Authors:	Westmeier, Dana
Title:	Nanoparticle binding affects the pathobiology and fate of microorganisms
Online publication date:	7-Oct-2020
Year of first publication:	2017
Language:	english
Abstract:	Applications of engineered nanoparticles (NPs) are not only increasing in industry and consumer products but also in various areas of life sciences, such as basic biology, biotechnology, and biomedicine. Owing to their unique nanoscale physical and chemical properties combined with their potential for multiple surface functionalizations, the repertoire of NPs has raised high expectations, ranging from tools to dissect fundamental cellular mechanisms, unique drug carriers or biosensors to novel antimicrobials against bacterial or fungal infections. Notably, all major exposure and entry sites of NPs in the human body overlap with the infection path of pathogens or are naturally inhabited by various types of commensal microorganisms. However, a mechanistic understanding of the potential crosstalk of NPs with microbes and the (patho)biological consequences thereof has not been investigated in detail so far. We hypothesized that simultaneous exposure to NPs and microorganisms may trigger complex formation generating novel NP-biomaterial hybrid structures to which biological systems have to react. Consequently, the presented work performed a comprehensive in situ, in vitro, and in vivo analysis to understand the complex crosstalk of NPs with microorganisms as well as its impact on various aspects of the (patho)biological identity and fate of pathogens and NPs. Within this work, a library of model NPs varying in size, charge, and surface modifications were combined with bacterial and fungal models to dissect the underlying physico-chemical forces dictating NP-microbe crosstalk. This work demonstrated for the first time that various NPs rapidly and stably associate with fungal spores or bacterial pathogens depending on the NPs’ physico-chemical characteristics, the bacterial surface as well as the physiological environment. Collectively, improved binding was observed for negatively charged, small NPs lacking steric surface modifications. Among the investigated microbes, most efficient assembly occurred on Aspergillus fumigatus conidia, followed by Gram-positive bacteria. Interestingly, NP binding was reduced in the presence of biomolecules but enhanced at low pH for bacteria, such as for Helicobacter pylori in the gastric environment. Notably, the identified pH-switch increased the antibiotic activity of metal-based NPs, enabling also the killing of multidrug-resistant primary clinical isolates, such as Staphylococcus aureus, even in biomolecule-containing physiological environments. Employing gastric organoid and respiratory tract murine models combined with latest imaging technologies, stable NP-microbe complexes were detected in experimental settings, strongly mimicking human pathophysiologies. Here, self-assembly of NP-fungal hybrids affected Aspergillus fumigatus' pathobiology by increasing TLR-/cytokine-mediated inflammatory responses and reducing phagocytosis in vitro as well as in murine lung infections. In summary, the performed work demonstrates that NP-microbe crosstalk may indeed affect (patho)biological reactions of humans and ecosystems towards microbes. The obtained knowledge not only sets the stage for further in depth investigations but also for the rational exploitation of NPs as potential novel antimicrobials.
DDC:	570 Biowissenschaften 570 Life sciences
Department:	FB 04 Medizin
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-5188
URN:	urn:nbn:de:hebis:77-diss-1000016057
Publication type:	Dissertation
License:	In Copyright
Information on rights of use:	https://rightsstatements.org/vocab/InC/1.0/
Extent:	196 Seiten
Publisher:	Johannes Gutenberg-Universität
Publisher place:	Mainz
Issue date:	2017
Appears in collections:	JGU-Publikationen