Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands.
Laboratory of Genetics, Wageningen University, Wageningen, Netherlands.
Lancet Infect Dis. 2016 Nov;16(11):e251-e260. doi: 10.1016/S1473-3099(16)30138-4. Epub 2016 Sep 13.
Aspergillus fumigatus causes a range of diseases in human beings, some of which are characterised by fungal persistence. A fumigatus can persist by adapting to the human lung environment through physiological and genomic changes. The physiological changes are based on the large biochemical versatility of the fungus, and the genomic changes are based on the capacity of the fungus to generate genetic diversity by spontaneous mutations or recombination and subsequent selection of the genotypes that are most adapted to the new environment. In this Review, we explore the adaptation strategies of A fumigatus in relation to azole resistance selection and the clinical implications thereof for management of diseases caused by Aspergillus spp. We hypothesise that the current diagnostic tools and treatment strategies do not take into account the biology of the fungus and might result in an increased likelihood of fungal persistence in patients. Stress factors, such as triazole exposure, cause mutations that render resistance. The process of reproduction-ie, sexual, parasexual, or asexual-is probably crucial for the adaptive potential of Aspergillus spp. As any change in the environment can provoke adaptation, switching between triazoles in patients with chronic pulmonary aspergillosis might result in a high-level pan-triazole-resistant phenotype through the accumulation of resistance mutations. Alternatively, when triazole therapy is stopped, an azole-free environment is created that could prompt selection for compensatory mutations that overcome any fitness costs that are expected to accompany resistance development. As a consequence, starting, switching, and stopping azole therapy has the risk of selecting for highly resistant strains with wildtype fitness. A similar adaptation is expected to occur in response to other stress factors, such as endogenous antimicrobial peptides; over time the fungus will become increasingly adapted to the lung environment, thereby limiting the probability of eradication. Our hypothesis challenges current management strategies, and future research should investigate the genomic dynamics during infection to understand the key factors facilitating adaptation of Aspergillus spp.
烟曲霉可引起人类一系列疾病，其中一些疾病的特征是真菌持续存在。烟曲霉可通过生理和基因组变化来适应人类肺部环境从而持续存在。生理变化基于真菌巨大的生化多样性，基因组变化基于真菌通过自发突变或重组产生遗传多样性的能力，以及随后选择最适应新环境的基因型。在这篇综述中，我们探讨了烟曲霉的适应策略与唑类耐药性选择的关系及其对曲霉属相关疾病管理的临床意义。我们假设当前的诊断工具和治疗策略没有考虑真菌生物学，可能会增加患者真菌持续存在的可能性。应激因素（如唑类药物暴露）会导致产生耐药性的突变。繁殖过程（即有性、准性或无性繁殖）可能对曲霉属的适应潜能至关重要。由于环境的任何变化都可能引发适应性改变，慢性肺部曲霉病患者在转换唑类药物时，可能会因耐药突变的积累而导致高水平的泛唑类耐药表型。或者，当停止唑类药物治疗时，会形成一个无唑类药物的环境，从而促使选择可能克服耐药发展所预期带来的任何适应性代价的补偿性突变。因此，开始、转换和停止唑类药物治疗都有可能选择出具有野生型适应性的高度耐药菌株。预计这种适应性也会出现在对其他应激因素的反应中，如内源性抗菌肽；随着时间的推移，真菌将越来越适应肺部环境，从而降低根除的可能性。我们的假设挑战了当前的管理策略，未来的研究应该调查感染过程中的基因组动态，以了解促进曲霉属适应的关键因素。
