Dysregulated Pulmonary Inflammatory Responses Exacerbate the Outcome of Secondary Aspergillosis Following Influenza.
Dysregulated Pulmonary Inflammatory Responses Exacerbate the Outcome of Secondary Aspergillosis Following Influenza.
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肺部炎症反应失调会加剧流感后继发曲霉病的结果。
DOI：
10.1101/2023.06.27.546808
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Levitz,StuartM
中科院分区：
文献类型：
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作者：
Lee,ChronoK;Oliveira,LorenaVN;Akalin,Ali;Specht,CharlesA;Lourenco,Diana;Gomez,ChristinaL;Ramirez-Ortiz,ZaidaG;Wang,JenniferP;Levitz,StuartM
吸入无处不在的真菌烟曲霉的空气分生孢子通常发生，但侵袭性曲霉病是罕见的，除非在严重免疫功能低下的人。严重流感使患者易患侵袭性肺曲霉病，发病机制尚不明确。使用流感后曲霉病模型，我们发现当a攻击时，超感染小鼠的死亡率为100%。在甲型流感病毒感染的第2天和第5天（早期阶段），烟曲霉孢子虫存活，但在第8天和第14天（晚期阶段）挑战时，存活率为100%。感染流感的老鼠被a病毒感染。烟熏菌增加了促炎细胞因子和趋化因子白介素(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）、巨噬细胞炎症蛋白(MIP)-1α、MIP-1β、活化调节的正常T细胞表达和推测分泌（RANTES）和单核细胞趋化蛋白(MCP)-1的水平。令人惊讶的是，在组织病理学分析中，与单独感染流感的小鼠相比，重复感染的小鼠没有更大的肺部炎症。感染流感的小鼠在随后的a攻击后，抑制了中性粒细胞向肺部的募集。但前提是在流感感染的早期阶段进行真菌攻击。然而，流感感染对中性粒细胞吞噬和a的杀死没有主要影响。fumigatusconidia。此外，在组织病理学上，即使在重复感染的小鼠中，也可以看到极小的分生孢子萌发。综上所述，我们的数据表明，在流感相关肺曲霉病的早期阶段，小鼠的高死亡率是多因素的，炎症失调比微生物生长的贡献更大。重要性：严重流感是致死性侵袭性肺曲霉病的危险因素；然而，其致死性的机制基础尚不清楚。利用流感相关肺曲霉病（IAPA）模型，我们发现感染甲型流感病毒和烟曲霉感染的小鼠在流感早期重复感染时死亡率为100%，但在后期存活。虽然与对照组相比，过度感染小鼠的肺部炎症反应失调，但它们既没有增加炎症，也没有广泛的真菌生长。尽管流感感染的小鼠在随后的a攻击后抑制了中性粒细胞向肺部的募集。烟曲霉、流感不影响中性粒细胞清除真菌的能力。我们的数据表明，在我们的IAPA模型中看到的致死率是多因素的，失调的炎症比不可控的微生物生长更重要。如果在人类中得到证实，我们的发现为辅助抗炎药治疗IAPA的临床研究提供了依据。
Inhalation of airborne conidia of the ubiquitous fungusAspergillus fumigatuscommonly 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 withA. fumigatusconidia 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 withA. fumigatushad 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 withA. 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 ofA. fumigatusconidia. 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.IMPORTANCESevere 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 byAspergillus fumigatushad 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 withA. 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.