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.
Highlights
Helicobacter pylori is a Gram-negative bacterial pathogen that colonizes half of the world’s population and contributes to a variety of disease outcomes, including peptic or duodenal ulcer disease, gastric adenocarcinoma, and mucosal-associated lymphoid tissue (MALT) lymphoma [1]
We demonstrate that H. pylori-infected CP-deficient mice (A92/2 mice) have decreased bacterial burden and a trend towards increased gastric inflammation compared to infected WT mice, a phenotype which is not observed in mice infected with an H. pylori isogenic cagE mutant, which lacks cag T4SS activity
In order to determine if CP is elevated in the context of H. pylori infection, real-time RT-PCR analysis of s100a8 and s100a9 transcripts in RNA isolated from either mouse or human gastric tissue was performed
Summary
Helicobacter pylori is a Gram-negative bacterial pathogen that colonizes half of the world’s population and contributes to a variety of disease outcomes, including peptic or duodenal ulcer disease, gastric adenocarcinoma, and mucosal-associated lymphoid tissue (MALT) lymphoma [1]. H. pylori-induced gastritis is characterized by neutrophil and mononuclear leukocyte infiltration to the lamina propria, involving cells in both the innate and adaptive arms of the immune response This gastric mucosal inflammatory response to H. pylori is enhanced if persons are infected with strains that possess a cagtype IV secretion system (cag T4SS). The cag T4SS is a macromolecular assembly that is responsible for translocating the oncogenic effector molecule, CagA and peptidoglycan, into host cells [3,4] These translocated effectors elicit a variety of host cell responses, including activation of nuclear factor kB (NFkB) and secretion of the proinflammatory cytokines, IL-1b and IL-8 [5,6,7,8].
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