A cell-free DNA metagenomic sequencing assay that integrates the host injury response to infection

Alexandre Pellan Cheng, Philip Burnham, John Richard Lee, Matthew Pellan Cheng, Manikkam Suthanthiran, Darshana Dadhania, Iwijn De Vlaminck

Research output: Contribution to journalArticle

Abstract

High-throughput metagenomic sequencing offers an unbiased approach to identify pathogens in clinical samples. Conventional metagenomic sequencing, however, does not integrate information about the host, which is often critical to distinguish infection from infectious disease, and to assess the severity of disease. Here, we explore the utility of high-throughput sequencing of cell-free DNA (cfDNA) after bisulfite conversion to map the tissue and cell types of origin of host-derived cfDNA, and to profile the bacterial and viral metagenome. We applied this assay to 51 urinary cfDNA isolates collected from a cohort of kidney transplant recipients with and without bacterial and viral infection of the urinary tract. We find that the cell and tissue types of origin of urinary cfDNA can be derived from its genome-wide profile of methylation marks, and strongly depend on infection status.We find evidence of kidney and bladder tissue damage due to viral and bacterial infection, respectively, and of the recruitment of neutrophils to the urinary tract during infection. Through direct comparison to conventional metagenomic sequencing aswell as clinical tests of infection, we find this assay accurately captures the bacterial and viral composition of the sample. The assay presented here is straightforward to implement, offers a systems view into bacterial and viral infections of the urinary tract, and can find future use as a tool for the differential diagnosis of infection.

Original languageEnglish
Pages (from-to)18738-18744
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number37
DOIs
Publication statusPublished - 10 Sep 2019

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Metagenomics
DNA Sequence Analysis
Wounds and Injuries
Virus Diseases
Infection
Bacterial Infections
DNA
Urinary Tract
Metagenome
Kidney
Neutrophil Infiltration
Urinary Tract Infections
Methylation
Communicable Diseases
Urinary Bladder
Differential Diagnosis
Genome

Keywords

  • Cell-free DNA
  • Host injury
  • Metagenomics

ASJC Scopus subject areas

  • General

Cite this

A cell-free DNA metagenomic sequencing assay that integrates the host injury response to infection. / Cheng, Alexandre Pellan; Burnham, Philip; Lee, John Richard; Cheng, Matthew Pellan; Suthanthiran, Manikkam; Dadhania, Darshana; De Vlaminck, Iwijn.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 37, 10.09.2019, p. 18738-18744.

Research output: Contribution to journalArticle

Cheng, Alexandre Pellan ; Burnham, Philip ; Lee, John Richard ; Cheng, Matthew Pellan ; Suthanthiran, Manikkam ; Dadhania, Darshana ; De Vlaminck, Iwijn. / A cell-free DNA metagenomic sequencing assay that integrates the host injury response to infection. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 37. pp. 18738-18744.
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