PLoS Pathogens (2014-10-01)

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

  • Jennifer A Gaddy,
  • Jana N Radin,
  • John T Loh,
  • M Blanca Piazuelo,
  • Thomas E Kehl-Fie,
  • Alberto G Delgado,
  • Florin T Ilca,
  • Richard M Peek,
  • Timothy L Cover,
  • Walter J Chazin,
  • Eric P Skaar,
  • Holly M Scott Algood

Journal volume & issue
Vol. 10, no. 10
p. e1004450


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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.