The clinical outcome of COVID-19 is strongly associated with microbiome dynamics in the upper respiratory tract

Linlin Xie; Gengyan Luo; Zhongzhou Yang; Wei-chen Wu; Jintao Chen; Yuting Ren; Zhikun Zeng; Guangming Ye; Yunbao Pan; Wen-jing Zhao; Yao-qing Chen; Wei Hou; Yanni Sun; Deying Guo; Zifeng Yang; Jun Li; Edward C. Holmes; Yirong Li; Liangjun Chen; Mang Shi

doi:10.1016/j.jinf.2024.01.017

The clinical outcome of COVID-19 is strongly associated with microbiome dynamics in the upper respiratory tract

Linlin Xie (Co-first Author), Gengyan Luo (Co-first Author), Zhongzhou Yang, Wei-chen Wu, Jintao Chen, Yuting Ren, Zhikun Zeng, Guangming Ye, Yunbao Pan, Wen-jing Zhao, Yao-qing Chen, Wei Hou, Yanni Sun, Deying Guo, Zifeng Yang, Jun Li, Edward C. Holmes, Yirong Li^*, Liangjun Chen^*, Mang Shi^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

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Abstract

Objectives: The respiratory tract is the portal of entry for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although a variety of respiratory pathogens other than SARS-CoV-2 have been associated with severe cases of COVID-19 disease, the dynamics of the upper respiratory microbiota during disease the course of disease, and how they impact disease manifestation, remain uncertain. Methods: We collected 349 longitudinal upper respiratory samples from a cohort of 65 COVID-19 patients (cohort 1), 28 samples from 28 recovered COVID-19 patients (cohort 2), and 59 samples from 59 healthy controls (cohort 3). All COVID-19 patients originated from the earliest stage of the epidemic in Wuhan. Based on a modified clinical scale, the disease course was divided into five clinical disease phases (pseudotimes): “Healthy” (pseudotime 0), “Incremental” (pseudotime 1), “Critical” (pseudotime 2), “Complicated” (pseudotime 3), “Convalescent” (pseudotime 4), and “Long-term follow-up” (pseudotime 5). Using meta-transcriptomics, we investigated the features and dynamics of transcriptionally active microbes in the upper respiratory tract (URT) over the course of COVID-19 disease, as well as its association with disease progression and clinical outcomes. Results: Our results revealed that the URT microbiome exhibits substantial heterogeneity during disease course. Two clusters of microbial communities characterized by low alpha diversity and enrichment for multiple pathogens or potential pathobionts (including Acinetobacter and Candida) were associated with disease progression and a worse clinical outcome. We also identified a series of microbial indicators that classified disease progression into more severe stages. Longitudinal analysis revealed that although the microbiome exhibited complex and changing patterns during COVID-19, a restoration of URT microbiomes from early dysbiosis toward more diverse status in later disease stages was observed in most patients. In addition, a group of potential pathobionts were strongly associated with the concentration of inflammatory indicators and mortality. Conclusion: This study revealed strong links between URT microbiome dynamics and disease progression and clinical outcomes in COVID-19, implying that the treatment of severe disease should consider the full spectrum of microbial pathogens present. © 2024 The Authors

Original language	English
Article number	106118
Journal	Journal of Infection
Volume	88
Issue number	3
Online published	10 Feb 2024
DOIs	https://doi.org/10.1016/j.jinf.2024.01.017
Publication status	Published - Mar 2024

Funding

This work was supported by the National Natural Science Foundation of China (82000021), Shenzhen Science and Technology Program (KQTD20200820145822023 and RCJC20210706092009004), Shenzhen Key Laboratory of Systems Medicine for inflammatory diseases (ZDSYS20220606100803007), Guangdong Province “Pearl River Talent Plan” Innovation and Entrepreneurship Team Project (2019ZT08Y464), the Key Research and Development Program of Hubei Province (2022BCA019), 2021 Hubei Provincial Leading Public Health Talents Project (WSJKRC2022012), the Young Elite Scientist Sponsorship Program By CAST (YESS20200394)，Joint Funds of the National Natural Science Foundation of China (U20A20396), Hong Kong Innovation and Technology Fund (ITF) (MRP/071/20X), AIR@InnoHK administered by the Innovation and Technology Commission, Hong Kong (Institute of Data Discovery for Health), the National Health and Medical Research Council (GNT2017197), the Health and Medical Research Fund (COVID190206), Open Project of State Key Laboratory of Respiratory Disease (SKLRD-OP-202001) and Guangzhou Institute of Respiratory Health Open Project (2020GIRHHMS01).

Research Keywords

COVID-19
Meta-transcriptomics
Microbiome
SARS-CoV-2
Upper respiratory tract

Publisher's Copyright Statement

This full text is made available under CC-BY-NC-ND 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jinf.2024.01.017

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Xie, L., Luo, G., Yang, Z., Wu, W., Chen, J., Ren, Y., Zeng, Z., Ye, G., Pan, Y., Zhao, W., Chen, Y., Hou, W., Sun, Y., Guo, D., Yang, Z., Li, J., Holmes, E. C., Li, Y., Chen, L., & Shi, M. (2024). The clinical outcome of COVID-19 is strongly associated with microbiome dynamics in the upper respiratory tract. Journal of Infection, 88(3), Article 106118. https://doi.org/10.1016/j.jinf.2024.01.017

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title = "The clinical outcome of COVID-19 is strongly associated with microbiome dynamics in the upper respiratory tract",

abstract = "Objectives: The respiratory tract is the portal of entry for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although a variety of respiratory pathogens other than SARS-CoV-2 have been associated with severe cases of COVID-19 disease, the dynamics of the upper respiratory microbiota during disease the course of disease, and how they impact disease manifestation, remain uncertain. Methods: We collected 349 longitudinal upper respiratory samples from a cohort of 65 COVID-19 patients (cohort 1), 28 samples from 28 recovered COVID-19 patients (cohort 2), and 59 samples from 59 healthy controls (cohort 3). All COVID-19 patients originated from the earliest stage of the epidemic in Wuhan. Based on a modified clinical scale, the disease course was divided into five clinical disease phases (pseudotimes): “Healthy” (pseudotime 0), “Incremental” (pseudotime 1), “Critical” (pseudotime 2), “Complicated” (pseudotime 3), “Convalescent” (pseudotime 4), and “Long-term follow-up” (pseudotime 5). Using meta-transcriptomics, we investigated the features and dynamics of transcriptionally active microbes in the upper respiratory tract (URT) over the course of COVID-19 disease, as well as its association with disease progression and clinical outcomes. Results: Our results revealed that the URT microbiome exhibits substantial heterogeneity during disease course. Two clusters of microbial communities characterized by low alpha diversity and enrichment for multiple pathogens or potential pathobionts (including Acinetobacter and Candida) were associated with disease progression and a worse clinical outcome. We also identified a series of microbial indicators that classified disease progression into more severe stages. Longitudinal analysis revealed that although the microbiome exhibited complex and changing patterns during COVID-19, a restoration of URT microbiomes from early dysbiosis toward more diverse status in later disease stages was observed in most patients. In addition, a group of potential pathobionts were strongly associated with the concentration of inflammatory indicators and mortality. Conclusion: This study revealed strong links between URT microbiome dynamics and disease progression and clinical outcomes in COVID-19, implying that the treatment of severe disease should consider the full spectrum of microbial pathogens present. {\textcopyright} 2024 The Authors",

keywords = "COVID-19, Meta-transcriptomics, Microbiome, SARS-CoV-2, Upper respiratory tract",

author = "Linlin Xie and Gengyan Luo and Zhongzhou Yang and Wei-chen Wu and Jintao Chen and Yuting Ren and Zhikun Zeng and Guangming Ye and Yunbao Pan and Wen-jing Zhao and Yao-qing Chen and Wei Hou and Yanni Sun and Deying Guo and Zifeng Yang and Jun Li and Holmes, {Edward C.} and Yirong Li and Liangjun Chen and Mang Shi",

year = "2024",

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doi = "10.1016/j.jinf.2024.01.017",

language = "English",

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issn = "0163-4453",

publisher = "W.B. Saunders Ltd",

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Xie, L, Luo, G, Yang, Z, Wu, W, Chen, J, Ren, Y, Zeng, Z, Ye, G, Pan, Y, Zhao, W, Chen, Y, Hou, W, Sun, Y, Guo, D, Yang, Z, Li, J, Holmes, EC, Li, Y, Chen, L & Shi, M 2024, 'The clinical outcome of COVID-19 is strongly associated with microbiome dynamics in the upper respiratory tract', Journal of Infection, vol. 88, no. 3, 106118. https://doi.org/10.1016/j.jinf.2024.01.017

TY - JOUR

T1 - The clinical outcome of COVID-19 is strongly associated with microbiome dynamics in the upper respiratory tract

AU - Xie, Linlin

AU - Luo, Gengyan

AU - Yang, Zhongzhou

AU - Wu, Wei-chen

AU - Chen, Jintao

AU - Ren, Yuting

AU - Zeng, Zhikun

AU - Ye, Guangming

AU - Pan, Yunbao

AU - Zhao, Wen-jing

AU - Chen, Yao-qing

AU - Hou, Wei

AU - Sun, Yanni

AU - Guo, Deying

AU - Yang, Zifeng

AU - Li, Jun

AU - Holmes, Edward C.

AU - Li, Yirong

AU - Chen, Liangjun

AU - Shi, Mang

PY - 2024/3

Y1 - 2024/3

N2 - Objectives: The respiratory tract is the portal of entry for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although a variety of respiratory pathogens other than SARS-CoV-2 have been associated with severe cases of COVID-19 disease, the dynamics of the upper respiratory microbiota during disease the course of disease, and how they impact disease manifestation, remain uncertain. Methods: We collected 349 longitudinal upper respiratory samples from a cohort of 65 COVID-19 patients (cohort 1), 28 samples from 28 recovered COVID-19 patients (cohort 2), and 59 samples from 59 healthy controls (cohort 3). All COVID-19 patients originated from the earliest stage of the epidemic in Wuhan. Based on a modified clinical scale, the disease course was divided into five clinical disease phases (pseudotimes): “Healthy” (pseudotime 0), “Incremental” (pseudotime 1), “Critical” (pseudotime 2), “Complicated” (pseudotime 3), “Convalescent” (pseudotime 4), and “Long-term follow-up” (pseudotime 5). Using meta-transcriptomics, we investigated the features and dynamics of transcriptionally active microbes in the upper respiratory tract (URT) over the course of COVID-19 disease, as well as its association with disease progression and clinical outcomes. Results: Our results revealed that the URT microbiome exhibits substantial heterogeneity during disease course. Two clusters of microbial communities characterized by low alpha diversity and enrichment for multiple pathogens or potential pathobionts (including Acinetobacter and Candida) were associated with disease progression and a worse clinical outcome. We also identified a series of microbial indicators that classified disease progression into more severe stages. Longitudinal analysis revealed that although the microbiome exhibited complex and changing patterns during COVID-19, a restoration of URT microbiomes from early dysbiosis toward more diverse status in later disease stages was observed in most patients. In addition, a group of potential pathobionts were strongly associated with the concentration of inflammatory indicators and mortality. Conclusion: This study revealed strong links between URT microbiome dynamics and disease progression and clinical outcomes in COVID-19, implying that the treatment of severe disease should consider the full spectrum of microbial pathogens present. © 2024 The Authors

AB - Objectives: The respiratory tract is the portal of entry for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although a variety of respiratory pathogens other than SARS-CoV-2 have been associated with severe cases of COVID-19 disease, the dynamics of the upper respiratory microbiota during disease the course of disease, and how they impact disease manifestation, remain uncertain. Methods: We collected 349 longitudinal upper respiratory samples from a cohort of 65 COVID-19 patients (cohort 1), 28 samples from 28 recovered COVID-19 patients (cohort 2), and 59 samples from 59 healthy controls (cohort 3). All COVID-19 patients originated from the earliest stage of the epidemic in Wuhan. Based on a modified clinical scale, the disease course was divided into five clinical disease phases (pseudotimes): “Healthy” (pseudotime 0), “Incremental” (pseudotime 1), “Critical” (pseudotime 2), “Complicated” (pseudotime 3), “Convalescent” (pseudotime 4), and “Long-term follow-up” (pseudotime 5). Using meta-transcriptomics, we investigated the features and dynamics of transcriptionally active microbes in the upper respiratory tract (URT) over the course of COVID-19 disease, as well as its association with disease progression and clinical outcomes. Results: Our results revealed that the URT microbiome exhibits substantial heterogeneity during disease course. Two clusters of microbial communities characterized by low alpha diversity and enrichment for multiple pathogens or potential pathobionts (including Acinetobacter and Candida) were associated with disease progression and a worse clinical outcome. We also identified a series of microbial indicators that classified disease progression into more severe stages. Longitudinal analysis revealed that although the microbiome exhibited complex and changing patterns during COVID-19, a restoration of URT microbiomes from early dysbiosis toward more diverse status in later disease stages was observed in most patients. In addition, a group of potential pathobionts were strongly associated with the concentration of inflammatory indicators and mortality. Conclusion: This study revealed strong links between URT microbiome dynamics and disease progression and clinical outcomes in COVID-19, implying that the treatment of severe disease should consider the full spectrum of microbial pathogens present. © 2024 The Authors

KW - COVID-19

KW - Meta-transcriptomics

KW - Microbiome

KW - SARS-CoV-2

KW - Upper respiratory tract

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U2 - 10.1016/j.jinf.2024.01.017

DO - 10.1016/j.jinf.2024.01.017

M3 - RGC 21 - Publication in refereed journal

C2 - 38342382

SN - 0163-4453

VL - 88

JO - Journal of Infection

JF - Journal of Infection

IS - 3

M1 - 106118

ER -

The clinical outcome of COVID-19 is strongly associated with microbiome dynamics in the upper respiratory tract

Abstract

Funding

Research Keywords

Publisher's Copyright Statement

UN SDGs

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ITF: Viral Metagenomic Sequencing As A road-spectrum Pathogen Detection Technology For Viral Diseases

HMRF: A System-Level and Multidimensional Quantification and Prediction of SARS-CoV-2 Infection in Animals: Are There Implications for Control of Human Infections?

Cite this

The clinical outcome of COVID-19 is strongly associated with microbiome dynamics in the upper respiratory tract

Abstract

Funding

Research Keywords

Publisher's Copyright Statement

UN SDGs

Access Output

Other Access Options

Permanent Link

Other Files and Links

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Projects

ITF: Viral Metagenomic Sequencing As A road-spectrum Pathogen Detection Technology For Viral Diseases

HMRF: A System-Level and Multidimensional Quantification and Prediction of SARS-CoV-2 Infection in Animals: Are There Implications for Control of Human Infections?

Cite this