Professor of Ultrastructural biology / Co-director NeCEN
I am professor in electron cryotomography and bacterial chemotaxis. I am interested in understanding how microbes sense and respond to their environment. In order to gain insight into the structure and function of the molecular complexes involved in these behaviors, my lab uses electron cryotomography (ECT). This technique allows us to directly study microbes in their native state at resolutions capable of visualizing individual proteins. I am also a co-director at NeCEN, the Netherlands Centre for Electron Nanoscopy. Lastly, I am a member of the interdisciplinary research programme Society, Artificial Intelligence and Life Sciences (SAILS).
Cellular electron cryotomography allows the study of individual microbial cells in their native state and in three dimensions at macromolecular resolutions.
Our experiments rely on highly sophisticated and specialized equipment. We have access to the electron microscopes at the NeCEN, the dutch cryo-electron microscopy center located in the Biology Institute of the Leiden University. The available instruments include 2 TITAN Krios microscopes with state-of-the-art equipment for highest quality data collection, as well as a fully equipped sample preparation laboratory.
Bacterial interactions with their environment
The Briegel lab is interested in understanding how microbes interact with their environment on a structural level. We address research questions such as: how are bacterial cells able to actively seek out their preferred environmental niches, how can they evade toxins and predators, how do they interact with phages, each other and with host tissue, and how can they adapt to thrive in changing environments? In order to gain insight into the structure and function of the molecular complexes involved in these behaviors, we use cryo-electron tomography (cryo-ET) as our key research tool. This technique allows us to directly study microbes in their native state at resolutions capable of visualizing individual proteins.
More specifically, we are currently pursuing three major research lines in the laboratory:
- Chemotaxis in pathogenic bacteria (Vibrio cholerae and Treponema denticola)
- Bacterial hitchhiking
- Bacterial interactions in changing environments
1. Chemosensing in pathogenic bacteria
Bacteria are nearly ubiquitous, play vital roles in industry and the environment, and are crucial factors for health and disease of all organisms. They are also small, tractable cells that are ideal to study biological processes. As such, the bacterial chemotaxis system serves as a paradigm for signal transduction pathways. Chemotaxis allows motile bacteria, including some pathogens, to monitor their environment and swim toward nutrients and away from toxins. Chemical signals bind to chemoreceptors, which are typically found at the cell poles and organize into highly cooperative, ordered arrays. Chemoreceptor arrays ultimately control whether the cell moves forward or changes direction. The chemotaxis system in the model species E. coli is now structurally well understood. This detailed knowledge can be used for practical applications: this signalling system provides an ideal platform to design biosensors: For example, we are currently developing Neuroblastoma cancer screen based on the ability of the E. coli chemoreceptor Tsr to quickly detect a marker molecule for the disease (funded by KWF).
Besides, it is becoming increasingly clear that there is an underappreciated variability of chemotaxis systems among the motile bacteria. We are especially interested in the chemotaxis systems of two pathogenic bacteria: Vibrio cholerae and Treponema denticola, human pathogen that use their chemotaxis sensing system for infectivity. We discovered recently that the organization of both of these pathogens is structurally distinct from E.coli (Muok et al., 2020b; Yang et al., 2018; Yang and Briegel, 2019). We are investing these alternate architectures and their implications in the pathogenicity of these organisms.
2. Bacterial hitchhiking
Nearly all motile bacteria are able direct their motility to actively seek out favorable conditions (Hazelbauer et al., 2008). Most commonly, these bacterial cells use so-called flagella to swim through liquid environments or swarm on surfaces. These whip-like appendages that are anchored to a rotary motor in the cell envelope. For many pathogens, this type of motility is the first step in host invasion and is essential for survival within host tissues (Matilla and Krell, 2018; Shi et al., 1998). However, many bacteria are non-motile, such as bacteria lacking a motility apparatus. How do they reach their preferred environments without the means to move by themselves? There is now growing evidence that non-motile species can attach to motile species to benefit from motility without investing energy themselves (Muok and Briegel, 2020). For example, my lab recently discovered that non-motile bacterial spores are transported to beneficial environments by chemotactic soil bacteria via ‘hitchhiking’ (Muok et al., 2020a).
In this research line, my lab is determining the structural interactions that enable hitchhiking behavior between motile bacteria and non-motile species and the implications for microbial distributions and pathogenicity.
3. Bacterial interactions in changing environments
Bacteria are able to sense environmental changes in their surroundings and adapt themselves, both structurally and metabolically, in order to survive. These cells are able to switch between free-living states, sessile states in biofilms and active infection of a host organism. Cells selectively express and employ distinct macromolecular machines according to specific growth conditions to interact with and manipulate their environment. Consequently, cells of the same species may have vastly different morphological and behavioral characteristics depending on the environment they are in, and the susceptibility to stressors such as antibiotics and phage infection also may vary dramatically depending on cell morphology. For example we recently investigated the dramatic changes Vibrio cholerae undergoes when the cells encounter long periods of low temperature and nutrient limitation and enter a persister-like state (Brenzinger et al., 2019). Due to this innate adaptability, it is necessary to form a detailed understanding of how the cells first sense diverse environments and subsequently how they structurally remodel to counter and thrive despite often dramatically changing conditions. This structural insight is a crucial prerequisite for designing novel drugs aiming to target the specific molecular machines during infection. More specifically, we study the remodeling of V. cholerae during infection of V. cholerae in Zebrafish, a natural host for this pathogen (NWO BBOL grant). In order to investigate this interaction at the nanoscale level and near-native sample preservation, we are developing novel workflows that will allow us extract tissue samples and process them for subsequent cryo-ET investigations. This workflow will be generally applicable to investigate microbial interactions in complex environments, such as microbes inside a host organism. For example, we are also investigating a key microbe-host symbiosis system (luminescent bacteria inside the light organ of the Hawaiian bobtail squid (funded by the Moore foundation), as well as bacteria living inside plants (funded by NWO).
Brenzinger, S., van der Aart, L.T., van Wezel, G.P., Lacroix, J.M., Glatter, T., and Briegel, A. (2019). Structural and Proteomic Changes in Viable but Non-culturable Vibrio cholerae. Frontiers in microbiology 10, 793.
Hazelbauer, G.L., Falke, J.J., and Parkinson, J.S. (2008). Bacterial chemoreceptors: high-performance signaling in networked arrays. Trends Biochem Sci 33, 9-19.
Matilla, M.A., and Krell, T. (2018). The effect of bacterial chemotaxis on host infection and pathogenicity. FEMS Microbiol Rev 42.
Muok, A., Claessen, D., and Briegel, A. (2020a). Microbial piggy-back: how Streptomyces spores are transported by motile soil bacteria. biorxiv.
Muok, A.R., and Briegel, A. (2020). Intermicrobial Hitchhiking: How Nonmotile Microbes Leverage Communal Motility. Trends Microbiol.
Muok, A.R., Ortega, D.R., Kurniyati, K., Yang, W., Maschmann, Z.A., Sidi Mabrouk, A., Li, C., Crane, B.R., and Briegel, A. (2020b). Atypical chemoreceptor arrays accommodate high membrane curvature. Nature communications 11, 5763.
Shi, W., Yang, Z., Geng, Y., Wolinsky, L.E., and Lovett, M.A. (1998). Chemotaxis in Borellia burgdorferi. Journal of Bacteriology 180, 231-235.
Yang, W., Alvarado, A., Glatter, T., Ringgaard, S., and Briegel, A. (2018). Baseplate variability of Vibrio cholerae chemoreceptor arrays. Proceedings of the National Academy of Sciences of the United States of America 115, 13365-13370.
Yang, W., and Briegel, A. (2019). Diversity of Bacterial Chemosensory Arrays. Trends Microbiol.
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