HapX Positively and Negatively Regulates the Transcriptional Response to Iron Deprivation in Cryptococcus neoformans

PLoS Pathogens

Won Hee Jung¹  Rick White²  Sanjay Saikia³  James W. Kronstad³  Guanggan Hu³  Cletus D'Souza³  Carlen Ka-Yin Fung³  Joyce Wang³ 

[1]Department of Biotechnology, Chung-Ang University, Daedeok-Myeon, Anseong-Si, Gyeonggi-Do, Republic of Korea

[2]Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada

[3]The Michael Smith Laboratories, Department of Microbiology and Immunology, and Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada

关键词: Cryptococcus neoformans;    Gene expression;    Gene regulation;    Microarrays;    Heme;    Virulence factors;    Iron;    Transcriptional control;   

DOI  :  10.1371/journal.ppat.1001209

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The fungal pathogen Cryptococcus neoformans is a major cause of illness in immunocompromised individuals such as AIDS patients. The ability of the fungus to acquire nutrients during proliferation in host tissue and the ability to elaborate a polysaccharide capsule are critical determinants of disease outcome. We previously showed that the GATA factor, Cir1, is a major regulator both of the iron uptake functions needed for growth in host tissue and the key virulence factors such as capsule, melanin and growth at 37°C. We are interested in further defining the mechanisms of iron acquisition from inorganic and host-derived iron sources with the goal of understanding the nutritional adaptation of C. neoformans to the host environment. In this study, we investigated the roles of the HAP3 and HAPX genes in iron utilization and virulence. As in other fungi, the C. neoformans Hap proteins negatively influence the expression of genes encoding respiratory and TCA cycle functions under low-iron conditions. However, we also found that HapX plays both positive and negative roles in the regulation of gene expression, including a positive regulatory role in siderophore transporter expression. In addition, HapX also positively regulated the expression of the CIR1 transcript. This situation is in contrast to the negative regulation by HapX of genes encoding GATA iron regulatory factors in Aspergillus nidulans and Schizosaccharomyces pombe. Although both hapX and hap3 mutants were defective in heme utilization in culture, only HapX made a contribution to virulence, and loss of HapX in a strain lacking the high-affinity iron uptake system did not cause further attenuation of disease. Therefore, HapX appears to have a minimal role during infection of mammalian hosts and instead may be an important regulator of environmental iron uptake functions. Overall, these results indicated that C. neoformans employs multiple strategies for iron acquisition during infection.

【 授权许可】

CC BY