空气中孢子体的吸入是普遍存在的真菌Aspergillus fumigatus的常见现象，但仅在免疫功能极度受损的患者中才会出现侵袭性曲霉病。给予严重流感病人的器官浸润性曲霉病提供条件的机制尚未明确定义。通过使用后续感染曲霉的流感模型，我们发现，在流感A病毒感染的早期阶段（第2天和第5天）挑战A. fumigatus孢子时，受到超感染的小鼠的死亡率达到100％，而在后期阶段（第8天和第14天）挑战时，生存率达到100％。感染流感的小鼠超感染A. fumigatus后，新发炎性细胞因子和趋化因子间白质（IL-6），肿瘤坏死因子（TNF）α，干扰素（IFN）β，IL-12p70，IL-1α，IL-1β，CXC基序趋化因子配体1（CXCL1），粒细胞-集落刺激因子（G-CSF），巨噬细胞炎性蛋白（MIP）-1α，MIP-1β，活化调节，正常的T细胞表达和疑似分泌（RANTES），以及单核细胞趋化蛋白（MCP）-1的水平增加。令人惊讶的是，在组织病理学分析中，超感染的小鼠肺部炎症程度与仅感染流感的小鼠相比没有显著增加。流感感染后，小鼠的肺部对A. fumigatus的后续挑战引起的中性粒细胞招募减少，但仅适用于在流感感染的早期阶段执行真菌挑战。然而，流感感染对中性粒细胞吞噬和杀死A. fumigatus孢子没有重大影响。此外，即使在超感染的小鼠中，病理观察中也很少见到孢子的萌发。综上所述，我们的数据表明，在流感相关的肺曲霉病的早期阶段，小鼠死亡率较高的原因是多方面的，其中受控制的炎症比微生物生长对其死亡起更大的贡献作用。重要性严重流感是致命的侵袭性肺曲霉病的风险因素；然而，致死性的机制尚不清楚。利用流感相关的肺曲霉病（IAPA）模型，我们发现，感染流感A病毒然后随之感染Aspergillus fumigatus的小鼠在流感的早期阶段超感染时有100％的死亡率，但在后期阶段幸存下来。与对照组相比，超感染小鼠肺部的炎症反应存在异常，但它们既没有增加的炎症反应，也没有广泛的真菌生长。尽管感染流感的小鼠在随后挑战A. fumigatus后肺部中性粒细胞的招募减少，但流感不影响中性粒细胞清除真菌的能力。我们的数据表明，我们的IAPA模型中观察到的致死性是多方面的，其中失调的炎症是一个比难以控制的微生物生长更大的贡献因素。如果在人体中得到证实，我们的研究结果为临床研究提供了合适的理由，以评估抗炎辅助药物在IAPA治疗中的作用。

Inhalation of airborne conidia of the ubiquitous fungus Aspergillus fumigatus commonly occurs but invasive aspergillosis is rare except in profoundly immunocompromised persons. Severe influenza predisposes patients to invasive pulmonary aspergillosis by mechanisms that are poorly defined. Using a post-influenza aspergillosis model, we found that superinfected mice had 100% mortality when challenged with A. fumigatus conidia on days 2 and 5 (early stages) of influenza A virus infection but 100% survival when challenged on days 8 and 14 (late stages). Influenza-infected mice superinfected with A. fumigatus had increased levels of the pro-inflammatory cytokines and chemokines interleukin (IL)-6, tumor necrosis factor (TNF)α, interferon (IFN)β, IL-12p70, IL-1α, IL-1β, CXC motif chemokine ligand 1 (CXCL1), granulocyte-colony-stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated upon activation, normal T cell expressed and presumably secreted (RANTES), and monocyte chemoattractant protein (MCP)-1. Surprisingly, on histopathological analysis, superinfected mice did not have greater lung inflammation compared with mice infected with influenza alone. Mice infected with influenza had dampened neutrophil recruitment to the lungs following subsequent challenge with A. fumigatus, but only if the fungal challenge was executed during the early stages of influenza infection. However, influenza infection did not have a major effect on neutrophil phagocytosis and killing of A. fumigatus conidia. Moreover, minimal germination of conidia was seen on histopathology even in the superinfected mice. Taken together, our data suggest that the high mortality rate seen in mice during the early stages of influenza-associated pulmonary aspergillosis is multifactorial with a greater contribution from dysregulated inflammation than microbial growth. IMPORTANCE Severe influenza is a risk factor for fatal invasive pulmonary aspergillosis; however, the mechanistic basis for the lethality is unclear. Utilizing an influenza-associated pulmonary aspergillosis (IAPA) model, we found that mice infected with influenza A virus followed by Aspergillus fumigatus had 100% mortality when superinfected during the early stages of influenza but survived at later stages. While superinfected mice had dysregulated pulmonary inflammatory responses compared to controls, they had neither increased inflammation nor extensive fungal growth. Although influenza-infected mice had dampened neutrophil recruitment to the lungs following subsequent challenge with A. fumigatus, influenza did not affect the ability of neutrophils to clear the fungi. Our data suggest that the lethality seen in our model of IAPA is multifactorial with dysregulated inflammation being a greater contributor than uncontrollable microbial growth. If confirmed in humans, our findings provide a rationale for clinical studies of adjuvant anti-inflammatory agents in the treatment of IAPA.