HcZrt2, a zinc responsive gene, is indispensable for the survival of Histoplasma capsulatum in vivo.

Abstract

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.

• Authors: Jessica Dade, Juwen C DuBois, Rajamouli Pasula, Anna M Donnell, Joseph A Caruso, A George Smulian, George S Deepe Jr
• Journal: Medical mycology (Med Mycol) Vol. 54 Issue 8 Pg. 865-75 (Nov 01 2016) ISSN: 1460-2709 [Electronic] England
• PMID: 27335059 (Publication Type: Journal Article)
• Copyright: © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Cation Transport Proteins
• Culture Media
• Virulence Factors
• Zinc

Topics

• Animals
• Cation Transport Proteins (genetics, metabolism)
• Cell Survival
• Colony Count, Microbial
• Culture Media (chemistry)
• Disease Models, Animal
• Gene Deletion
• Gene Knockdown Techniques
• Genetic Complementation Test
• Histoplasma (genetics, growth & development, physiology)
• Histoplasmosis (microbiology)
• Male
• Mice, Inbred C57BL
• RNA Interference
• Saccharomyces cerevisiae (genetics, growth & development)
• Survival Analysis
• Virulence Factors (genetics, metabolism)
• Zinc (metabolism)