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Updated: Jun 23, 2026
Passive Administration of Monoclonal Antibodies Against H. capsulatum and Others Fungal Pathogens
Published on: February 14, 2011
Histoplasma capsulatum encodes a dipeptidyl peptidase active against the mammalian immunoregulatory peptide,
Kendal G Cooper1, Robert Zarnowski, Jon P Woods
1Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, United States of America.
Abstract:
The pathogenic fungus Histoplasma capsulatum secretes dipeptidyl peptidase (Dpp) IV enzyme activity and has two putative DPPIV homologs (HcDPPIVA and HcDPPIVB). We previously showed that HcDPPIVB is the gene responsible for the majority of secreted DppIV activity in H. capsulatum culture supernatant, while we could not detect any functional contribution from HcDPPIVA. In order to determine whether HcDPPIVA encodes a functional DppIV enzyme, we expressed HcDPPIVA in Pichia pastoris and purified the recombinant protein. The recombinant enzyme cleaved synthetic DppIV substrates and had similar biochemical properties to other described DppIV enzymes, with temperature and pH optima of 42 degrees C and 8, respectively. Recombinant HcDppIVA cleaved the host immunoregulatory peptide substance P, indicating the enzyme has the potential to affect the immune response during infection. Expression of HcDPPIVA under heterologous regulatory sequences in H. capsulatum resulted in increased secreted DppIV activity, indicating that the encoded protein can be expressed and secreted by its native organism. However, HcDPPIVA was not required for virulence in a murine model of histoplasmosis. This work reports a fungal enzyme that can function to cleave the immunomodulatory host peptide substance P.
Insights
The pathogenic fungus Histoplasma capsulatum has a dipeptidyl peptidase (Dpp) IV enzyme, HcDPPIVA, that cleaves the host peptide substance P. This enzyme is expressed and secreted by the fungus but is not essential for virulence.
Area of Science:
- Mycology
- Enzymology
- Immunology
Background:
- Histoplasma capsulatum, a pathogenic fungus, exhibits dipeptidyl peptidase (Dpp) IV enzyme activity.
- Two putative Dpp IV homologs, HcDPPIVA and HcDPPIVB, exist in H. capsulatum.
- Previous studies indicated HcDPPIVB contributes most secreted Dpp IV activity, with HcDPPIVA's role unclear.
Purpose of the Study:
- To determine if HcDPPIVA encodes a functional Dpp IV enzyme.
- To characterize the biochemical properties of HcDPPIVA.
- To investigate the role of HcDPPIVA in H. capsulatum virulence and host immune modulation.
Main Methods:
- Recombinant HcDPPIVA expression and purification in Pichia pastoris.
- Biochemical characterization of recombinant HcDPPIVA activity, including substrate cleavage, temperature, and pH optima.
- Analysis of HcDPPIVA expression in H. capsulatum using heterologous regulatory sequences.
- Assessment of HcDPPIVA's contribution to virulence in a murine model of histoplasmosis.
Main Results:
- Recombinant HcDPPIVA demonstrated Dpp IV enzyme activity, cleaving synthetic substrates.
- The enzyme exhibited optimal activity at 42°C and pH 8.
- HcDPPIVA was shown to cleave the immunomodulatory host peptide substance P.
- Expression of HcDPPIVA in H. capsulatum led to increased secreted Dpp IV activity.
- HcDPPIVA was not essential for virulence in a murine histoplasmosis model.
Conclusions:
- HcDPPIVA is a functional fungal dipeptidyl peptidase IV enzyme.
- The enzyme can cleave the host peptide substance P, suggesting a potential role in modulating host immunity.
- While expressed and secreted by H. capsulatum, HcDPPIVA does not appear to be a major virulence factor.
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