Boyce Kylie J, McLauchlan Alisha, Schreider Lena, Andrianopoulos Alex
School of BioSciences, The University of Melbourne, Parkville, Australia.
South Australian Clinical Genetics Service, SA Pathology, Adelaide, Australia.
PLoS Pathog. 2015 Mar 26;11(3):e1004790. doi: 10.1371/journal.ppat.1004790. eCollection 2015 Mar.
During infection, pathogens must utilise the available nutrient sources in order to grow while simultaneously evading or tolerating the host's defence systems. Amino acids are an important nutritional source for pathogenic fungi and can be assimilated from host proteins to provide both carbon and nitrogen. The hpdA gene of the dimorphic fungus Penicillium marneffei, which encodes an enzyme which catalyses the second step of tyrosine catabolism, was identified as up-regulated in pathogenic yeast cells. As well as enabling the fungus to acquire carbon and nitrogen, tyrosine is also a precursor in the formation of two types of protective melanin; DOPA melanin and pyomelanin. Chemical inhibition of HpdA in P. marneffei inhibits ex vivo yeast cell production suggesting that tyrosine is a key nutrient source during infectious growth. The genes required for tyrosine catabolism, including hpdA, are located in a gene cluster and the expression of these genes is induced in the presence of tyrosine. A gene (hmgR) encoding a Zn(II)2-Cys6 binuclear cluster transcription factor is present within the cluster and is required for tyrosine induced expression and repression in the presence of a preferred nitrogen source. AreA, the GATA-type transcription factor which regulates the global response to limiting nitrogen conditions negatively regulates expression of cluster genes in the absence of tyrosine and is required for nitrogen metabolite repression. Deletion of the tyrosine catabolic genes in the cluster affects growth on tyrosine as either a nitrogen or carbon source and affects pyomelanin, but not DOPA melanin, production. In contrast to other genes of the tyrosine catabolic cluster, deletion of hpdA results in no growth within macrophages. This suggests that the ability to catabolise tyrosine is not required for macrophage infection and that HpdA has an additional novel role to that of tyrosine catabolism and pyomelanin production during growth in host cells.
在感染过程中，病原体必须利用可用的营养源来生长，同时逃避或耐受宿主的防御系统。氨基酸是致病真菌的重要营养源，可从宿主蛋白质中吸收，以提供碳和氮。双态真菌马尔尼菲青霉的hpdA基因编码一种催化酪氨酸分解代谢第二步的酶，该基因在致病酵母细胞中被鉴定为上调表达。酪氨酸不仅使真菌能够获取碳和氮，也是两种保护性黑色素（多巴黑色素和脓黑素）形成的前体。化学抑制马尔尼菲青霉中的HpdA可抑制体外酵母细胞的产生，这表明酪氨酸是感染性生长过程中的关键营养源。酪氨酸分解代谢所需的基因，包括hpdA，位于一个基因簇中，这些基因的表达在酪氨酸存在时被诱导。一个编码Zn(II)2-Cys6双核簇转录因子的基因（hmgR）存在于该基因簇中，是酪氨酸诱导表达以及在存在优选氮源时进行抑制所必需的。AreA是一种GATA型转录因子，可调节对有限氮条件的全局反应，在没有酪氨酸的情况下负调节基因簇基因的表达，并且是氮代谢物阻遏所必需的。基因簇中酪氨酸分解代谢基因的缺失会影响以酪氨酸作为氮源或碳源时的生长，并影响脓黑素的产生，但不影响多巴黑色素的产生。与酪氨酸分解代谢基因簇的其他基因不同，hpdA的缺失导致在巨噬细胞内无法生长。这表明巨噬细胞感染不需要酪氨酸分解代谢的能力，并且HpdA在宿主细胞生长过程中除了酪氨酸分解代谢和脓黑素产生之外还具有额外的新作用。
