HcZrt2, a zinc responsive gene, is indispensable for the survival ofHistoplasma capsulatum in vivo
- Resource Type
- Authors
- Jessica E. Dade; Joseph A. Caruso; Rajamouli Pasula; A. George Smulian; Juwen C. DuBois; George S. Deepe; Anna M. Donnell
- Source
- Medical Mycology. 54:865-875
- Subject
- Male
0301 basic medicine
Cell Survival
Virulence Factors
Histoplasma
030106 microbiology
Colony Count, Microbial
chemistry.chemical_element
Saccharomyces cerevisiae
Zinc
Biology
Microbiology
03 medical and health sciences
RNA interference
medicine
Animals
Gene silencing
Cation Transport Proteins
Histoplasmosis
Gene knockdown
Genetic Complementation Test
Lethal dose
General Medicine
medicine.disease
biology.organism_classification
Survival Analysis
Culture Media
Mice, Inbred C57BL
Complementation
Disease Models, Animal
030104 developmental biology
Infectious Diseases
chemistry
Gene Knockdown Techniques
Zinc deficiency
RNA Interference
Original Article
Gene Deletion
- Language
- ISSN
- 1460-2709
1369-3786
Histoplasma capsulatum (Hc) exists in the soil and is capable of adapting to the shift in environment during infection to ensure survival. Yeast encounter a restrictive host environment low in nutrients such as zinc. In this study we functionally analyzed a putative zinc regulated transporter, HcZrt2, in zinc limiting conditions by complementation of HcZrt2 and gene knockdown through RNA interference (RNAi). Complementation analysis demonstrated HcZrt2's ability to functionally replace the characterized Saccharomyces cerevisiae zinc plasma membrane transporters Zrt1 and Zrt2 in zinc deficient medium. Gene silencing revealed that HcZrt2 is essential for growth in zinc deficient medium and plays a role in zinc accumulation. Fungal burden was reduced in mice infected with HcZrt2 silenced strains compared to a control strain. Sixty-seven percent of mice infected with a lethal dose of HcZrt2-RNAi#1 survived, and 100% of mice infected with HcZrt2-RNAi#2 withstood lethal infection. Our data suggest that HcZrt2 is a vital part of zinc homeostasis and essential for the pathogenesis of histoplasmosis.