Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-University of California Los Angeles (UCLA) Medical Center, Torrance, CA, USA.
Mol Microbiol. 2010 Aug;77(3):587-604. doi: 10.1111/j.1365-2958.2010.07234.x. Epub 2010 Jun 1.
Rhizopus oryzae is the most common cause of mucormycosis, an angioinvasive fungal infection that causes more then 50% mortality rate despite first-line therapy. Clinical and animal model data clearly demonstrate that the presence of elevated available serum iron predisposes the host to mucormycosis. The high affinity iron permease gene (FTR1) is required for R. oryzae iron transport in iron-depleted environments. Here we demonstrate that FTR1 is required for full virulence of R. oryzae in mice. We show that FTR1 is expressed during infection in diabetic ketoacidosis (DKA) mice. In addition, we disrupted FTR1 by double cross-over homologous recombination, but multinucleated R. oryzae could not be forced to segregate to a homokaryotic null allele. Nevertheless, a reduction of the relative copy number of FTR1 and inhibition of FTR1 expression by RNAi compromised the ability of R. oryzae to acquire iron in vitro and reduced its virulence in DKA mice. Importantly, passive immunization with anti-Ftr1p immune sera protected DKA mice from infection with R. oryzae. Thus, FTR1 is a virulence factor for R. oryzae, and anti-Ftr1p passive immunotherapy deserves further evaluation as a strategy to improve outcomes of deadly mucormycosis.
米根霉是毛霉病（一种血管侵袭性真菌感染）最常见的病因，尽管采用一线治疗，其死亡率仍超过 50%。临床和动物模型数据清楚地表明，血清铁含量升高会使宿主易患毛霉病。高亲和力铁渗透酶基因（FTR1）是米根霉在缺铁环境中进行铁转运所必需的。在这里，我们证明 FTR1 是米根霉在小鼠中完全毒力所必需的。我们表明，FTR1 在糖尿病酮症酸中毒（DKA）小鼠的感染过程中表达。此外，我们通过双交叉同源重组破坏了 FTR1，但不能迫使多核米根霉分离为纯合缺失等位基因。尽管如此，FTR1 的相对拷贝数减少和 RNAi 抑制 FTR1 表达会削弱米根霉在体外获取铁的能力，并降低其在 DKA 小鼠中的毒力。重要的是，用抗 Ftr1p 免疫血清进行被动免疫可以保护 DKA 小鼠免受米根霉感染。因此，FTR1 是米根霉的毒力因子，抗 Ftr1p 被动免疫疗法值得进一步评估，以作为改善致命性毛霉病预后的策略。
