Limits...
The host protein calprotectin modulates the Helicobacter pylori cag type IV secretion system via zinc sequestration.

Gaddy JA, Radin JN, Loh JT, Piazuelo MB, Kehl-Fie TE, Delgado AG, Ilca FT, Peek RM, Cover TL, Chazin WJ, Skaar EP, Scott Algood HM - PLoS Pathog. (2014)

Bottom Line: When infected with an H. pylori strain harboring a functional cag T4SS, calprotectin-deficient mice exhibited decreased bacterial burdens and a trend toward increased cag T4SS -dependent inflammation compared to wild-type mice.In vitro data demonstrate that culturing H. pylori with sub-inhibitory doses of CP reduces the activity of the cag T4SS and the biogenesis of cag T4SS-associated pili in a zinc-dependent fashion.Taken together, these data indicate that zinc homeostasis plays a role in regulating the proinflammatory activity of the cag T4SS.

View Article: PubMed Central - PubMed

Affiliation: Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.

ABSTRACT
Transition metals are necessary for all forms of life including microorganisms, evidenced by the fact that 30% of all proteins are predicted to interact with a metal cofactor. Through a process termed nutritional immunity, the host actively sequesters essential nutrient metals away from invading pathogenic bacteria. Neutrophils participate in this process by producing several metal chelating proteins, including lactoferrin and calprotectin (CP). As neutrophils are an important component of the inflammatory response directed against the bacterium Helicobacter pylori, a major risk factor for gastric cancer, it was hypothesized that CP plays a role in the host response to H. pylori. Utilizing a murine model of H. pylori infection and gastric epithelial cell co-cultures, the role CP plays in modifying H. pylori -host interactions and the function of the cag Type IV Secretion System (cag T4SS) was investigated. This study indicates elevated gastric levels of CP are associated with the infiltration of neutrophils to the H. pylori-infected tissue. When infected with an H. pylori strain harboring a functional cag T4SS, calprotectin-deficient mice exhibited decreased bacterial burdens and a trend toward increased cag T4SS -dependent inflammation compared to wild-type mice. In vitro data demonstrate that culturing H. pylori with sub-inhibitory doses of CP reduces the activity of the cag T4SS and the biogenesis of cag T4SS-associated pili in a zinc-dependent fashion. Taken together, these data indicate that zinc homeostasis plays a role in regulating the proinflammatory activity of the cag T4SS.

Show MeSH

Related in: MedlinePlus

Model of H. pylori cag T4SS regulation in response to neutrophil recruitment and deposition of calprotectin at the site of infection.In the presence of available zinc, H. pylori elaborates a functional cag T4SS and translocates CagA into host epithelial cells, resulting in increased NFκB activation and IL-8 secretion. The chemokine IL-8 recruits neutrophils to the site of infection, increasing the amount of CP present. CP sequesters the nutrient zinc away from the bacterial cell, downregulating the activity of the cag T4SS, and thereby decreasing the translocation of CagA, NFκB activation and IL-8 secretion.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4199781&req=5

ppat-1004450-g007: Model of H. pylori cag T4SS regulation in response to neutrophil recruitment and deposition of calprotectin at the site of infection.In the presence of available zinc, H. pylori elaborates a functional cag T4SS and translocates CagA into host epithelial cells, resulting in increased NFκB activation and IL-8 secretion. The chemokine IL-8 recruits neutrophils to the site of infection, increasing the amount of CP present. CP sequesters the nutrient zinc away from the bacterial cell, downregulating the activity of the cag T4SS, and thereby decreasing the translocation of CagA, NFκB activation and IL-8 secretion.

Mentions: Results from these studies indicate that zinc homeostasis plays an important role in regulating the cag T4SS in H. pylori. Previous reports have shown that when H. pylori interacts with gastric epithelial cells, the cag T4SS translocates CagA into host cells leading to activation of c-Src and changes in the cytoskeleton [34]–[36]. A functional cag T4SS also increases the activation of NOD and NFkB [33], which ultimately results in the production of IL-8 and the recruitment of neutrophils [34]–[36]. Based on our results, we propose a model which is presented in Figure 7. In response to H. pylori infection, neutrophils are recruited to the site of infection. CP is deposited, and nutrient manganese and zinc are sequestered. Sequestration of zinc by CP represses cag T4SS pilus formation and CagA translocation, and results in diminished NFκB activation and IL-8 secretion. With reduced IL-8, less inflammation develops and the end result of CP-dependent zinc-sequestration is increased bacterial persistence.


The host protein calprotectin modulates the Helicobacter pylori cag type IV secretion system via zinc sequestration.

Gaddy JA, Radin JN, Loh JT, Piazuelo MB, Kehl-Fie TE, Delgado AG, Ilca FT, Peek RM, Cover TL, Chazin WJ, Skaar EP, Scott Algood HM - PLoS Pathog. (2014)

Model of H. pylori cag T4SS regulation in response to neutrophil recruitment and deposition of calprotectin at the site of infection.In the presence of available zinc, H. pylori elaborates a functional cag T4SS and translocates CagA into host epithelial cells, resulting in increased NFκB activation and IL-8 secretion. The chemokine IL-8 recruits neutrophils to the site of infection, increasing the amount of CP present. CP sequesters the nutrient zinc away from the bacterial cell, downregulating the activity of the cag T4SS, and thereby decreasing the translocation of CagA, NFκB activation and IL-8 secretion.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4199781&req=5

ppat-1004450-g007: Model of H. pylori cag T4SS regulation in response to neutrophil recruitment and deposition of calprotectin at the site of infection.In the presence of available zinc, H. pylori elaborates a functional cag T4SS and translocates CagA into host epithelial cells, resulting in increased NFκB activation and IL-8 secretion. The chemokine IL-8 recruits neutrophils to the site of infection, increasing the amount of CP present. CP sequesters the nutrient zinc away from the bacterial cell, downregulating the activity of the cag T4SS, and thereby decreasing the translocation of CagA, NFκB activation and IL-8 secretion.
Mentions: Results from these studies indicate that zinc homeostasis plays an important role in regulating the cag T4SS in H. pylori. Previous reports have shown that when H. pylori interacts with gastric epithelial cells, the cag T4SS translocates CagA into host cells leading to activation of c-Src and changes in the cytoskeleton [34]–[36]. A functional cag T4SS also increases the activation of NOD and NFkB [33], which ultimately results in the production of IL-8 and the recruitment of neutrophils [34]–[36]. Based on our results, we propose a model which is presented in Figure 7. In response to H. pylori infection, neutrophils are recruited to the site of infection. CP is deposited, and nutrient manganese and zinc are sequestered. Sequestration of zinc by CP represses cag T4SS pilus formation and CagA translocation, and results in diminished NFκB activation and IL-8 secretion. With reduced IL-8, less inflammation develops and the end result of CP-dependent zinc-sequestration is increased bacterial persistence.

Bottom Line: When infected with an H. pylori strain harboring a functional cag T4SS, calprotectin-deficient mice exhibited decreased bacterial burdens and a trend toward increased cag T4SS -dependent inflammation compared to wild-type mice.In vitro data demonstrate that culturing H. pylori with sub-inhibitory doses of CP reduces the activity of the cag T4SS and the biogenesis of cag T4SS-associated pili in a zinc-dependent fashion.Taken together, these data indicate that zinc homeostasis plays a role in regulating the proinflammatory activity of the cag T4SS.

View Article: PubMed Central - PubMed

Affiliation: Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.

ABSTRACT
Transition metals are necessary for all forms of life including microorganisms, evidenced by the fact that 30% of all proteins are predicted to interact with a metal cofactor. Through a process termed nutritional immunity, the host actively sequesters essential nutrient metals away from invading pathogenic bacteria. Neutrophils participate in this process by producing several metal chelating proteins, including lactoferrin and calprotectin (CP). As neutrophils are an important component of the inflammatory response directed against the bacterium Helicobacter pylori, a major risk factor for gastric cancer, it was hypothesized that CP plays a role in the host response to H. pylori. Utilizing a murine model of H. pylori infection and gastric epithelial cell co-cultures, the role CP plays in modifying H. pylori -host interactions and the function of the cag Type IV Secretion System (cag T4SS) was investigated. This study indicates elevated gastric levels of CP are associated with the infiltration of neutrophils to the H. pylori-infected tissue. When infected with an H. pylori strain harboring a functional cag T4SS, calprotectin-deficient mice exhibited decreased bacterial burdens and a trend toward increased cag T4SS -dependent inflammation compared to wild-type mice. In vitro data demonstrate that culturing H. pylori with sub-inhibitory doses of CP reduces the activity of the cag T4SS and the biogenesis of cag T4SS-associated pili in a zinc-dependent fashion. Taken together, these data indicate that zinc homeostasis plays a role in regulating the proinflammatory activity of the cag T4SS.

Show MeSH
Related in: MedlinePlus