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Functional plasticity in the type IV secretion system of Helicobacter pylori.

Barrozo RM, Cooke CL, Hansen LM, Lam AM, Gaddy JA, Johnson EM, Cariaga TA, Suarez G, Peek RM, Cover TL, Solnick JV - PLoS Pathog. (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Center for Comparative Medicine, University of California Davis, Davis, California, United States of America.

ABSTRACT
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.

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H. pylori colonization of rhesus monkeys and mice is associated with changes in the motif structure of the CagY middle repeat region.As in strains J99 and 26695 [19], the predicted amino acid sequence of CagY in WT H. pylori J166 is organized into a 5′ repeat region (residues 9–398), a 3′ region orthologous to VirB10 (residues 1784–2028), and a middle repeat region (residues 715–1512) that is composed of a series of B motifs (yellow) that bracket one to four A motifs (orange). Passage of WT J166 in rhesus monkeys and in mice results in some strains that lose one or more A or B motifs, which is sometimes sufficient to reduce the capacity to induce IL-8 (rOut1 and rOut2; mOut1 and mOut2) and other times is not (rOut3; mOut3 and mOut4).
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ppat-1003189-g006: H. pylori colonization of rhesus monkeys and mice is associated with changes in the motif structure of the CagY middle repeat region.As in strains J99 and 26695 [19], the predicted amino acid sequence of CagY in WT H. pylori J166 is organized into a 5′ repeat region (residues 9–398), a 3′ region orthologous to VirB10 (residues 1784–2028), and a middle repeat region (residues 715–1512) that is composed of a series of B motifs (yellow) that bracket one to four A motifs (orange). Passage of WT J166 in rhesus monkeys and in mice results in some strains that lose one or more A or B motifs, which is sometimes sufficient to reduce the capacity to induce IL-8 (rOut1 and rOut2; mOut1 and mOut2) and other times is not (rOut3; mOut3 and mOut4).

Mentions: Previous analysis of 14 full-length CagY sequences in the NCBI non-redundant protein data base suggested that the MRR is organized into two α-helical principal motifs, which occur in tandem arrays of one to six 38–39 residue A motifs flanked by single copies of a 31 residue B motif [19]. Both principal motifs are made up of three distinct submotifs, which remain invariant in their order. This annotation suggests that CagY variants that are selected in vivo are likely a result of duplication or deletion of principal motif segments, without compromising the underlying submotif composition. To examine this, we first identified the A and B principal amino acid motifs in the CagY MRR of WT H. pylori J166. Similar to other H. pylori strains previously described [19], the CagY MRR of H. pylori J166 is organized into six tandem arrays of one to four A motifs flanked by B motifs (Figure 6). We next examined the motif structure of CagY from rhesus (rOut1-3) and mouse (mOut1-4) output strains that were previously characterized (Figures 2 and 4). All output strains from monkeys and mice with variant cagY alleles had lost one or more A or B motifs, though there were multiple CagY motif structures associated with the same IL-8 phenotype. One output strain each from monkey (rOut1) and from mouse (mOut1), which had both lost the capacity to induce IL-8, had identical motif structures. Interestingly, loss of a single A motif was sufficient to markedly reduce IL-8 induction (rOut2), while loss of 14 A and B motifs (mOut3), representing a reduction in predicted size from 233 kDa to 175 kDa, was not. Although we were unable to identify a motif pattern associated with the IL-8 phenotype, these results suggest that CagY function is based on a higher order structure and not on any critical motif within the MRR.


Functional plasticity in the type IV secretion system of Helicobacter pylori.

Barrozo RM, Cooke CL, Hansen LM, Lam AM, Gaddy JA, Johnson EM, Cariaga TA, Suarez G, Peek RM, Cover TL, Solnick JV - PLoS Pathog. (2013)

H. pylori colonization of rhesus monkeys and mice is associated with changes in the motif structure of the CagY middle repeat region.As in strains J99 and 26695 [19], the predicted amino acid sequence of CagY in WT H. pylori J166 is organized into a 5′ repeat region (residues 9–398), a 3′ region orthologous to VirB10 (residues 1784–2028), and a middle repeat region (residues 715–1512) that is composed of a series of B motifs (yellow) that bracket one to four A motifs (orange). Passage of WT J166 in rhesus monkeys and in mice results in some strains that lose one or more A or B motifs, which is sometimes sufficient to reduce the capacity to induce IL-8 (rOut1 and rOut2; mOut1 and mOut2) and other times is not (rOut3; mOut3 and mOut4).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585145&req=5

ppat-1003189-g006: H. pylori colonization of rhesus monkeys and mice is associated with changes in the motif structure of the CagY middle repeat region.As in strains J99 and 26695 [19], the predicted amino acid sequence of CagY in WT H. pylori J166 is organized into a 5′ repeat region (residues 9–398), a 3′ region orthologous to VirB10 (residues 1784–2028), and a middle repeat region (residues 715–1512) that is composed of a series of B motifs (yellow) that bracket one to four A motifs (orange). Passage of WT J166 in rhesus monkeys and in mice results in some strains that lose one or more A or B motifs, which is sometimes sufficient to reduce the capacity to induce IL-8 (rOut1 and rOut2; mOut1 and mOut2) and other times is not (rOut3; mOut3 and mOut4).
Mentions: Previous analysis of 14 full-length CagY sequences in the NCBI non-redundant protein data base suggested that the MRR is organized into two α-helical principal motifs, which occur in tandem arrays of one to six 38–39 residue A motifs flanked by single copies of a 31 residue B motif [19]. Both principal motifs are made up of three distinct submotifs, which remain invariant in their order. This annotation suggests that CagY variants that are selected in vivo are likely a result of duplication or deletion of principal motif segments, without compromising the underlying submotif composition. To examine this, we first identified the A and B principal amino acid motifs in the CagY MRR of WT H. pylori J166. Similar to other H. pylori strains previously described [19], the CagY MRR of H. pylori J166 is organized into six tandem arrays of one to four A motifs flanked by B motifs (Figure 6). We next examined the motif structure of CagY from rhesus (rOut1-3) and mouse (mOut1-4) output strains that were previously characterized (Figures 2 and 4). All output strains from monkeys and mice with variant cagY alleles had lost one or more A or B motifs, though there were multiple CagY motif structures associated with the same IL-8 phenotype. One output strain each from monkey (rOut1) and from mouse (mOut1), which had both lost the capacity to induce IL-8, had identical motif structures. Interestingly, loss of a single A motif was sufficient to markedly reduce IL-8 induction (rOut2), while loss of 14 A and B motifs (mOut3), representing a reduction in predicted size from 233 kDa to 175 kDa, was not. Although we were unable to identify a motif pattern associated with the IL-8 phenotype, these results suggest that CagY function is based on a higher order structure and not on any critical motif within the MRR.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Center for Comparative Medicine, University of California Davis, Davis, California, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus