This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.A number of pathogens such as H. pylori, Campylobacter sp. and Bacillus anthracis can cause serious and even lethal disease states in humans by invading the host through the highly acidic environment of the stomach. While the post-colonization defense mechanism used by individual microorganisms to survive this hostile environment may be known well characterized, it is not as clear how the organisms survive the 'transit time' necessary to establish those conditions favorable to disease. Indeed, it is well known that several of the microorganisms can be killed by brief exposure to HCl at pH ? 4.0. During the transit time, proteins could be exposed to an HCl rich, acidic environment for significant periods of time These conditions are more than sufficient to inactivate many proteins. This raises the question as to how these organisms survive the transit time without necessarily benefiting from 'pre-incubations' that are normally required for a strong acid tolerance response. Long-term goals of the research are to study the mechanism by which proteins maintain their biological activity in highly acidic environments. We propose to use the periplasmic redox protein systems of the genus Thiobacillus as a model system to study protein structure-function and stability in low pH environments. We choose this model because; 1) it avoids the need to work directly with pathogens, 2) several species within the Thiobacillus genus are capable of growth at pH ranging as low as 0.8, 3) the redox reactions offer easy to assay biological activities, and 4) the conditions experienced by the thiobacilli during growth on sulfur containing substrates are a good representation of the pH of the gastric environment. Hence the information gained in this study should be directly applicable to the pathogenic species.
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