Intracellular parasitism by Histoplasma capsulatum: fungal virulence and calcium dependence

Science. 2000 Nov 17;290(5495):1368-72. doi: 10.1126/science.290.5495.1368.

Abstract

Histoplasma capsulatum is an effective intracellular parasite of macrophages and causes the most prevalent fungal respiratory disease in the United States. A "dimorphic" fungus, H. capsulatum exists as a saprophytic mold in soil and converts to the parasitic yeast form after inhalation. Only the yeasts secrete a calcium-binding protein (CBP) and can grow in calcium-limiting conditions. To probe the relation between calcium limitation and intracellular parasitism, we designed a strategy to disrupt CBP1 in H. capsulatum using a telomeric linear plasmid and a two-step genetic selection. The resultingcbp1 yeasts no longer grew when deprived of calcium, and they were also unable to destroy macrophages in vitro or proliferate in a mouse model of pulmonary infection.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Calcium / metabolism*
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / metabolism*
  • Cell Line
  • Cell Survival
  • Gene Targeting
  • Genes, Fungal
  • Genetic Complementation Test
  • Histoplasma / genetics
  • Histoplasma / growth & development
  • Histoplasma / metabolism
  • Histoplasma / pathogenicity*
  • Histoplasmosis / microbiology*
  • Lung Diseases, Fungal / microbiology
  • Macrophages / microbiology*
  • Mice
  • Mutagenesis
  • Phenotype
  • Plasmids
  • Recombination, Genetic
  • Transformation, Genetic
  • Virulence

Substances

  • Calcium-Binding Proteins
  • Cbp1 protein, histoplasma
  • Calcium