Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
mSphere. 2020 Aug 26;5(4):e00742-20. doi: 10.1128/mSphere.00742-20.
is an endemic dimorphic fungus that can cause disease in healthy and immunocompromised individuals after the transition of inhaled spores into the facultative intracellular yeast form. There is substantial diversity among species, but it is not clear how this heterogeneity impacts the progression of pathology and cellular immune responses during acute respiratory infection, which represents the vast majority of histoplasmosis disease burden. After inoculating mice intranasally with a sublethal inoculum, we characterized the immune response to (strain G186A) and (strain G217B) using comprehensive flow cytometric and single-cell analyses. Within 8 days after inoculation, induced a significantly higher infiltration of neutrophils and inflammatory monocytes into the lung compared to Microscopic analysis of infected lung tissue revealed that although the total number of fungi was similar within inflamed lung lesions, we observed different species-dependent intracellular yeast distribution patterns. Inoculation with -expressing strains indicated that , but not , was associated primarily with alveolar macrophages early after infection. Interestingly, we observed a significant reduction in the total number of alveolar macrophages 12 to 16 days after but not infection, despite similar intracellular growth dynamics within AMJ2-C11 alveolar macrophages Together, our data suggest that , but not , preferentially interacts with alveolar macrophages early after infection, which may lead to a different course of inflammation and resolution despite similar rates of fungal clearance. Acute pulmonary histoplasmosis in healthy individuals comprises most of the disease burden caused by the fungal pathogen Fungal pneumonia is frequently delayed in diagnosis and treatment due to a prolonged period of quiescence early during infection. In this study, we used a murine respiratory model of histoplasmosis to investigate how different species modulate lung inflammation throughout the complete course of infection. We propose that a relatively low, sublethal inoculum is ideal to model acute pulmonary histoplasmosis in humans, primarily due to the quiescent stage of fungal growth that occurs in the lungs of mice prior to the initiation of inflammation. Our results reveal the unique course of lung immunity associated with divergent species of and imply that the progression of clinical disease is considerably more heterogeneous than previously recognized.
组织胞浆菌是一种地方性二态真菌，在吸入的孢子转变为兼性细胞内酵母形式后，可在健康和免疫功能低下的个体中引起疾病。种间存在着很大的多样性，但尚不清楚这种异质性如何影响急性呼吸道感染期间的病理学和细胞免疫反应的进展，而急性呼吸道感染代表了大多数组织胞浆菌病的负担。在用亚致死剂量接种鼻腔内的小鼠后，我们使用全面的流式细胞术和单细胞分析来描述对（菌株 G186A）和（菌株 G217B）的免疫反应。接种后 8 天内，与相比，诱导了更多的中性粒细胞和炎症性单核细胞浸润肺部。感染肺部组织的显微镜分析表明，尽管在炎症性肺损伤内的真菌总数相似，但我们观察到不同的种依赖性细胞内酵母分布模式。用表达菌株接种表明，主要与感染后早期的肺泡巨噬细胞有关，但不是。有趣的是，我们观察到感染后 12 至 16 天内，尽管 AMJ2-C11 肺泡巨噬细胞内的细胞内生长动态相似，但总肺泡巨噬细胞数量显著减少，但不是感染后。总的来说，我们的数据表明，主要与感染后早期的肺泡巨噬细胞相互作用，但不是，这可能导致尽管真菌清除率相似，但炎症和消退的过程不同。健康个体中的急性肺部组织胞浆菌病构成了真菌病原体引起的疾病负担的大部分。由于感染早期真菌生长的潜伏期较长，真菌性肺炎的诊断和治疗常常被延迟。在这项研究中，我们使用了组织胞浆菌的小鼠呼吸模型来研究不同的种如何在整个感染过程中调节肺部炎症。我们提出，相对较低的亚致死接种量是模拟人类急性肺部组织胞浆菌病的理想选择，主要是由于在炎症开始之前，肺部中的真菌生长处于静止阶段。我们的结果揭示了与不同种组织胞浆菌相关的独特的肺部免疫过程，并暗示临床疾病的进展比以前认识到的更为复杂。
