Who’s in control? Regulation of metabolism and pathogenesis in space and time
Graphical abstract
Introduction
All microorganisms must sense the environment and align their physiology to the current conditions. Pathogenic bacteria must contend with hostile environments of the host, which impose nutritional and environmental stresses and deploy immune cells to attack and eventually destroy invading microbes. Thus, pathogens must reconfigure both metabolism and the production of virulence factors simultaneously. Such a response is essential to optimize the production of needed proteins and enzymes as well as biological polymers including DNA, RNA, cell wall components and extracellular polymeric substances (EPS). Individual bacterial cells align and coordinate production of these molecules in part using regulatory proteins that monitor the availability of key nutrients. These proteins can act individually or in combination with multiple global and operon-specific regulators in a hierarchical fashion to adjust gene expression. For instance, the prokaryotic transcription factor Lrp (responsive to leucine) and the Firmicute-specific transcription factor CodY (responsive to branched-chain amino acids (BCAAs) and GTP) serve to link the physiological state of the cell to pathogenicity [1,2]. Bacteria utilize transcriptional regulators responsive to ligands [3] and two-component systems (TCSs) to sense and respond to environmental cues including secreted defense molecules in a transcriptional manner [4]. In addition, RNA-binding proteins (RBPs) and small, non-coding regulatory RNAs (sRNAs) mediate cellular responses to physiological and environmental stresses post-transcriptionally [5]. However, bacteria rarely act as individual cells. Rather, they communicate using a chemical language that allows them to sense one another, essentially behaving socially with complex intraspecies and interspecies interactions of a cooperative or an antagonistic nature [6,7]. Previously, researchers used reductionist approaches to study the molecular basis of individual components. While we now have a greater appreciation for their role in more complex systems, our knowledge about physiology and gene regulation during infection is still limited. We posit that integrating this information on varying time and spatial scales is key to understanding pathogen behavior and can inform our design of new therapies as our antibiotics become increasingly ineffective. Just as The Doctor in the revered UK television program explores all of space and time, in this short review, we will explore recent developments on spatio-temporal regulation of gene expression, emphasizing the intertwining of metabolism with production of virulence factors. For the sake of brevity, we provide highlights from Salmonella enterica (hereafter referred to as Salmonella) and Escherichia coli, model Gram-negative intestinal pathogens that intercept cues from the microbiota or the host in the gastrointestinal tract [8], and Staphylococcus aureus, a model Gram-positive pathogen that can exploit nearly every niche of the body. However, regulating metabolism and virulence in space and time applies to all bacteria of medical importance and we encourage the reader to reflect on the concepts described here as to how they might apply to other microorganisms.
Section snippets
Nutrient gradients and gene expression
The ability to acquire and process available nutrients efficiently is essential for pathogen survival and multiplication in the host as well as eventual dissemination. While the production of secreted virulence factors can act to extract needed nutrients from host cells or tissues, key regulators can adjust the activities of catabolic pathways to exploit carbon source availability in various environments, particularly when host metabolism is disturbed. Classic carbon catabolite repression (CCR)
Posttranscriptional regulation enhances cell adaptation to the host environment
Recent studies have underscored the importance of posttranscriptional regulation of metabolism for cell fitness in diverse environments, including host niches. RNA binding proteins and sRNAs are critical for regulating a multitude of bacterial stress responses, by adjusting the flow of metabolites through central metabolic pathways in both Gram-negative and Gram-positive bacteria, therefore being critical for adaptation to the host environment. As we also highlight, they are essential for
Conclusion
The dramatic surge of multidrug resistance to our current antibiotics emphasizes the need for new therapies. Pathogens use complex intertwined layers of regulation to adjust metabolism and virulence factor production during infection; thus, targeting these circuits is one exciting alternative approach in addition to other anti-virulence strategies like quorum quenching [76] that would allow the host immune response to naturally clear the infection. Importantly, emerging views of behavior in vivo
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by the National Institutes of Health [grant number AI137403] and Georgetown University startup funds to SRB; and Achievement Rewards for College Scientists Foundation (ARCS) fellowship [no grant number] to ANK. The funders had no role in decision to publish, or preparation of this review manuscript.
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These authors made equal contributions.