title: Diversification of Orientia tsutsugamushi genotypes by intragenic recombination and their potential expansion in endemic areas.
abstract: Scrub typhus is a mite-borne febrile disease caused by O. tsutsugamushi infection. Recently, emergence of scrub typhus has attracted considerable attention in several endemic countries in Asia and the western Pacific. In addition, the antigenic diversity of the intracellular pathogen has been a serious obstacle for developing effective diagnostics and vaccine.
  
  
  
  To understand the evolutionary pathway of genotypic diversification of O. tsutsugamushi and the environmental factors associated with the epidemiological features of scrub typhus, we analyzed sequence data, including spatiotemporal information, of the tsa56 gene encoding a major outer membrane protein responsible for antigenic variation. A total of 324 tsa56 sequences covering more than 85% of its open reading frame were analyzed and classified into 17 genotypes based on phylogenetic relationship. Extensive sequence analysis of tsa56 genes using diverse informatics tools revealed multiple intragenic recombination events, as well as a substantially higher mutation rate than other house-keeping genes. This suggests that genetic diversification occurred via frequent point mutations and subsequent genetic recombination. Interestingly, more diverse bacterial genotypes and dominant vector species prevail in Taiwan compared to other endemic regions. Furthermore, the co-presence of identical and sub-identical clones of tsa56 gene in geographically distant areas implies potential spread of O. tsutsugamushi genotypes.
  
  
  
  Fluctuation and diversification of vector species harboring O. tsutsugamushi in local endemic areas may facilitate genetic recombination among diverse genotypes. Therefore, careful monitoring of dominant vector species, as well as the prevalence of O. tsutsugamushi genotypes may be advisable to enable proper anticipation of epidemiological changes of scrub typhus.
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Gwanghun
authors.initials: G
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Na-Young
authors.initials: NY
authors.lastname: Ha
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Chan-Ki
authors.initials: CK
authors.lastname: Min
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hong-Il
authors.initials: HI
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Nguyen Thi Hai
authors.initials: NT
authors.lastname: Yen
authors.affiliation: Department of Microbiology and Immunology, Jeju National University School of Medicine, Jeju, Republic of Korea.
authors.forename: Keun-Hwa
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Environmental Health Center, University of Ulsan College of Medicine, Ulsan, Republic of Korea.
authors.forename: Inbo
authors.initials: I
authors.lastname: Oh
authors.affiliation: Department of Microbiology, Inha University School of Medicine, Incheon, Republic of Korea.
authors.forename: Jae-Seung
authors.initials: JS
authors.lastname: Kang
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Myung-Sik
authors.initials: MS
authors.lastname: Choi
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ik-Sang
authors.initials: IS
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.|Institute of Endemic Disease, Seoul National University Medical Research Center and Bundang Hospital, Seoul, Republic of Korea.
authors.forename: Nam-Hyuk
authors.identifier: 0000-0003-3673-6397
authors.initials: NH
authors.lastname: Cho
mesh_terms: D000940:Antigenic Variation; D000942:Antigens, Bacterial / Q000235:genetics; D001208:Asia / Q000453:epidemiology; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics; D019353:Endemic Diseases; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D059645:Mutation Rate; D012285:Orientia tsutsugamushi / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification; D011995:Recombination, Genetic; D012612:Scrub Typhus / Q000453:epidemiology* / Q000382:microbiology*; D017422:Sequence Analysis, DNA; D062211:Spatio-Temporal Analysis
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins