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:

Burnet, Meagan C.; Zamith-Miranda, Daniel; Heyman, Heino M.; Weitz, Karl K.; Bredeweg, Erin L.; Nosanchuk, Joshua D. ;

• Search DOE PAGES for author "Nosanchuk, Joshua D."
• Search DOE PAGES for ORCID "0000-0001-9905-5754"

Nakayasu, Ernesto S.

• Search DOE PAGES for author "Nakayasu, Ernesto S."
• Search DOE PAGES for ORCID "0000-0002-4056-2695"

Publication Date:

Tue Jun 02 00:00:00 EDT 2020

Research Org.:

Pacific Northwest National Laboratory (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