Bacterial Stress Responses during Host Infection

Abstract

Pathogenic bacteria must withstand diverse host environments during infection. Environmental signals, such as pH, temperature, nutrient limitation, etc., not only trigger adaptive responses within bacteria to these specific stress conditions but also direct the expression of virulence genes at an appropriate time and place. An appreciation of stress responses and their regulation is therefore essential for an understanding of bacterial pathogenesis. This review considers specific stresses in the host environment and their relevance to pathogenesis, with a particular focus on the enteric pathogen Salmonella.

Figure 1. Stresses encountered by a typical foodborne enteric pathogen

Following ingestion, an enteric pathogen encounters distinctive stress conditions in the oral cavity, stomach, small intestine and colon of the host. Invasive pathogens must also withstand stresses imposed by phagocytic cells following the invasion of deeper tissues and the bloodstream. (Modified from a drawing by Mariana Ruiz Villareal, Wikimedia Commons).

Figure 2. Examples of Stress-Responsive Regulatory Systems

(A) PhoPQ Two-Component System. A conformational change in the PhoQ periplasmic sensor domain under acidic conditions or upon binding by cationic pepdides leads to a conformational change and activation of cytoplasmic domain kinase activity. PhoQ autophosphorylation followed by phosphorylation of the cognate response regulator PhoP results in the activation of stress response genes. (B) FNR Transcriptional Regulator. Under anaerobic conditions, the transcriptional regulator FNR exists as a DNA-binding homodimer containing a [4Fe-4S] cluster. At increasing oxygen levels, degradation of the cluster produces inactive [2Fe-2S] cluster-containing FNR monomers that further degrade to a monomeric apo-protein. (C) SigmaE Regulatory Cascade. Misfolded proteins in the periplasm interact with the DegS protease to relieve PDZ-mediated inhibition and allow cleavage of the anti-sigma RseA at site 1. This in turn allows RseP to cleave RseA at site 2, releasing the alternative sigma factor σ^E into the cytoplasm. The adapter protein SspB directs the σ^E-RseA complex to the ClpX/P protease, releasing σ^E to activate stress gene expression. Alternatively, acidic conditions allow RseA cleavage by RseP at site 2 (red arrow) in the absence of initial site 1 processing by DegS. (D) SrrAB Two-Component System. Under aerobic conditions, electrons are carried by menaquinone (MK, orange) from the NADH dehydrogenase (blue) to the Cyt aa3 and Cyt bd terminal oxidases (green, yellow). During hypoxia or following binding of the oxidase heme centers by nitric oxide, reduction of the menaquinone pool activates the sensor kinase SrrB, which in turn phosphorylates the response regulator SrrA, leading to the activation of genes involved in anaerobic metabolism and nitric oxide detoxification.