The effect of monoclonal antibodies against HSP60 on Histoplasma capsulatum extracellular vesicles
EMSL Project ID
50568
Abstract
The capacity of the human fungal pathogen Histoplasma capsulatum (Hc) to cause severe invasive disease is attributed to the fungus’ ability to subvert host responses, especially in the setting of immune compromise due to advanced HIV infection. For example, the capacity of the fungus to impair phagosome maturation and the presence of melanin in the fungal cell wall contribute to the capacity of the fungus to survive intracellularly and avoid host surveillance as well as block the effects of host effector responses. We have shown that Hc produces extracellular vesicles containing biologically active molecules. However, many questions on disease pathogenesis arise from this process of vesiculogenesis. We will explore how protective and non-protective antibodies regulate the production and release of extracellular vesicles from Hc. We are pursuing this work based on our findings that protective antibodies to Hc alter gene expression and that cross-linking by antibodies changes the outcome of interactions with host effector cells. Using a pair of protective and non-protective monoclonal antibodies (mAb) that bind to the same region on heat shock protein 60 expressed on the Hc cell surface, we will determine the mAbs’ capacity to alter the formation and secretion of these bilayered vesicles as well as their impact on the cargo within the vesicles. The resources located at EMSL will be essential for the detailed characterization of the vesicular composition and the impact of antibody treatment on it. We are pursuing this work based on our observations that the vesicles can alter the behavior of host cells and that the cargo within the vesicles includes compounds that are toxic to host cells. The results of the studies in this project will provide new insights into the basic biology of Hc, elucidate new activities of antibody, and serve as a potential foundation for new therapeutic approaches to combat this important fungus as well as other eukaryotic pathogens.
Project Details
Start Date
2018-10-01
End Date
2019-08-06
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Bürgel P.H., C.L. Marina, P.H. Saavedra, P. Albuquerque, P.H. Holanda, R.A. Castro, and H.M. Heyman, et al. 2019. "Cryptococcus neoformans secretes small molecules that inhibit IL-1ß inflammasome-dependent secretion." bioRxiv. PNNL-SA-140752. doi:10.1101/554048.
Cleare L.G., D. Zamith-Miranda, H.M. Heyman, S.P. Couvillion, L. Nimrichter, M.L. Rodrigues, and E.S. Nakayasu, et al. 2020. "Media Matters! Alterations in the loading and release of Histoplasma capsulatum extracellular vesicles in response to different nutritional milieus." Cellular Microbiology 22, no. 9:Article No. e13217. PNNL-SA-151908. doi:10.1111/cmi.13217
Zamith-Miranda D., H.M. Heyman, L.G. Cleare, S.P. Couvillion, G. Clair, E.L. Bredeweg, and A. Gacser, et al. 2019. "Multi-omics signature of Candida Auris, an emerging and multidrug-resistant pathogen." mSystems 4, no. 4:e00257-19. PNNL-SA-140174. doi:10.1128/mSystems.00257-19