The Ferric Uptake Regulator of Helicobacter Pylori
The Ferric Uptake Regulator of Helicobacter Pylori
Helicobacter pylori is arguably one of the most successful pathogens; it colonizes the stomachs of more than half of the human population. Colonization and persistence in such an inhospitable niche requires the presence of exquisite adaptive mechanisms. One of the proteins that contributes significantly to the remarkable adaptability of H. pylori is the ferric uptake regulator (Fur), which functions as a master regulator of gene expression. In addition to genes directly related to iron homeostasis, Fur controls expression of several enzymes that play a central role in metabolism and energy production. The absence of Fur leads to severe H. pylori colonization defects and, accordingly, several Fur-regulated genes have been shown to be essential for colonization. Moreover, proteins encoded by Fur-regulated genes have a strong impact on redox homeostasis in the stomach and are major determinants of inflammation. In this review, we discuss the main roles of Fur in the biology of H. pylori and highlight the importance of this regulatory protein in the infectious process.
Helicobacter pylori is a human pathogen with a unique capacity to efficiently colonize the hostile environment of the stomach. Gastric colonization by H. pylori induces chronic active gastritis in nearly all infected individuals, but most patients do not develop any apparent clinical signs of infection. However, in a subset of individuals, H. pylori infection progresses from gastritis to more severe upper gastrointestinal disorders such as peptic ulcers, mucosa-associated lymphoid tissue lymphoma or gastric adenocarcinoma. The reasons why certain individuals develop clinical disease while the majority of people remain asymptomatic are poorly understood. However, some progress has been made in the identification of factors that affect the wide range of disease states observed. Interestingly, these factors are multifactorial and include bacterial, host and environmental elements. Among the identified bacterial factors, the expression of the cytotoxin-associated protein CagA and the vacuolating cytotoxin VacA have been shown to be major contributors to disease severity. For example, CagA-positive H. pylori strains are at least twice as likely to cause cancer as H. pylori strains without CagA. From the environmental perspective, diets rich in salt, pickled or smoked foods, or saturated fat, as well as the consumption of alcoholic beverages, exacerbate the severity of the infection symptoms. On the other hand, several studies examining host factors indicate that H. pylori is more likely to cause peptic ulcers in people with blood type O, while those with blood type A are more likely to develop gastric cancer.
According to the WHO, gastric cancer is the second most common cause of cancer-related death in the world, responsible for up to 736,000 deaths in 2008. Of note, it is estimated that H. pylori infection is responsible for 5.5% of all global cancers and 65% of gastric cancers worldwide. The prevalence of H. pylori infection ranges from 20% in industrialized countries to more than 90% in the developing world, which makes H. pylori the most prevalent infection worldwide. Currently, treatment of H. pylori infection involves triple therapy with a proton pump inhibitor or ranitidine, combined with clarithromycin and amoxicillin or metronidazole. However, the rapid increase in antibiotic resistance may soon require the use of quadruple therapy. The complexity of the eradication therapy and the cost of these drugs is often excessive in nations where H. pylori is endemic, and thus often results in poor patient compliance. Moreover, even successful eradication therapy does not protect the host from potential reinfection nor prevent asymptomatic infected individuals who do not realize that they need treatment from ultimately developing gastric cancer. Therefore, the identification of potential new drugs and new drug targets, along with the development of effective vaccines to prevent or cure chronic H. pylori infection, constitute a fundamental area of research. This endeavor demands a profound understanding of H. pylori pathogenesis and virulence factors.
As with many other organisms, H. pylori regulates gene expression in response to environmental change. To achieve this, H. pylori is equipped with a rather limited repertoire of response regulators and two component systems. Control of iron homeostasis is mediated by the ferric uptake regulator (Fur), which essentially regulates transcription of genes involved in iron acquisition and storage in response to changes in iron availability. However, Fur also regulates gene expression in response to low pH, oxidative stress and salt. Thus, this iron-sensing protein is actually a global regulator of gene expression in H. pylori that contributes significantly to the unique plasticity that is characteristic of this bacterium. In keeping with this, Fur has been shown to be important for survival under stressful conditions other than iron limitation. Consequently, the Fur regulon includes genes involved in acid acclimation, resistance to oxygen reactive species and nitrogen metabolism. Therefore, collectively, Fur plays a key role in the adaptation of H. pylori to the hostile conditions that exist in the stomach. In H. pylori, as well as other pathogenic bacteria such as Staphylococcus aureus,Campylobacter jejuniListeria monocytogenes,Actinobacillus pleuropneumoniae,Bacillus cereus and Vibrio cholerae, inactivation of the fur locus leads to reduced virulence of the corresponding mutants. Hence, Fur plays a critical role in bacterial pathogenesis. In the present review, we summarize the diverse means by which Fur maintains the intracellular iron balance in H. pylori, and discuss the importance of this regulatory protein in H. pylori colonization of the stomach.
Abstract and Introduction
Abstract
Helicobacter pylori is arguably one of the most successful pathogens; it colonizes the stomachs of more than half of the human population. Colonization and persistence in such an inhospitable niche requires the presence of exquisite adaptive mechanisms. One of the proteins that contributes significantly to the remarkable adaptability of H. pylori is the ferric uptake regulator (Fur), which functions as a master regulator of gene expression. In addition to genes directly related to iron homeostasis, Fur controls expression of several enzymes that play a central role in metabolism and energy production. The absence of Fur leads to severe H. pylori colonization defects and, accordingly, several Fur-regulated genes have been shown to be essential for colonization. Moreover, proteins encoded by Fur-regulated genes have a strong impact on redox homeostasis in the stomach and are major determinants of inflammation. In this review, we discuss the main roles of Fur in the biology of H. pylori and highlight the importance of this regulatory protein in the infectious process.
Introduction
Helicobacter pylori is a human pathogen with a unique capacity to efficiently colonize the hostile environment of the stomach. Gastric colonization by H. pylori induces chronic active gastritis in nearly all infected individuals, but most patients do not develop any apparent clinical signs of infection. However, in a subset of individuals, H. pylori infection progresses from gastritis to more severe upper gastrointestinal disorders such as peptic ulcers, mucosa-associated lymphoid tissue lymphoma or gastric adenocarcinoma. The reasons why certain individuals develop clinical disease while the majority of people remain asymptomatic are poorly understood. However, some progress has been made in the identification of factors that affect the wide range of disease states observed. Interestingly, these factors are multifactorial and include bacterial, host and environmental elements. Among the identified bacterial factors, the expression of the cytotoxin-associated protein CagA and the vacuolating cytotoxin VacA have been shown to be major contributors to disease severity. For example, CagA-positive H. pylori strains are at least twice as likely to cause cancer as H. pylori strains without CagA. From the environmental perspective, diets rich in salt, pickled or smoked foods, or saturated fat, as well as the consumption of alcoholic beverages, exacerbate the severity of the infection symptoms. On the other hand, several studies examining host factors indicate that H. pylori is more likely to cause peptic ulcers in people with blood type O, while those with blood type A are more likely to develop gastric cancer.
According to the WHO, gastric cancer is the second most common cause of cancer-related death in the world, responsible for up to 736,000 deaths in 2008. Of note, it is estimated that H. pylori infection is responsible for 5.5% of all global cancers and 65% of gastric cancers worldwide. The prevalence of H. pylori infection ranges from 20% in industrialized countries to more than 90% in the developing world, which makes H. pylori the most prevalent infection worldwide. Currently, treatment of H. pylori infection involves triple therapy with a proton pump inhibitor or ranitidine, combined with clarithromycin and amoxicillin or metronidazole. However, the rapid increase in antibiotic resistance may soon require the use of quadruple therapy. The complexity of the eradication therapy and the cost of these drugs is often excessive in nations where H. pylori is endemic, and thus often results in poor patient compliance. Moreover, even successful eradication therapy does not protect the host from potential reinfection nor prevent asymptomatic infected individuals who do not realize that they need treatment from ultimately developing gastric cancer. Therefore, the identification of potential new drugs and new drug targets, along with the development of effective vaccines to prevent or cure chronic H. pylori infection, constitute a fundamental area of research. This endeavor demands a profound understanding of H. pylori pathogenesis and virulence factors.
As with many other organisms, H. pylori regulates gene expression in response to environmental change. To achieve this, H. pylori is equipped with a rather limited repertoire of response regulators and two component systems. Control of iron homeostasis is mediated by the ferric uptake regulator (Fur), which essentially regulates transcription of genes involved in iron acquisition and storage in response to changes in iron availability. However, Fur also regulates gene expression in response to low pH, oxidative stress and salt. Thus, this iron-sensing protein is actually a global regulator of gene expression in H. pylori that contributes significantly to the unique plasticity that is characteristic of this bacterium. In keeping with this, Fur has been shown to be important for survival under stressful conditions other than iron limitation. Consequently, the Fur regulon includes genes involved in acid acclimation, resistance to oxygen reactive species and nitrogen metabolism. Therefore, collectively, Fur plays a key role in the adaptation of H. pylori to the hostile conditions that exist in the stomach. In H. pylori, as well as other pathogenic bacteria such as Staphylococcus aureus,Campylobacter jejuniListeria monocytogenes,Actinobacillus pleuropneumoniae,Bacillus cereus and Vibrio cholerae, inactivation of the fur locus leads to reduced virulence of the corresponding mutants. Hence, Fur plays a critical role in bacterial pathogenesis. In the present review, we summarize the diverse means by which Fur maintains the intracellular iron balance in H. pylori, and discuss the importance of this regulatory protein in H. pylori colonization of the stomach.
