Phage diversity in cell-free DNA identifies bacterial pathogens in human sepsis cases

Haddock, Naomi L.; Barkal, Layla J.; Ram-Mohan, Nikhil; Kaber, Gernot; Chiu, Charles Y.; Bhatt, Ami S.; Yang, Samuel; Bollyky, Paul L.

doi:10.1038/s41564-023-01406-x

Cited by 15 publications

(11 citation statements)

References 51 publications

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“…We found from this study that Burkholderia -free phage particles could be found in the blood circulation of melioidosis patients. This significant discovery is corroborated by Haddock et al (2023) , who observed E. coli phage DNA in the blood of sepsis patients.…”

Section: Discussionmentioning

confidence: 59%

Induced Burkholderia prophages detected from the hemoculture: a biomarker for Burkholderia pseudomallei infection

Withatanung,

Janesomboon,

Vanaporn

et al. 2024

Front. Microbiol.

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Bacteriophages (phages), viruses that infect bacteria, are found in abundance not only in the environment but also in the human body. The use of phages for the diagnosis of melioidosis, a tropical infectious disease caused by Burkholderia pseudomallei, is emerging as a promising novel approach, but our understanding of conditions under which Burkholderia prophages can be induced remains limited. Here, we first demonstrated the isolation of Burkholderia phages from the hemocultures of melioidosis patients. The B. pseudomallei-positive hemoculture bottles were filtered to remove bacteria, and then phages were isolated and purified by spot and double agar overlay plaque assays. Forty blood samples (hemoculture-confirmed melioidosis) were tested, and phages were found in 30% of the samples. Transmission electron microscopy and genome analysis of the isolated phages, vB_HM387 and vB_HM795, showed that both phages are Myoviruses. These two phages were stable at a pH of 5–7 and temperatures of 25–37°C, suggesting their ability to survive in human blood. The genome sizes of vB_HM387 and vB_HM795 are 36.3 and 44.0 kb, respectively. A phylogenetic analysis indicated that vB_HM387 has homologs, but vB_HM795 is a novel Myovirus, suggesting the heterogeneity of Burkholderia phages in melioidosis patients. The key finding that Burkholderia phages could be isolated from the blood of melioidosis patients highlights the potential application of phage-based assays by detecting phages in blood as a pathogen-derived biomarker of infection.

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Section: Discussionmentioning

confidence: 59%

Induced Burkholderia prophages detected from the hemoculture: a biomarker for Burkholderia pseudomallei infection

Withatanung,

Janesomboon,

Vanaporn

et al. 2024

Front. Microbiol.

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“…For bacteriophage annotation, the cleaned reads were aligned against a curated phage database (CPD) containing 26,159 phage representative genomes using BLAST (word size: 18, e-value: 0.0005, culling limit: 1) 24 . Phage counting in mNGS data relied on relative abundances 25 .…”

Section: Methodsmentioning

confidence: 99%

Metagenomic Analysis of Bronchoalveolar Lavage Fluid Enables Differential Diagnosis Between Lung Cancer and Pulmonary Infections

Chen,

Han,

et al. 2024

Preprint

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Recent advances in unbiased metagenomic next-generation sequencing (mNGS) have enabled the simultaneous examination of both microbial and host genetic material in a single test. This study harnesses cost-effective bronchoalveolar lavage fluid (BALF) mNGS data from patients with lung cancer (n=123) and pulmonary infections (n=279). We developed a machine learning-based diagnostic approach to differentiate between these two conditions, which are often misdiagnosed in clinical settings. To ensure independence between model construction and validation, we divided the cohorts based on the collection dates of the samples. The training cohort (lung cancer, n=87; pulmonary infection, n=197) revealed distinct differences in DNA/RNA microbial composition, bacteriophage abundances, and host responses, including gene expression, transposable element levels, immune cell composition, and tumor fraction determined by copy number variation (CNV). These features, blinded to the validation cohort, were integrated into a host/microbe metagenomics-driven machine learning model (Model VI). The model demonstrated an Area Under the Curve (AUC) of 0.87 (95% CI = 0.857-0.883) in the training cohort and 0.831 (95% CI = 0.819-0.843) in the validation cohort for differentiating between patients with lung cancer and pulmonary infections. Applying a composite predictive model based on a rule-in and rule-out strategy significantly increased accuracy in distinguishing lung cancer from tuberculosis (ACC=0.913), fungal infection (ACC=0.955), and bacterial infection (ACC=0.836). These results underscore the potential of mNGS-based analysis as a valuable, cost-effective tool for the early differentiation of lung cancer from pulmonary infections, offering a comprehensive testing solution in a clinical context.

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“…There was an association between infection and overrepresentation of pathogen-specific phages, which may allow for the identification of pathogens in septic patients. 67 Although the systemic phageome has not been evaluated in patients with gastrointestinal and liver diseases, information about the systemic phageome may provide insight into specific pathobionts.…”

Section: Phageome In the Intestinal Microbiomementioning

confidence: 99%

Phage diversity in cell-free DNA identifies bacterial pathogens in human sepsis cases

Cited by 15 publications

References 51 publications

Induced Burkholderia prophages detected from the hemoculture: a biomarker for Burkholderia pseudomallei infection

Induced Burkholderia prophages detected from the hemoculture: a biomarker for Burkholderia pseudomallei infection

Metagenomic Analysis of Bronchoalveolar Lavage Fluid Enables Differential Diagnosis Between Lung Cancer and Pulmonary Infections

Phage therapy: Targeting intestinal bacterial microbiota for the treatment of liver diseases

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