The HopQ-CEACAM Interaction Controls CagA Translocation, Phosphorylation, and Phagocytosis of <italic toggle="yes">Helicobacter pylori</italic> in Neutrophils

ABSTRACT The cag type IV secretion system (cag-T4SS) of Helicobacter pylori exploits specific cellular carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), such as CEACAM1, -3, -5, and -6, as cellular receptors for CagA translocation into human gastric epithelial cells. We studied the...

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Autores principales:	Ina-Kristin Behrens, Benjamin Busch, Hellen Ishikawa-Ankerhold, Pia Palamides, John E. Shively, Cliff Stanners, Carlos Chan, Nelly Leung, Scott Gray-Owen, Rainer Haas
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Helicobacter pylori cag-type IV secretion system CagA translocation tyrosine-phosphorylation phagocytosis neutrophils Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ddb179f2f9174e459c0be8f3bc5d3a80
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spelling	oai:doaj.org-article:ddb179f2f9174e459c0be8f3bc5d3a802021-11-15T15:56:57ZThe HopQ-CEACAM Interaction Controls CagA Translocation, Phosphorylation, and Phagocytosis of <italic toggle="yes">Helicobacter pylori</italic> in Neutrophils10.1128/mBio.03256-192150-7511https://doaj.org/article/ddb179f2f9174e459c0be8f3bc5d3a802020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03256-19https://doaj.org/toc/2150-7511ABSTRACT The cag type IV secretion system (cag-T4SS) of Helicobacter pylori exploits specific cellular carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), such as CEACAM1, -3, -5, and -6, as cellular receptors for CagA translocation into human gastric epithelial cells. We studied the interaction of H. pylori with human CEACAM1, CEACAM3, and CEACAM6 receptors (hCEACAMs) expressed on myeloid cells from CEACAM-humanized mice. Human and CEACAM-humanized mouse polymorphonuclear neutrophils (PMNs) allowed a specific HopQ-dependent interaction strongly enhancing CagA translocation. Translocated CagA was tyrosine phosphorylated, which was not seen in wild-type (wt) murine neutrophils. In contrast, human or murine bone marrow-derived macrophages and dendritic cells (DCs) revealed a low hCEACAM expression and bacterial binding. CagA translocation and tyrosine-phosphorylation was low and independent of the HopQ-CEACAM interaction. Neutrophils, but not macrophages or DCs, from CEACAM-humanized mice, significantly upregulated the proinflammatory chemokine MIP-1α. However, macrophages showed a significantly reduced amount of CXCL1 (KC) and CCL2 (MCP-1) secretion in CEACAM-humanized versus wt cells. Thus, H. pylori, via the HopQ-CEACAM interaction, controls the production and secretion of chemokines differently in PMNs, macrophages, and DCs. We further show that upon H. pylori contact the oxidative burst of neutrophils and phagocytosis of H. pylori was strongly enhanced, but hCEACAM3/6 expression on neutrophils allowed the extended survival of H. pylori within neutrophils in a HopQ-dependent manner. Finally, we demonstrate that during a chronic mouse infection, H. pylori is able to systemically downregulate hCEACAM1 and hCEACAM6 receptor expression on neutrophils, probably to limit CagA translocation efficiency and most likely gastric pathology. IMPORTANCE Helicobacter pylori is highly adapted to humans and evades host immunity to allow its lifelong colonization. However, the H. pylori mouse model is artificial for H. pylori, and few adapted strains allow gastric colonization. Here, we show that human or CEACAM-humanized, but not mouse neutrophils are manipulated by the H. pylori HopQ-CEACAM interaction. Human CEACAMs are responsible for CagA phosphorylation, activation, and processing in neutrophils, whereas CagA translocation and tyrosine phosphorylation in DCs and macrophages is independent of the HopQ-CEACAM interaction. H. pylori affects the secretion of distinct chemokines in CEACAM-humanized neutrophils and macrophages. Most importantly, human CEACAMs on neutrophils enhance binding, oxidative burst, and phagocytosis of H. pylori and enhance bacterial survival in the phagosome. The H. pylori-CEACAM interaction modulates PMNs to reduce the H. pylori CagA translocation efficiency in vivo and to fine-tune the expression of CEACAM receptors on neutrophils to limit translocation of CagA and gastric pathology.Ina-Kristin BehrensBenjamin BuschHellen Ishikawa-AnkerholdPia PalamidesJohn E. ShivelyCliff StannersCarlos ChanNelly LeungScott Gray-OwenRainer HaasAmerican Society for MicrobiologyarticleHelicobacter pyloricag-type IV secretion systemCagA translocationtyrosine-phosphorylationphagocytosisneutrophilsMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Helicobacter pylori cag-type IV secretion system CagA translocation tyrosine-phosphorylation phagocytosis neutrophils Microbiology QR1-502
spellingShingle	Helicobacter pylori cag-type IV secretion system CagA translocation tyrosine-phosphorylation phagocytosis neutrophils Microbiology QR1-502 Ina-Kristin Behrens Benjamin Busch Hellen Ishikawa-Ankerhold Pia Palamides John E. Shively Cliff Stanners Carlos Chan Nelly Leung Scott Gray-Owen Rainer Haas The HopQ-CEACAM Interaction Controls CagA Translocation, Phosphorylation, and Phagocytosis of <italic toggle="yes">Helicobacter pylori</italic> in Neutrophils
description	ABSTRACT The cag type IV secretion system (cag-T4SS) of Helicobacter pylori exploits specific cellular carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), such as CEACAM1, -3, -5, and -6, as cellular receptors for CagA translocation into human gastric epithelial cells. We studied the interaction of H. pylori with human CEACAM1, CEACAM3, and CEACAM6 receptors (hCEACAMs) expressed on myeloid cells from CEACAM-humanized mice. Human and CEACAM-humanized mouse polymorphonuclear neutrophils (PMNs) allowed a specific HopQ-dependent interaction strongly enhancing CagA translocation. Translocated CagA was tyrosine phosphorylated, which was not seen in wild-type (wt) murine neutrophils. In contrast, human or murine bone marrow-derived macrophages and dendritic cells (DCs) revealed a low hCEACAM expression and bacterial binding. CagA translocation and tyrosine-phosphorylation was low and independent of the HopQ-CEACAM interaction. Neutrophils, but not macrophages or DCs, from CEACAM-humanized mice, significantly upregulated the proinflammatory chemokine MIP-1α. However, macrophages showed a significantly reduced amount of CXCL1 (KC) and CCL2 (MCP-1) secretion in CEACAM-humanized versus wt cells. Thus, H. pylori, via the HopQ-CEACAM interaction, controls the production and secretion of chemokines differently in PMNs, macrophages, and DCs. We further show that upon H. pylori contact the oxidative burst of neutrophils and phagocytosis of H. pylori was strongly enhanced, but hCEACAM3/6 expression on neutrophils allowed the extended survival of H. pylori within neutrophils in a HopQ-dependent manner. Finally, we demonstrate that during a chronic mouse infection, H. pylori is able to systemically downregulate hCEACAM1 and hCEACAM6 receptor expression on neutrophils, probably to limit CagA translocation efficiency and most likely gastric pathology. IMPORTANCE Helicobacter pylori is highly adapted to humans and evades host immunity to allow its lifelong colonization. However, the H. pylori mouse model is artificial for H. pylori, and few adapted strains allow gastric colonization. Here, we show that human or CEACAM-humanized, but not mouse neutrophils are manipulated by the H. pylori HopQ-CEACAM interaction. Human CEACAMs are responsible for CagA phosphorylation, activation, and processing in neutrophils, whereas CagA translocation and tyrosine phosphorylation in DCs and macrophages is independent of the HopQ-CEACAM interaction. H. pylori affects the secretion of distinct chemokines in CEACAM-humanized neutrophils and macrophages. Most importantly, human CEACAMs on neutrophils enhance binding, oxidative burst, and phagocytosis of H. pylori and enhance bacterial survival in the phagosome. The H. pylori-CEACAM interaction modulates PMNs to reduce the H. pylori CagA translocation efficiency in vivo and to fine-tune the expression of CEACAM receptors on neutrophils to limit translocation of CagA and gastric pathology.
format	article
author	Ina-Kristin Behrens Benjamin Busch Hellen Ishikawa-Ankerhold Pia Palamides John E. Shively Cliff Stanners Carlos Chan Nelly Leung Scott Gray-Owen Rainer Haas
author_facet	Ina-Kristin Behrens Benjamin Busch Hellen Ishikawa-Ankerhold Pia Palamides John E. Shively Cliff Stanners Carlos Chan Nelly Leung Scott Gray-Owen Rainer Haas
author_sort	Ina-Kristin Behrens
title	The HopQ-CEACAM Interaction Controls CagA Translocation, Phosphorylation, and Phagocytosis of <italic toggle="yes">Helicobacter pylori</italic> in Neutrophils
title_short	The HopQ-CEACAM Interaction Controls CagA Translocation, Phosphorylation, and Phagocytosis of <italic toggle="yes">Helicobacter pylori</italic> in Neutrophils
title_full	The HopQ-CEACAM Interaction Controls CagA Translocation, Phosphorylation, and Phagocytosis of <italic toggle="yes">Helicobacter pylori</italic> in Neutrophils
title_fullStr	The HopQ-CEACAM Interaction Controls CagA Translocation, Phosphorylation, and Phagocytosis of <italic toggle="yes">Helicobacter pylori</italic> in Neutrophils
title_full_unstemmed	The HopQ-CEACAM Interaction Controls CagA Translocation, Phosphorylation, and Phagocytosis of <italic toggle="yes">Helicobacter pylori</italic> in Neutrophils
title_sort	hopq-ceacam interaction controls caga translocation, phosphorylation, and phagocytosis of <italic toggle="yes">helicobacter pylori</italic> in neutrophils
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/ddb179f2f9174e459c0be8f3bc5d3a80
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The HopQ-CEACAM Interaction Controls CagA Translocation, Phosphorylation, and Phagocytosis of <italic toggle="yes">Helicobacter pylori</italic> in Neutrophils

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