The pathogenesis of experimental Emergomycosis in mice

Emergomyces africanus is a recently identified thermally-dimorphic fungal pathogen that causes disseminated infection in people living with advanced HIV disease. Known as emergomycosis, this disseminated disease is associated with very high case fatality rates. Over the last decade, improved diagnostics and fungal identification in South Africa resulted in a dramatic increase in the number of reported cases. Although the true burden of disease is still unknown, emergomycosis is among the most frequently diagnosed dimorphic fungal infections in Southern Africa; and additional species in the genus have been identified on four continents. Little is known about the pathogenesis and the host’s immune response to this emerging pathogen. Therefore, we established a murine model of pulmonary infection using a clinical isolate, E. africanus (CBS 136260). Both conidia and yeast forms caused pulmonary and disseminated infection in mice with organisms isolated in culture from lung, spleen, liver, and kidney. Wild-type C57BL/6 mice demonstrated a drop in body weight at two weeks post-infection, corresponding to a peak in fungal burden in the lung, spleen, liver, and kidney. An increase in pro-inflammatory cytokine production was detected in homogenized lung supernatants including IFN-γ, IL-1β, IL-6, IL12-p40 and IL-17 at three- and four-weeks post-infection. No significant differences in TNF, IL-12p70 and IL-10 were observed in wild-type mice between one and four-weeks post-infection. Rag-1-deficient mice, lacking mature T-and B-cells, had an increased fungal burden associated with reduced IFN-γ production. Together our data support a protective T-helper type-1 immune response to E. africanus infection. This may provide a possible explanation for the susceptibility of only a subset of people living with advanced HIV disease despite hypothesized widespread environmental exposure. In summary, we have established a novel murine model of E. africanus disease providing critical insights into the host immune components required for eliminating the infection.

Emergomyces africanus（非洲热变真菌病原体）是一种近期被发现的温变型真菌病原体，其感染导致生活在晚期HIV疾病患者中的个体出现播散性感染。被称为emergomycosis的这种播散性疾病与极高的病例死亡率相关。在过去十年中，南非在诊断技术和真菌鉴定方面的改进导致报告病例数急剧增加。尽管疾病的真实负担尚不清楚，但emergomycosis已成为南非最常诊断的温变型真菌感染之一；在四大洲已鉴定出该属的更多物种。关于该新兴病原体的发病机制以及宿主对该病原体的免疫反应知之甚少。因此，我们利用临床分离株E. africanus（CBS 136260）建立了小鼠肺感染模型。无论是分生孢子还是酵母型，均在小鼠体内引起肺和播散性感染，并在肺、脾、肝和肾脏中从培养物中分离出该病原体。野生型C57BL/6小鼠在感染后两周体重下降，这与肺、脾、肝和肾脏中真菌负荷达到峰值相对应。在感染后三周和四周，肺匀浆上清液中检测到促炎细胞因子产生增加，包括IFN-γ、IL-1β、IL-6、IL12-p40和IL-17。在感染后一周至四周，野生型小鼠中TNF、IL-12p70和IL-10无明显差异。Rag-1缺陷型小鼠，缺乏成熟的T和B细胞，其真菌负荷增加，同时IFN-γ产生减少。我们的数据支持了对E. africanus感染的保护性T辅助1型免疫反应。这或许可以解释为何尽管假设广泛的环境暴露，只有生活在晚期HIV疾病患者中的一小部分人群容易感染。总之，我们建立了E. africanus疾病的新型小鼠模型，为消除感染所需的宿主免疫成分提供了关键的见解。