Aspergillus Utilizes Extracellular Heme as an Iron Source During Invasive Pneumonia, Driving Infection Severity.
Aspergillus Utilizes Extracellular Heme as an Iron Source During Invasive Pneumonia, Driving Infection Severity.
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曲霉菌在侵袭性肺炎期间利用细胞外血红素作为铁源，导致感染严重程度。
DOI：
10.1093/infdis/jiac079
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Mehrad,Borna
中科院分区：
文献类型：
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作者：
Michels,Kathryn;Solomon,AngelicaL;Scindia,Yogesh;SordoVieira,Luis;Goddard,Yana;Whitten,Spencer;Vaulont,Sophie;Burdick,MarieD;Atkinson,Carl;Laubenbacher,Reinhard;Mehrad,Borna
背景去除微生物中的铁对宿主防御至关重要。血红素蛋白是脊椎动物体内最大的铁源，在出血引起的曲霉病的感染组织中含量丰富，但曲霉属物种一直被认为缺乏血红素输入机制。我们假设在侵袭性肺炎期间，血红素为曲霉菌提供了铁，从而加重了感染的结局。方法我们在不同的体外条件下和在中性粒细胞减少的侵袭性肺曲霉菌病小鼠模型中评估了血红素对真菌表型的影响。在低铁条件下培养的真菌细胞吸收血红素，导致真菌铁含量增加，解决了铁饥饿问题，增加了分生孢子，并增强了对氧化应激的抵抗力。对于中性粒细胞减少的侵袭性曲霉病小鼠，肺内注射血红素可显著增加肺部真菌负荷、肺损伤和死亡率，而给予血红素类似物或含灭活曲霉的血红素则不会。结论侵袭性曲霉病可引起感染组织的局部溶血，从而为真菌提供血红素铁，导致致死性感染。
BackgroundDepriving microbes of iron is critical to host defense. Hemeproteins, the largest source of iron within vertebrates, are abundant in infected tissues in aspergillosis due to hemorrhage, butAspergillusspecies have been thought to lack heme import mechanisms. We hypothesized that heme provides iron toAspergillusduring invasive pneumonia, thereby worsening the outcomes of the infection.MethodsWe assessed the effect of heme on fungal phenotype in various in vitro conditions and in a neutropenic mouse model of invasive pulmonary aspergillosis.ResultsIn mice with neutropenic invasive aspergillosis, we found a progressive and compartmentalized increase in lung heme iron. Fungal cells cultured under low iron conditions took up heme, resulting in increased fungal iron content, resolution of iron starvation, increased conidiation, and enhanced resistance to oxidative stress. Intrapulmonary administration of heme to mice with neutropenic invasive aspergillosis resulted in markedly increased lung fungal burden, lung injury, and mortality, whereas administration of heme analogs or heme with killedAspergillusdid not. Finally, infection caused by fungal germlings cultured in the presence of heme resulted in a more severe infection.ConclusionsInvasive aspergillosis induces local hemolysis in infected tissues, thereby supplying heme iron to the fungus, leading to lethal infection.