Department of Microbiology, University of Georgia, Athens, Georgia, USA.
mSphere. 2024 Jul 30;9(7):e0037224. doi: 10.1128/msphere.00372-24. Epub 2024 Jul 9.
Iron acquisition is critical for pathogens to proliferate during invasive infection, and the human fungal pathogen is no exception. The iron regulatory network, established in reference strain SC5314 and derivatives, includes the central player Sef1, a transcription factor that activates iron acquisition genes in response to iron limitation. Here, we explored potential variation in this network among five diverse strains through mutant analysis, Nanostring gene expression profiling, and, for two strains, RNA-Seq. Our findings highlight four features that may inform future studies of natural variation and iron acquisition in this species. (i) Conformity: In all strains, major iron acquisition genes are upregulated during iron limitation, and a Δ/Δ mutation impairs that response and growth during iron limitation. (ii) Response variation: Some aspects of the iron limitation response vary among strains, notably the activation of hypha-associated genes. As this gene set is tied to tissue damage and virulence, variation may impact the progression of infection. (iii) Genotype-phenotype variation: The impact of a Δ/Δ mutation on cell wall integrity varies, and for the two strains examined the phenotype correlated with Δ/Δ impact on several cell wall integrity genes. (iv) Phenotype discovery: DNA repair genes were induced modestly by iron limitation in Δ/Δ mutants, with fold changes we would usually ignore. However, the response occurred in both strains tested and was reminiscent of a much stronger response described in , a suggestion that it may have biological meaning. In fact, we observed that the iron limitation of a Δ/Δ mutant caused recessive phenotypes to emerge at two heterozygous loci. Overall, our results show that a network that is critical for pathogen proliferation presents variation outside of its core functions.IMPORTANCEA key virulence factor of is the ability to maintain iron homeostasis in the host where iron is scarce. We focused on a central iron regulator, . We found that iron regulator Sef1 is required for growth, cell wall integrity, and genome integrity during iron limitation. The novel aspect of this work is the characterization of strain variation in a circuit that is required for survival in the host and the connection of iron acquisition to genome integrity in .
铁的获取对于病原体在侵袭性感染期间增殖至关重要，而人类真菌病原体也不例外。在参考菌株 SC5314 和其衍生物中建立的铁调控网络包括核心因子 Sef1，这是一种转录因子，可在缺铁时激活铁摄取基因。在这里，我们通过突变分析、Nanostring 基因表达谱分析以及对其中两个菌株进行 RNA-Seq 分析，探索了五个不同 菌株中该网络的潜在差异。我们的研究结果突出了四个特征，这些特征可能为该物种中自然变异和铁摄取的未来研究提供信息。（i）一致性：在所有菌株中，主要的铁摄取基因在缺铁时上调，而 Δ/Δ 突变会削弱该反应并在缺铁时限制生长。（ii）反应变异性：在菌株之间，铁限制反应的某些方面存在差异，特别是菌丝相关基因的激活。由于这个基因集与组织损伤和毒力有关，因此变异可能会影响感染的进展。（iii）基因型-表型变异：Δ/Δ 突变对细胞壁完整性的影响存在差异，而且对于所研究的两个菌株，表型与 Δ/Δ 对几个细胞壁完整性基因的影响相关。（iv）表型发现：在 Δ/Δ 突变体中，铁限制适度诱导 DNA 修复基因，其倍数变化通常会被忽略。然而，这种反应发生在两个测试菌株中，让人联想到在 中描述的更强烈的反应，这表明它可能具有生物学意义。事实上，我们观察到，在 Δ/Δ 突变体的铁限制下，两个杂合基因座的隐性表型会出现。总体而言，我们的研究结果表明，对于病原体增殖至关重要的网络在其核心功能之外存在变异性。
重要性：
在宿主中， 维持铁稳态的能力是其毒力的一个关键因素，而铁在宿主中是稀缺的。我们专注于一个核心铁调节因子，Sef1。我们发现，铁调节因子 Sef1 是在缺铁时生长、细胞壁完整性和基因组完整性所必需的。这项工作的新颖之处在于，在一个需要在宿主中生存的电路中，对菌株变异进行了特征描述，以及在 中，将铁摄取与基因组完整性联系起来。
