CTW: Biofilms in Infectious Disease: Biology to Mathematical Models and Back Again: Titles & Abstracts
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- Titles & Abstracts
Biofilms are colonies of microbial cells encased in a self-produced organic polymeric matrix and represent a common mode of microbial growth. Microbes growing as biofilm are highly resistant to commonly used antimicrobial drugs. Recently, microbial biofilms have gained prominence because of the increase in infections related to indwelling medical devices (IMD). Candida albicans, the pathogenic fungus which is a major cause of morbidity and mortality in blood stream infections, is the most common fungal pathogen isolated from patients with IMD-associated infections. Biofilm formation by Candida species is believed to contribute to invasiveness of these fungal species. We discuss experimental methods used to study fungal biofilms as well as the biology of biofilm formation by clinically relevant Candida species. This lecture will take us in a journey from basic science to translational research.
Pathogen populations produce persisters, specialized survivor cells that are dormant and highly tolerant to all known antibiotics. Molecular mechanisms of persister formation will be discussed, as well as their role in disease, such as biofilm infections of catheters, cystic fibrosis, and oropharyngeal candidiasis. Approaches to eradicating persisters will be discussed as well.
The important human pathogen Pseudomonas aeruginosa has been linked to numerous biofilm-related chronic infections Biofilms are complex communities of microorganisms encased in a matrix and attached to surfaces. It is well recognized that biofilm cells differ from their free swimming counterparts with respect to gene expression, protein production, and resistance to antibiotics and the human immune system. However, little is known about the underlying regulatory events that lead to the formation of biofilms, the primary cause of many chronic and persistent human infections. By mapping the phosphoproteome over the course of P. aeruginosa biofilm development, demonstrated that biofilm formation following the transition to the surface attached lifestyle is regulated by three previously undescribed two-component systems: BfiSR (PA4196-4197) harboring an RpoD-like domain, an OmpR-like BfmSR (PA4101-4102), and MifSR (PA5511-5512) belonging to the family of NtrC-like transcriptional regulators. we identified three novel two-component regulatory systems that were required for the development and maturation of P. aeruginosa biofilms. These two-component systems become sequentially phosphorylated during biofilm formation. Inactivation of bfiS, bfmR, and mifR arrested biofilm formation at the transition to the irreversible attachment, maturation-1 and -2 stages, respectively, as indicated by analyses of biofilm architecture, and protein and phosphoprotein patterns. Moreover, discontinuation of bfiS, bfmR, and mifR expression in established biofilms resulted in the collapse of biofilms to an earlier developmental stage indicating a requirement for these regulatory systems for the development and maintenance of normal biofilm architecture. Interestingly, inactivation did not affect planktonic growth, motility, polysaccharide production, or initial attachment. Further, we demonstrate the interdependency of this two-component systems network with GacS (PA0928), which was found to play a dual role in biofilm formation. This work describes a novel signal transduction network regulating committed biofilm developmental steps following attachment, in which phosphorelays and two sigma factor-dependent response regulators appear to be key components of the regulatory machinery that coordinates gene expression during P. aeruginosa biofilm development in response to environmental cues.
Driven by recent advances in noninvasive microscopy, staining techniques, and genetic probes, there has been enormous increase in our understanding of biofilms. Along with this increase in understanding, has been increasing interest in mathematical models of biofilms to get at important mechanisms. Most recent modeling in the field has been directed towards understanding the mechanisms underlying the remarkable spatial structure of biofilms which has become evident through the use of modern imaging techniques. Most of these models are so complex that they can be investigated only using sophisticated numerical simulations.
On the other hand, there are relatively few simple, conceptual biofilm models which are amenable to mathematical analysis yet which yield significant and useful results. Here, we speak of models which do not attempt to provide much detail on the spatial structure of biofilms but which provide information on conditions suitable for biofilm formation and maintenance and which model the formation of biofilms directly, starting from an inoculum of planktonic bacteria. Freter et al. formulated a mathematical model to understand the phenomena of colonization resistance in the mammalian gut (stability of resident microflora to colonization). Essentially, their model can be viewed as a crude biofilm model. In contrast to state of the art biofilm models, the Freter model completely ignores the three-dimensional spatial structure of the biofilm. Yet it can give useful results. The model and its implications will be surveyed.
