Aggregatibacter actinomycetemcomitans • Anders Johansson and Joseph M. DiRienzo Aggregatibacter actinomycetemcomitans Gram-Negative Bacterial Pathogen Edited by Anders Johansson and Joseph M. DiRienzo Printed Edition of the Special Issue Published in Pathogens www.mdpi.com/journal/pathogens Aggregatibacter actinomycetemcomitans— Gram-Negative Bacterial Pathogen Aggregatibacter actinomycetemcomitans— Gram-Negative Bacterial Pathogen Editors Anders Johansson Joseph M. DiRienzo MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade • Manchester • Tokyo • Cluj • Tianjin Editors Anders Johansson Joseph M. DiRienzo Umea˚ University University of Pennsylvania Sweden USA Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Pathogens (ISSN 2076-0817) (available at: https://www.mdpi.com/journal/pathogens/special issues/Aggregatibacter actinomycetemcomitans). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03943-376-6 (Pbk) ISBN 978-3-03943-377-3 (PDF) c 2020 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Editors .............................................. vii Preface to ”Aggregatibacter actinomycetemcomitans—Gram-Negative Bacterial Pathogen” .. ix Jan Oscarsson, Joseph M. DiRienzo and Anders Johansson Editorial Comments to the Special Issue: “Aggregatibacter actinomycetemcomitans—Gram-Negative Bacterial Pathogen” Reprinted from: Pathogens 2020, 9, 441, doi:10.3390/pathogens9060441 ............... 1 Daniel H. Fine, Helen Schreiner and Senthil Kumar Velusamy Aggregatibacter, a Low Abundance Pathobiont That Influences Biogeography, Microbial Dysbiosis, and Host Defense Capabilities in Periodontitis: The History of a Bug, and Localization of Disease Reprinted from: Pathogens 2020, 9, 179, doi:10.3390/pathogens9030179 ............... 7 Niels Nørskov-Lauritsen, Rolf Claesson, Anne Birkeholm Jensen, Carola H¨oglund Aberg˚ and Dorte Haubek Aggregatibacter Actinomycetemcomitans: Clinical Significance of a Pathobiont Subjected to Ample Changes in Classification and Nomenclature Reprinted from: Pathogens 2019, 8, 243, doi:10.3390/pathogens8040243 ............... 33 Georgios N. Belibasakis, Terhi Maula, Kai Bao, Mark Lindholm, Nagihan Bostanci, Jan Oscarsson, Riikka Ihalin and Anders Johansson Virulence and Pathogenicity Properties of Aggregatibacter actinomycetemcomitans Reprinted from: Pathogens 2019, 8, 222, doi:10.3390/pathogens8040222 ............... 51 Alexandra St¨ahli,Anton Sculean and Sigrun Eick JP2 Genotype of Aggregatibacter actinomycetemcomitans in Caucasian Patients: A Presentation of Two Cases Reprinted from: Pathogens 2020, 9, 178, doi:10.3390/pathogens9030178 ............... 75 Ellen S. Ando-Suguimoto, Manjunatha R. Benakanakere, Marcia P.A. Mayer and Denis F. Kinane Distinct Signaling Pathways Between Human Macrophages and Primary Gingival Epithelial Cells by Aggregatibacter actinomycetemcomitans Reprinted from: Pathogens 2020, 9, 248, doi:10.3390/pathogens9040248 ............... 85 Sanae Akkaoui, Anders Johansson, Maˆamar Yagoubi, Dorte Haubek, Adnane El hamidi, Sana Rida, Rolf Claesson and OumKeltoum Ennibi Chemical Composition, Antimicrobial activity, In Vitro Cytotoxicity and Leukotoxin Neutralization of Essential Oil from Origanum vulgare against Aggregatibacter actinomycetemcomitans Reprinted from: Pathogens 2020, 9, 192, doi:10.3390/pathogens9030192 ............... 99 Edward T Lally, Kathleen Boesze-Battaglia, Anuradha Dhingra, Nestor M Gomez, Jinery Lora, Claire H Mitchell, Alexander Giannakakis, Syed A Fahim, Roland Benz and Nataliya Balashova Aggregatibacter actinomycetemcomitans LtxA Hijacks Endocytic Trafficking Pathways in Human Lymphocytes Reprinted from: Pathogens 2020, 9, 74, doi:10.3390/pathogens9020074 ................113 v Bruce J. Shenker, Lisa M. Walker, Ali Zekavat, Robert H. Weiss and Kathleen Boesze-Battaglia The Cell-Cycle Regulatory Protein p21CIP1/WAF1 Is Required for Cytolethal Distending Toxin (Cdt)-Induced Apoptosis Reprinted from: Pathogens 2020, 9, 38, doi:10.3390/pathogens9010038 ................137 Natalia O. Tjokro, Weerayuth Kittichotirat, Annamari Torittu, Riikka Ihalin, Roger E. Bumgarner and Casey Chen Transcriptomic Analysis of Aggregatibacter actinomycetemcomitans Core and Accessory Genes in Different Growth Conditions Reprinted from: Pathogens 2019, 8, 282, doi:10.3390/pathogens8040282 ...............157 Arzu Beklen, Annamari Torittu, Riikka Ihalin and Marja Poll¨anen¨ Aggregatibacter actinomycetemcomitans Biofilm Reduces Gingival Epithelial Cell Keratin Expression in an Organotypic Gingival Tissue Culture Model Reprinted from: Pathogens 2019, 8, 278, doi:10.3390/pathogens8040278 ...............171 Signe Nedergaard, Carl M. Kobel, Marie B. Nielsen, Rikke T. Møller, Anne B. Jensen and Niels Nørskov-Lauritsen Whole Genome Sequencing of Aggregatibacter actinomycetemcomitans Cultured from Blood Stream Infections Reveals Three Major Phylogenetic Groups Including a Novel Lineage Expressing Serotype a Membrane O Polysaccharide Reprinted from: Pathogens 2019, 8, 256, doi:10.3390/pathogens8040256 ...............181 Anne Birkeholm Jensen, Marianne Lund, Niels Nørskov-Lauritsen, Anders Johansson, Rolf Claesson, Jesper Reinholdt and Dorte Haubek Differential Cell Lysis Among Periodontal Strains of JP2 and Non-JP2 Genotype of Aggregatibacter actinomycetemcomitans Serotype B Is Not Reflected in Dissimilar Expression and Production of Leukotoxin Reprinted from: Pathogens 2019, 8, 211, doi:10.3390/pathogens8040211 ...............191 Anders Johansson, Rolf Claesson, Carola H¨oglund Aberg,˚ Dorte Haubek, Mark Lindholm, Sarah Jasim and Jan Oscarsson Genetic Profiling of Aggregatibacter actinomycetemcomitans Serotype B Isolated from Periodontitis Patients Living in Sweden Reprinted from: Pathogens 2019, 8, 153, doi:10.3390/pathogens8030153 ...............205 Nataliya Balashova In Memoriam: Edward “Ned” Lally Reprinted from: Pathogens 2020, 9, 177, doi:10.3390/pathogens9030177 ...............219 vi About the Editors Anders Johansson (Ph.D., Associate Professor) is a docent in experimental periodontology and has been active for several decades at Umea˚ university. His major research topics have been interactions between A. actinomycetemcomitans and leukocytes. Dr. Johansson and his co-workers have discovered active processes in the leukocytes that have been induced by the leukotoxin, like neutrophil degranulation and inflammasome activation in macrophages. His research has also involved clinical studies that contributed to clarifying the role of enhanced leukotoxin production for disease progression. Joseph M. DiRienzo (Ph.D., Emeritus Professor) received a Ph.D. in Microbiology from McGill University and postdoctoral training in the Department of Biochemistry at the State University of New York at Stony Brook. He recently retired, after 40 years of teaching and research, from the School of Dental Medicine at the University of Pennsylvania. Dr. DiRienzo studied the role of bacteria in the pathogenesis of periodontal diseases using molecular biology and biochemical approaches to identify and characterize virulence genes and their gene products from Aggregatibacter (Actinobacillus) actinomycetemcomitans. Studies were focused on the characterization of the cytolethal distending toxin and its effects on oral epithelial cells. Dr. DiRienzo also studied the role of horizontal gene transfer in the dissemination of virulence genes in A. actinomycetemcomitans. vii Preface to ”Aggregatibacter actinomycetemcomitans— Gram-Negative Bacterial Pathogen” Aggregatibacter actinomycetemcomitans, a member of the Gram-negative taxonomic family Pasteurellaceae, has attracted considerable attention as a potentially important pathogen in specific forms of periodontal disease and has earned a reputation as a member of the HACEK group of bacteria associated with some cases of infective endocarditis. The bacterium has acquired an impressive virulence-related armamentarium, including two well-characterized cytotoxins, exoenzymes, adhesins, and signaling molecules that promote its colonization and the perturbation of the tissues, structural cells, and inflammatory cells of the human oral cavity. This Special Issue focuses on the properties and activities of A. actinomycetemcomitans that promote its function as an infectious agent, that is, its ability to target specific host populations and define its interactions with specific mucosal tissues and cells. The objective is to present a complete picture of the participation of this bacterium in disease by presenting both in vitro and in vivo experimental and clinical studies. A comprehensive view of the contribution of this bacterium to the mechanisms of infection and disease should also provide a basis for the development of new control strategies that move beyond the classical antibiotics. Anders Johansson, Joseph M. DiRienzo Editors ix pathogens Editorial Editorial Comments to the