Chapter Two - The Escherichia coli Acid Stress Response and Its Significance for Pathogenesis
Introduction
The enteric and sometimes pathogenic bacterium Escherichia coli has a remarkable and well-studied ability to withstand exposure to extremely low pH. This property arises from the activation of several acid resistance (AR) mechanisms that are regulated in diverse and sometimes very complex ways. Resistance to low pH is commonly held to be an important pathogenic determinant, since it allows E. coli to traverse the stomach and potentially cause disease with a very low infectious dose. The AR mechanisms of E. coli have been studied largely in nonpathogenic laboratory strains, and, as we will discuss in this review, recent studies on pathogenic strains are starting to show a relationship between AR and the properties of these strains, with cross-talk between the AR regulators and other factors important in determining pathogenicity.
Understanding the ways in which E. coli enters and persists in the human gut is complicated. The gut is a diverse and dynamic environment, the pH of which varies considerably depending on the compartment, the digestive state, and the age and health of the individual. Bacteria passing through the gut are exposed to different acids, some produced as part of the digestive process, others by bacteria residing in the gut, and the effects of these acids depend both on their pKa and on their specific chemical nature. In addition, the simple term “E. coli” is shorthand for a large group of organisms with very diverse properties, including with regard to their levels of AR (Kaper, Nataro, & Mobley, 2004). The properties of any strain of E. coli are strongly influenced both by its current surroundings (such as whether it is growing as a biofilm or planktonically, aerobically, or anaerobically) and its past history, including past exposure to acid. Although the discussion here will focus on the human gastrointestinal tract (GIT), those of other animals are also of interest when we are considering pathogenic effects of E. coli, (Callaway et al., 2009, Huja et al., 2015) and these are all very different environments from each other. Clearly we cannot simply extrapolate from the behavior of a laboratory strain of E. coli grown in lysogeny broth in a shake flask to how a pathogenic strain may be affected by the acidic nature of the GIT or what the outcomes of the acid shock response may be in the gut. However, data derived from laboratory experiments are plentiful, while those done under GIT conditions are relatively sparse due to the difficulties in reproducing gut conditions in the laboratory.
Our aim in this review is to link the abundant literature on acid stress responses in E. coli to what is known about the nature of the GIT and the impact of GIT conditions on E. coli, with the aim of broadening our understanding of this complex area of E. coli physiology. We will first review what is currently known from laboratory studies about the mechanisms and regulation of the acid shock responses of E. coli with particular focus on the glutamate-dependent AR system (AR2), including looking at the wide range of different stimuli that appear to lead to induction of components of the AR2 system. We will also consider the question of how E. coli detects low pH. We will then discuss the GIT and the pH of its different compartments and look at the evidence about how well E. coli survives exposure to these compartments (particularly the stomach). We will review what is known about the roles of the AR systems in the gut and how they vary in different “non-laboratory” strains of E. coli, as well as the other factors that may determine survival under acidic conditions. To conclude, we will review the evidence that the acid sensing systems of E. coli also have important roles in other aspects of the colonization and infection processes.
Section snippets
What Do We Mean by Acid Resistance?
An early working definition of AR dates back to the work of Gorden and Small (Gorden & Small, 1993), who described AR as “the percentage of survival of an inoculum exposed to a pH 2.5 for 2 h.” Strains in which more than 10% of the inoculum survived after challenge were considered to be acid-resistant. In most cases, acid-sensitive isolates exhibited less than 0.001% survival after exposure to acid. AR is typically assayed by exposing cells to a pH of 2–2.5 for a particular time, or over a time
The pH Landscape of the Human Gut
The pH of the different compartments of the human gut has been measured in many studies, both in healthy people and in people with various types of gastric disorder (reviewed in Nugent, Kumar, Rampton, and Evans (2001)). The least invasive method for this is by swallowing a radiotelemetric capsule that contains a pH probe, so that the pH can be monitored as it passes through the gut over the course of one to three days (Evans et al., 1988). Conversely, other more invasive methods are needed to
Conclusions
This brief survey of what is known about AR and its potential roles in E. coli survival in the GIT has revealed both the depth of our knowledge about many molecular details of the systems involved and our relative ignorance about the roles they may play in vivo. Different strains of E. coli are capable of displaying a wide range of AR phenotypes, both intrinsically without induction by low pH and after exposure to moderate pH stress. A range of mechanisms exist to mediate these phenotypes and
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