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Interaction Dynamics of Bacterial Biofilms with Bacteriophages

Periodic Reporting for period 3 - BIOFAGE (Interaction Dynamics of Bacterial Biofilms with Bacteriophages)

Reporting period: 2020-01-01 to 2021-06-30

Bacteria mostly live in densely populated sessile communities, termed biofilms. In their natural environments, bacteria are frequently attacked by bacteriophages (or simply: phages), which are viruses that are a major driver of bacterial death. Although biofilms have been studied for several decades, and phages have been studied for a century, the interaction between these two ubiquitous features of bacterial life is largely unexplored. In the BIOFAGE project, we aim to fill this major gap in our understanding of microbial ecology, by revealing the interaction mechanisms between biofilms and phages and how these mechanisms drive the population dynamics.

The results of the BIOFAGE project have so far provided a mechanistic understanding of specific phage-biofilm interactions, and also biofilm-macrophage interactions, and bring us closer to general concepts for phage-biofilm interaction dynamics, which could provide new insights for applications in phage therapy.
In the BIOFAGE project, we have been investigating the biological, environmental, and physical determinants of phage spread. Using simulations, we have explored which properties of phages and biofilms could be most important in influencing their interactions, and predicted that the reduction of mobility of phages into the biofilm could be a major factor influencing phage spread in biofilms. We were able to confirm these predictions experimentally, by showing that Escherichia coli biofilms protect themselves from phage predation by secreting a particular matrix component (curli amyloid fibers) that tightens the biofilm architecture and binds phages, to prevent phage movement into the biofilm. We have also discovered that phages that get stuck on the outside biofilms serve as a protective barrier, which fends of external bacterial cells that seek to attach to the existing biofilms.

These findings have raised the question of manipulating the biofilm architecture and matrix composition to facilitate phage transport into biofilms. If phage penetration of biofilms is indeed a key hindrance to successfully removing biofilms, then it should be possible to improve biofilm removal by enhancing phage transport into biofilms. In this direction, we have now shown that antibiotic treatment of biofilms opens up the cell-cell spacing in biofilms, as a consequence of an antibiotic-induced breakdown of the extracellular matrix, which enables phages to pass through the biofilm community barrier.

Recently, we have also discovered that biofilms paly a crucial role in the interaction of bacteria with macrophages. Biofilms cover and engulf macrophages, before the macrophages die. We have determined the mechanisms of this interaction and found that biofilms significantly contribute to macrophage death, which reveals a new function of biofilms in the interaction with the immune system.

In the BIOFAGE project, we have also developed and published novel technologies for biofilm microscopy and image analysis, which are critical tools for advancing mechanistic research on biofilm-phage interactions.
For the remaining time of the BIOFAGE project, we expect to make major progress in understanding how biofilms respond to phage predation on the time scale of the physiological adaptation, and on the multi-generational time scale of evolutionary adaptation. In addition, we will explore to which extent it is possible to use phages to manipulate biofilm communities.
E. coli bacteria (yellow), surrounded by an extracellular biofilm matrix (pink) and phages (cyan).