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Francisella tularensis: persistence, dissemination and source attribution: a theoretical and computational approach
Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Swedish Defence Research Agency. (Anders Johansson)
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The bacterium Francisella tularensis causing tularemia in humans and other mammals displays little genetic diversity among genomes across temporal and spatial scales. F. tularensis infects humans with an extremely low infectious dose and causes natural seasonal tularemia outbreaks. During the Cold War, this bacterium was developed as a biological weapon.

In paper I, we aimed at investigating the genetic diversity of F. tularensis over space and time and were especially interested in the influence of spatial dispersal on the genetic diversity. By analyses of single-nucleotide polymorphisms (SNPs) among 205 F. tularensis genomes, we found that tularemia had moved from East to West over the European continent by dispersal patterns characterized by multiple long-range dispersal events. Evolutionary rate estimates based on the year of bacterial isolation from 1947 to 2012 indicated non-measurable rates. In outbreak areas with multiple recent outbreaks, however, there was a measurable rate of 0.4 SNPs/genome/year indicating that in areas with more intense disease activity, there is a detectable evolutionary rate. The findings suggest that long-range geographical dispersal events and mostly very low evolutionary rates are important factors contributing to a very low genetic diversity of F. tularensis populations.

In paper II, we focused on a geographically restricted area with a history of frequent tularemia outbreaks to study F. tularensis persistence. By analyzing F. tularensis genomes from 138 individuals infected from 1994 to 2010 in Örebro County in Sweden and performing a long-term laboratory storage experiment, we explored the microbial population concept of a pathogen seed-bank. We found that eight indistinguishable genomes – each of them defined by no SNPs across 1.65 million whole-genome nucleotides – locally persisted over 2-9 years. We found unmeasurable SNP accumulation rates and overlapping bacterial generations among the outbreak genomes and that F. tularensis survived in saline for four years without nutrients. By these findings, and analyses of nucleotide substitution patterns, we suggest that a pathogen seed-bank effect is an important feature of F. tularensis ecology influencing genetic diversity.

In paper III, we developed a new concept for source attribution of a F. tularensis sample. We aimed to identify genetic variation that is characteristic to laboratory culturing and we used culture amplification to identify genetic variation present at exceedingly low frequencies in a sample. Based on a biological enrichment scheme followed by high-throughput sequencing, we could track genetic variation back to a source sample. These results suggest that the concept has potential for linking a F. tularensis sample to its laboratory source sample.

Taken together, the results presented in this thesis provide new understanding of the dissemination patterns and local persistence of tularemia. This is important for the interpretation of molecular epidemiology investigations of the disease. In a wider context, the results demonstrate how spatial dispersal and a microbial seed-bank effect may contribute to the diversity of a disease-causing agent. Finally, we have described a promising concept for source attribution of F. tularensis samples

Place, publisher, year, edition, pages
Umeå: Umeå University , 2019. , p. 47
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2017
Keywords [en]
Francisella, genomics, evolution, microbial forensics, dispersal, persistence
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Microbiology
Identifiers
URN: urn:nbn:se:umu:diva-156079ISBN: 978-91-7855-027-2 (print)OAI: oai:DiVA.org:umu-156079DiVA, id: diva2:1285552
Public defence
2019-02-28, Major Groove, Clinical Microbiology, Nus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2019-02-07 Created: 2019-02-04 Last updated: 2019-02-06Bibliographically approved
List of papers
1. Long-range dispersal moved Francisella tularensis into Western Europe from the East
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2016 (English)In: Microbial Genomics, ISSN 2057-5858, Vol. 2, no 12Article in journal (Refereed) Published
Abstract [en]

For many infections transmitting to humans from reservoirs in nature, disease dispersal patterns over space and time are largely unknown. Here, a reversed genomics approach helped us understand disease dispersal and yielded insight into evolution and biological properties of Francisella tularensis, the bacterium causing tularemia. We whole-genome sequenced 67 strains and characterized by single-nucleotide polymorphism assays 138 strains, collected from individuals infected 1947-2012 across Western Europe. We used the data for phylogenetic, population genetic and geographical network analyses. All strains (n= 205) belonged to a monophyletic population of recent ancestry not found outside Western Europe. Most strains (n= 195) throughout the study area were assigned to a star-like phylogenetic pattern indicating that colonization of Western Europe occurred via clonal expansion. In the East of the study area, strains were more diverse, consistent with a founder population spreading from east to west. The relationship of genetic and geographic distance within the F. tularensis population was complex and indicated multiple long-distance dispersal events. Mutation rate estimates based on year of isolation indicated null rates; in outbreak hotspots only, there was a rate of 0.4 mutations/genome/year. Patterns of nucleotide substitution showed marked AT mutational bias suggestive of genetic drift. These results demonstrate that tularemia has moved from east to west in Europe and that F. tularensis has a biology characterized by long-range geographical dispersal events and mostly slow, but variable, replication rates. The results indicate that mutation-driven evolution, a resting survival phase, genetic drift and long-distance geographical dispersal events have interacted to generate genetic diversity within this species.

Place, publisher, year, edition, pages
Microbiology Society, 2016
Keywords
epidemiology, disease transmission, human, population genetics, Francisella tularensis, genetic variation
National Category
Evolutionary Biology
Identifiers
urn:nbn:se:umu:diva-151311 (URN)10.1099/mgen.0.000100 (DOI)000431154400004 ()28348839 (PubMedID)
Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2019-02-04Bibliographically approved
2. Tularemia outbreaks are caused by infective pathogen seedbanks
Open this publication in new window or tab >>Tularemia outbreaks are caused by infective pathogen seedbanks
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-156136 (URN)
Available from: 2019-02-06 Created: 2019-02-06 Last updated: 2019-02-06
3. Biological amplification of low frequency mutations for source attribution of Francisella tularensis
Open this publication in new window or tab >>Biological amplification of low frequency mutations for source attribution of Francisella tularensis
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-156138 (URN)
Available from: 2019-02-06 Created: 2019-02-06 Last updated: 2019-02-06

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Dwibedi, Chinmay Kumar

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