Loss of Upc2p-Inducible ERG3 Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity.
Loss of Upc2p-Inducible ERG3 Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity.
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DOI：
10.1128/mbio.00225-18
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发表时间：
2018-05-22
期刊：
影响因子：
6.4
通讯作者：
Palmer GE
中科院分区：
文献类型：
--
作者：
Luna-Tapia A;Willems HME;Parker JE;Tournu H;Barker KS;Nishimoto AT;Rogers PD;Kelly SL;Peters BM;Palmer GE
在常见的真菌病原体白色念珠菌中，甾醇Δ5,6-去饱和酶（Erg3p）的失活是导致对唑类抗真菌药物产生耐药性的几种机制之一。然而，在播散性感染小鼠模型中，Erg3p活性的丧失也与胁迫耐受性不足、侵袭性菌丝生长和毒性减弱有关。这也许可以解释为什么在抗唑临床分离株中报告的erg3缺陷菌株相对较少。在这项研究中，我们在粘膜和弥散性感染小鼠模型中检测了Erg3p失活对白色念珠菌致病性和唑敏感性的影响。虽然白色念珠菌erg3Δ/Δ突变体在弥散性模型中不能致死性，但它在阴道感染小鼠模型中引起病理。在两种感染模型中，erg3Δ/Δ突变体对氟康唑治疗的抗性也比野生型强。因此，Erg3p活性的完全丧失导致了唑抗性，但也造成了小生境特异性毒力缺陷。我们偶然发现，在两种小鼠模型中，唑诱导的ERG3转录缺失（而不是完全失活）足以赋予体外氟康唑抗性，而不会影响白色念珠菌的耐受性、菌丝生长或致病性。它也足以在小鼠阴道模型中赋予氟康唑耐药性，但在播散性感染模型中却没有，因此赋予利基特异性的唑耐药性，而不会损害白色念珠菌在任何部位的致病性。总之，这些结果表明，调节Erg3p的表达或活性可以对白色念珠菌的致病性和抗唑性产生特定的影响。在体外对唑类抗真菌药物产生抗性的同时，甾醇Δ5,6-去饱和酶（Erg3p）活性的丧失也被证明可以降低白色念珠菌的致病性。因此，人们推测这种机制在临床环境中可能并不重要。本研究的结果挑战了这一假设，揭示了Erg3p活性、唑耐药性、白色念珠菌致病性和特定感染部位之间更复杂的关系。最重要的是，我们已经证明，即使是适度的ERG3转录变化也足以在不影响白色念珠菌适应性或致病性的情况下赋予唑抗性。鉴于先前评估ERG3作为临床唑耐药性决定因素的重要性的努力几乎完全集中在检测无效突变体上，其作用可能被严重低估。基于我们的结果，在临床环境中对ERG3基因对唑类耐药的贡献进行更彻底的调查是必要的。
Inactivation of sterol Δ5,6-desaturase (Erg3p) in the prevalent fungal pathogen Candida albicans is one of several mechanisms that can confer resistance to the azole antifungal drugs. However, loss of Erg3p activity is also associated with deficiencies in stress tolerance, invasive hyphal growth, and attenuated virulence in a mouse model of disseminated infection. This may explain why relatively few erg3-deficient strains have been reported among azole-resistant clinical isolates. In this study, we examined the consequences of Erg3p inactivation upon C. albicans pathogenicity and azole susceptibility in mouse models of mucosal and disseminated infection. While a C. albicans erg3Δ/Δ mutant was unable to cause lethality in the disseminated model, it induced pathology in a mouse model of vaginal infection. The erg3Δ/Δ mutant was also more resistant to fluconazole treatment than the wild type in both models of infection. Thus, complete loss of Erg3p activity confers azole resistance but also niche-specific virulence deficiencies. Serendipitously, we discovered that loss of azole-inducible ERG3 transcription (rather than complete inactivation) is sufficient to confer in vitro fluconazole resistance, without compromising C. albicans stress tolerance, hyphal growth, or pathogenicity in either mouse model. It is also sufficient to confer fluconazole resistance in the mouse vaginal model, but not in the disseminated model of infection, and thus confers niche-specific azole resistance without compromising C. albicans pathogenicity at either site. Collectively, these results establish that modulating Erg3p expression or activity can have niche-specific consequences on both C. albicans pathogenicity and azole resistance. While conferring resistance to the azole antifungals in vitro, loss of sterol Δ5,6-desaturase (Erg3p) activity has also been shown to reduce C. albicans pathogenicity. Accordingly, it has been presumed that this mechanism may not be significant in the clinical setting. The results presented here challenge this assumption, revealing a more complex relationship between Erg3p activity, azole resistance, C. albicans pathogenicity, and the specific site of infection. Most importantly, we have shown that even modest changes in ERG3 transcription are sufficient to confer azole resistance without compromising C. albicans fitness or pathogenicity. Given that previous efforts to assess the importance of ERG3 as a determinant of clinical azole resistance have focused almost exclusively on detecting null mutants, its role may have been grossly underestimated. On the basis of our results, a more thorough investigation of the contribution of the ERG3 gene to azole resistance in the clinical setting is warranted.