A synthetic peptide selectively kills only virulent Paracoccidioides brasiliensis yeasts.
This work was conducted to identify virulence biomarkers for Paracoccidioides brasiliensis (Pb), the fungus responsible for Paracoccidioidomycosis (PCM), a systemic disease endemic in Latin America. Measurement of mortality showed that all B10.A mice were killed after 250 days by the virulent Pb18 isolate while only one of the mice that received the attenuated counterpart died. Also, number of lung CFUs from virulent Pb18 inoculated mice were much higher when these isolates were compared. Phage display methodology allowed selection of three phages that specifically bound to virulent Pb18. Variability of p04 phage binding to different Pb isolates were examples of variability of expression by the fungus of its binding molecule, strongly suggesting p04 as a biomarker of virulence. In vitro, its derived peptide pep04 killed only virulent fungi, and confocal microscopy showed that it was internalized only by the virulent isolate. Pep04 blocked establishment of Pb infection in mice and virulent Pb18 pre-incubated with p04 showed significantly inhibited lung infection. Furthermore, infected mice treated with p04 showed highly significant reduction in lung CFUs. These findings firmly establish p04 as a biomarker of Pb virulence. Therefore, after proper peptide engineering, p04 may become a useful adjuvant for the distressing treatment of PCM.
Department of Microbiology, Immunology and Parasitology, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Erika Seki
ES
Kioshima
Fabiana
F
Aliperti
Juliana Terzi
JT
Maricato
Renato Arruda
RA
Mortara
Eduardo
E
Bagagli
Mario
M
Mariano
José Daniel
JD
Lopes
D000704:Analysis of Variance; D000818:Animals; D000935:Antifungal Agents / Q000378:metabolism / Q000494:pharmacology*; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D015169:Colony Count, Microbial; D006651:Histocytochemistry; D008099:Liver / Q000382:microbiology; D008168:Lung / Q000382:microbiology; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D010228:Paracoccidioides / Q000187:drug effects* / Q000378:metabolism; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D015203:Reproducibility of Results; D013154:Spleen / Q000382:microbiology; D014774:Virulence
D000935:Antifungal Agents; D015415:Biomarkers; D019151:Peptide Library; D010455:Peptides