吞噬细胞相互作用改变，并清楚地区分了募集和吞噬摄取，表明调节这两个事件。在脊椎动物中对单个突变体进行的这一初步大规模筛选，加上对-吞噬细胞相互作用的高分辨率成像，为各种突变如何导致更有效的吞噬作用提供了更细致入微的观点，吞噬作用是阻止萌发并驱动抗真菌免疫的关键免疫过程。
是人类微生物群落的一部分，是一种危险的机会性病原体，能够阻止宿主免疫系统将其清除。尽管通过几种策略避免免疫攻击，但我们对其如何调节免疫吞噬细胞何时被募集到感染部位以及何时吞噬真菌细胞仍知之甚少。我们测试了130多个选定的突变体导致致命感染的能力，发现了几种低毒力突变体，它们引发了先天免疫反应改变，导致总体炎症降低和宿主存活率提高。特别有趣的是，它起到限制真菌吞噬作用的作用，并预测调节与应激相关的转录因子的活性。我们的高内涵筛选是通过在透明的脊椎动物斑马鱼幼体中模拟感染实现的。我们的发现有助于我们了解在共生和致病生长过程中如何在免疫攻击中存活，并最终可能为控制疾病的新策略提供信息。
