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Title: Remodeling of the Histoplasma Capsulatum Membrane Induced by Monoclonal Antibodies

Abstract

Antibodies play a central role in host immunity by directly inactivating or recognizing an invading pathogen to enhance different immune responses to combat the invader. However, the cellular responses of pathogens to the presence of antibodies are not well-characterized. Here, we used different mass spectrometry techniques to study the cellular responses of the pathogenic fungus Histoplasma capsulatum to monoclonal antibodies (mAb) against HSP60, the surface protein involved in infection. A proteomic analysis of H. capsulatum yeast cells revealed that mAb binding regulates a variety of metabolic and signaling pathways, including fatty acid metabolism, sterol metabolism, MAPK signaling and ubiquitin-mediated proteolysis. The regulation of the fatty acid metabolism was accompanied by increases in the level of polyunsaturated fatty acids, which further augmented the degree of unsaturated lipids in H. capsulatum’s membranes and energy storage lipids, such as triacylglycerols, phosphatidylcholines, phosphatidylethanolamines and phosphatidylinositols. MAb treatment also regulated sterol metabolism by increasing the levels of cholesterol and ergosterol in the cells. We also showed that global changes in the lipid profiles resulted in an increased susceptibility of H. capsulatum to the ergosterol-targeting drug amphotericin B. Overall, our data showed that mAb induction of global changes in the composition of H. capsulatum membranes canmore » potentially impact antifungal treatment during histoplasmosis.« less

Authors:
; ; ; ; ; ORCiD logo; ORCiD logo
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE Laboratory Directed Research and Development (LDRD) Program
OSTI Identifier:
1631468
Alternate Identifier(s):
OSTI ID: 1642389
Report Number(s):
PNNL-SA-152362
Journal ID: ISSN 2076-393X; VBSABP; PII: vaccines8020269
Grant/Contract Number:  
LDRD; AC05-76RL01830
Resource Type:
Published Article
Journal Name:
Vaccines
Additional Journal Information:
Journal Name: Vaccines Journal Volume: 8 Journal Issue: 2; Journal ID: ISSN 2076-393X
Publisher:
MDPI
Country of Publication:
Switzerland
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Histoplasma capsulatum; antibody; lipids; metabolism; multi-omics

Citation Formats

Burnet, Meagan C., Zamith-Miranda, Daniel, Heyman, Heino M., Weitz, Karl K., Bredeweg, Erin L., Nosanchuk, Joshua D., and Nakayasu, Ernesto S. Remodeling of the Histoplasma Capsulatum Membrane Induced by Monoclonal Antibodies. Switzerland: N. p., 2020. Web. doi:10.3390/vaccines8020269.
Burnet, Meagan C., Zamith-Miranda, Daniel, Heyman, Heino M., Weitz, Karl K., Bredeweg, Erin L., Nosanchuk, Joshua D., & Nakayasu, Ernesto S. Remodeling of the Histoplasma Capsulatum Membrane Induced by Monoclonal Antibodies. Switzerland. doi:https://doi.org/10.3390/vaccines8020269
Burnet, Meagan C., Zamith-Miranda, Daniel, Heyman, Heino M., Weitz, Karl K., Bredeweg, Erin L., Nosanchuk, Joshua D., and Nakayasu, Ernesto S. Tue . "Remodeling of the Histoplasma Capsulatum Membrane Induced by Monoclonal Antibodies". Switzerland. doi:https://doi.org/10.3390/vaccines8020269.
@article{osti_1631468,
title = {Remodeling of the Histoplasma Capsulatum Membrane Induced by Monoclonal Antibodies},
author = {Burnet, Meagan C. and Zamith-Miranda, Daniel and Heyman, Heino M. and Weitz, Karl K. and Bredeweg, Erin L. and Nosanchuk, Joshua D. and Nakayasu, Ernesto S.},
abstractNote = {Antibodies play a central role in host immunity by directly inactivating or recognizing an invading pathogen to enhance different immune responses to combat the invader. However, the cellular responses of pathogens to the presence of antibodies are not well-characterized. Here, we used different mass spectrometry techniques to study the cellular responses of the pathogenic fungus Histoplasma capsulatum to monoclonal antibodies (mAb) against HSP60, the surface protein involved in infection. A proteomic analysis of H. capsulatum yeast cells revealed that mAb binding regulates a variety of metabolic and signaling pathways, including fatty acid metabolism, sterol metabolism, MAPK signaling and ubiquitin-mediated proteolysis. The regulation of the fatty acid metabolism was accompanied by increases in the level of polyunsaturated fatty acids, which further augmented the degree of unsaturated lipids in H. capsulatum’s membranes and energy storage lipids, such as triacylglycerols, phosphatidylcholines, phosphatidylethanolamines and phosphatidylinositols. MAb treatment also regulated sterol metabolism by increasing the levels of cholesterol and ergosterol in the cells. We also showed that global changes in the lipid profiles resulted in an increased susceptibility of H. capsulatum to the ergosterol-targeting drug amphotericin B. Overall, our data showed that mAb induction of global changes in the composition of H. capsulatum membranes can potentially impact antifungal treatment during histoplasmosis.},
doi = {10.3390/vaccines8020269},
journal = {Vaccines},
number = 2,
volume = 8,
place = {Switzerland},
year = {2020},
month = {6}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: https://doi.org/10.3390/vaccines8020269

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