Characterisation of worldwide Helicobacter pylori strains reveals genetic conservation and essentiality of serine protease HtrA |
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| Authors: | Nicole Tegtmeyer Yoshan Moodley Yoshio Yamaoka Sandy Ramona Pernitzsch Vanessa Schmidt Francisco Rivas Traverso Thomas P Schmidt Roland Rad Khay Guan Yeoh Ho Bow Javier Torres Markus Gerhard Gisbert Schneider Silja Wessler Steffen Backert |
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| Institution: | 1. Lehrstuhl für Mikrobiologie, Friedrich‐Alexander‐Universit?t Erlangen‐Nürnberg, Erlangen, Germany;2. Institut für Medizinische Mikrobiologie, Otto‐von‐Guericke Universit?t Magdeburg, Magdeburg, Germany;3. Department of Zoology, University of Venda, Thohoyandou, South Africa;4. Konrad‐Lorenz‐Institut für Vergleichende Verhaltensforschung, Department für Integrative Biologie und Evolution, Veterin?rmedizinische Universit?t Wien, Wien, Austria;5. Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Dept. Medicine‐Gastroenterology, Houston, TX, USA;6. Oita University Faculty of Medicine, Dept. Environmental and Preventive Medicine, Yufu, Japan;7. Research Center for Infectious Diseases (ZINF), University of Würzburg, Würzburg, Germany;8. Department of Molecular Biology, Division of Microbiology, Paris‐Lodron University of Salzburg, Salzburg, Austria;9. II Medical Department, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany;10. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany;11. Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore;12. Unidad de Investigacion en Enfermedades Infecciosas, UMAE Pediatria, IMSS, Mexico City, Mexico;13. Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universit?t München, Munich, Germany;14. ETH Zürich, Institut für Pharmazeutische Wissenschaften, Zürich, Switzerland |
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| Abstract: | HtrA proteases and chaperones exhibit important roles in periplasmic protein quality control and stress responses. The genetic inactivation of htrA has been described for many bacterial pathogens. However, in some cases such as the gastric pathogen Helicobacter pylori, HtrA is secreted where it cleaves the tumour‐suppressor E‐cadherin interfering with gastric disease development, but the generation of htrA mutants is still lacking. Here, we show that the htrA gene locus is highly conserved in worldwide strains. HtrA presence was confirmed in 992 H. pylori isolates in gastric biopsy material from infected patients. Differential RNA‐sequencing (dRNA‐seq) indicated that htrA is encoded in an operon with two subsequent genes, HP1020 and HP1021. Genetic mutagenesis and complementation studies revealed that HP1020 and HP1021, but not htrA, can be mutated. In addition, we demonstrate that suppression of HtrA proteolytic activity with a newly developed inhibitor is sufficient to effectively kill H. pylori, but not other bacteria. We show that Helicobacter htrA is an essential bifunctional gene with crucial intracellular and extracellular functions. Thus, we describe here the first microbe in which htrA is an indispensable gene, a situation unique in the bacterial kingdom. HtrA can therefore be considered a promising new target for anti‐bacterial therapy. |
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