lancet-header
Preprints with The Lancet is part of SSRN´s First Look, a place where journals and other research experts identify content of interest prior to publication. These preprint papers are not peer-reviewed and are posted here as part of a 12-month trial. Authors have either opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet, or submitted directly via SSRN. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. These papers should not be used for clinical decision making or reporting of research to a lay audience without indicating that this is preliminary research that has not been peer-reviewed. For more information see the Comment published in The Lancet, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com

Direct Transmission of Within-Host Mycobacterium Tuberculosis Diversity to Secondary Cases Can Lead to Variable Between-Host Heterogeneity Without De Novo Mutation: A Genomic Investigation

28 Pages Posted: 9 May 2019

See all articles by Marie Séraphin

Marie Séraphin

University of Florida - Division of Infectious Diseases and Global Medicine

Anders Norman

Statens Serums Institut

Erik Michael Rasmussen

Statens Serums Institut

Alexandra M. Gerace

University of Florida - College of Medicine

Calin Chiribau

Florida Department of Health

Marie-Claire Rowlinson

University of Florida - College of Medicine

Troels Lillebaek

Statens Serums Institut

Michael Lauzardo

University of Florida - College of Medicine

More...

Abstract

Background: Whole genome sequencing (WGS) has enabled the development of new approaches to track Mycobacterium tuberculosis (Mtb) transmission between tuberculosis (TB) cases but the utility may be challenged by the discovery that Mtb diversifies within hosts.  Nevertheless, there is limited data on the mechanisms of within-host evolution.

Methods: We profiled a well-documented Mtb transmission cluster with three pulmonary TB cases to investigate within-host evolution and describe its impact on recent transmission estimates. We used deep sequencing to track minority allele frequencies (<0·5% abundance) during transmission and standard treatment.

Findings: Pre-treatment (n=3) and serial samples collected over two-months of chemotherapy (n=16) from all three cases were analyzed. Consistent with the epidemiological data, zero high confidence fixed SNPs separated all genomes. However, we identified five subclones in the index case. We recovered all subclones in one secondary case, while only the dominant clone was observed in the other secondary case. By tracking the frequency of these heterogeneous alleles over the two-month therapy, we observed distinct signatures of drift and negative selection, but limited evidence for de novo mutations, even under drug pressure.

Interpretation: Within-host diversity is composed of minority alleles selected against during transmission and disease latency. Incorporating data on heterogeneous alleles may refine our understanding of Mtb transmission dynamics. However, more evidence is needed on the role of transmission bottleneck on observed heterogeneity between cases.

Funding: This research was supported in part by a grant from the National Institute of Health, National Center for Advancement of Translational Science sponsored University of Florida Career Development Grant (5KL2TROO1429-04) to MNS.

Declaration of Interest: We declare no competing interests.

Ethical Approval: Data were collected as part of public health practice and shared anonymously after cases completed therapy, thus informed consent was not required. The use of the data for this study was approved by the Institutional Review Boards (IRB) of the University of Florida and the Florida Department of Health, respectively.

Keywords: Mycobacterium tuberculosis, within-host evolution, transmission dynamics, genomic epidemiology, rare variants, transmission bottleneck

Suggested Citation

Séraphin, Marie and Norman, Anders and Rasmussen, Erik Michael and Gerace, Alexandra M. and Chiribau, Calin and Rowlinson, Marie-Claire and Lillebaek, Troels and Lauzardo, Michael, Direct Transmission of Within-Host Mycobacterium Tuberculosis Diversity to Secondary Cases Can Lead to Variable Between-Host Heterogeneity Without De Novo Mutation: A Genomic Investigation (March 5, 2019). Available at SSRN: https://ssrn.com/abstract=3384856

Marie Séraphin (Contact Author)

University of Florida - Division of Infectious Diseases and Global Medicine ( email )

2055 Mowry Road
P.O. Box 103600
Gainesville, FL 32610
United States

Anders Norman

Statens Serums Institut

Copenhagen
Denmark

Erik Michael Rasmussen

Statens Serums Institut

Artillerivej 5
Copenhagen, 2300
Denmark

Alexandra M. Gerace

University of Florida - College of Medicine

1600 SW Archer Rd
M509
Gainesville, FL 32610
United States

Calin Chiribau

Florida Department of Health

1217 N Pearl Street
Jacksonville, FL 32202
United States

Marie-Claire Rowlinson

University of Florida - College of Medicine

1600 SW Archer Rd
M509
Gainesville, FL 32610
United States

Troels Lillebaek

Statens Serums Institut

Ørestads Boulevard 5
Copenhagen, 2300S
Denmark

Michael Lauzardo

University of Florida - College of Medicine

1600 SW Archer Rd
M509
Gainesville, FL 32610
United States

Click here to go to TheLancet.com

Go to TheLancet.com

Paper statistics

Abstract Views
196
Downloads
30