Propionate consumption activates mitochondrial activity, methylcitrate cycle and promotes changes in the cell wall of the human pathogen Histoplasma capsulatum

Abstract

Histoplasma capsulatum is the fungal causative agent of the systemic mycosis Histoplasmosis, a disease with high incidence in the Americas and with worldwide occurrence. During infection, H. capsulatum yeast cells may metabolize nutrients such as odd fatty acids and amino acids, which render propionyl-CoA, a three-carbon molecule that may be toxic in high concentrations. In fungi, propionyl-CoA metabolism occurs mainly via the methylcitrate cycle (MCC). Therefore, this work aimed to analyze the adaptation of H. capsulatum to propionate. In silico analysis indicated potential genes coding for MCC specific enzymes, such as methylcitrate synthase (MCS), methylcitrate dehydratase (MCD) and methylisocitrate lyase (MCL). Propionate-grown cells induced the expression of MCS and MCL. Additionally, MCS enzymatic activity increased in propionate, regardless of the presence of the preferred carbon source glucose. Although propionate alone does not promote strong growth of H. capsulatum, propionate was consumed from the medium. Proteomic analyses identified 348 propionate-regulated proteins, 133 down-regulated and 215 up-regulated. Propionate metabolization increased ROS accumulation, cell wall remodeling, and fatty acid and amino acid oxidations. Altogether, these findings suggest that propionate metabolization activates the MCC, promotes changes in the cell wall, increases oxidative stress and activates alternative carbon source utilization.