Research Article: Functional Plasticity in the Type IV Secretion System of Helicobacter pylori

Date Published: February 28, 2013

Publisher: Public Library of Science

Author(s): Roberto M. Barrozo, Cara L. Cooke, Lori M. Hansen, Anna M. Lam, Jennifer A. Gaddy, Elizabeth M. Johnson, Taryn A. Cariaga, Giovanni Suarez, Richard M. Peek, Timothy L. Cover, Jay V. Solnick, Raphael H. Valdivia.


Helicobacter pylori causes clinical disease primarily in those individuals infected with a strain that carries the cytotoxin associated gene pathogenicity island (cagPAI). The cagPAI encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into epithelial cells and is required for induction of the pro-inflammatory cytokine, interleukin-8 (IL-8). CagY is an essential component of the H. pylori T4SS that has an unusual sequence structure, in which an extraordinary number of direct DNA repeats is predicted to cause rearrangements that invariably yield in-frame insertions or deletions. Here we demonstrate in murine and non-human primate models that immune-driven host selection of rearrangements in CagY is sufficient to cause gain or loss of function in the H. pylori T4SS. We propose that CagY functions as a sort of molecular switch or perhaps a rheostat that alters the function of the T4SS and “tunes” the host inflammatory response so as to maximize persistent infection.

Partial Text

Helicobacter pylori commonly infects the human gastric epithelium and sometimes causes peptic ulcer disease or gastric cancer, which is the second most common cause of cancer death worldwide. The H. pylori virulence locus most strongly associated with clinical disease, rather than asymptomatic infection, is the cag pathogenicity island (cagPAI). The 40-kb cagPAI consists of approximately 27 genes, several of which encode a type IV secretion system (T4SS) that binds β1 integrins [1], [2] and translocates the CagA oncoprotein into gastric epithelial cells [3]. Phosphorylated and nonphosphorylated forms of intracellular CagA cause complex changes in host-cell signaling that lead to epithelial cell elongation [4], disruption of tight junctions [5], and alteration of cell polarity [6], [7]. The T4SS is also required for induction of interleukin-8 (IL-8), a member of the CXC cytokine family, which has long been used as a convenient assay to characterize the inflammatory potential of H. pylori strains [8], [9]. It has been proposed that IL-8 induction is mediated by cagPAI-dependent translocation of peptidoglycan, activation of nucleotide-binding oligomerization domain 1 (NOD1), and stimulation of NF-κB [10]. However, this remains controversial, as some have suggested that IL-8 and other NF-κB-dependent proinflammatory responses are mediated primarily by toll like receptors and MyD88, rather than NOD1 [11]. Very recently, a NOD1- and CagA-independent pathway of IL-8 induction has also been described [12].

The capacity to evade or circumvent host defense is considered a signature of pathogenic bacteria that distinguishes them from closely related commensals [36]. The mechanisms by which this occurs are varied, and they include elaboration of toxins that inhibit the function of immune cells, iron sequestration, antigenic variation of surface structures, intracellular invasion, and inducing host expression of immunosuppressive cytokines, to name just a few. But bacterial pathogens not only avoid host immune responses, they also sometimes exploit them. This is perhaps best understood for infection with Salmonella enterica serotype Typhimurium, where the T3SS-dependent host inflammatory response is required for colonization of mice [37]. Inflammation generates tetrathionate, an electron acceptor that can be used by S. Typhimurium but not by competing microbiota [38]. Inflammation also induces epithelial cells to express lipocalin-2 and calprotectin, which sequester iron and zinc from the gut microbiota but not from S. Typhimurium because it expresses specialized high affinity metal transporters [39], [40]. Thus, from the bacterial point of view, the host inflammatory response can be both deleterious and advantageous.




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