Ventilation-Associated Differences in Lower Airway Microbial Signatures and Peripheral Blood Transcriptome Among Critically Ill COVID-19 Patients

Yuxia Li,1, Mingzhu Huang,1, Zheying Mao,1, Chang Liu,1, Wenxin Qu,1 Jili Ni,1 Wang Xu,2 Aijing Li,2 Jiaqi Bao,1,3,4 Dongsheng Han,1,3,4 Fei Yu,1,3,4 Yifei Shen,1,3,4 Yuefeng Wang,5 Weizhen Chen,1,3,4 Shufa Zheng1,3,4 1Department of Laboratory Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Jinan Microecological Biomedicine Shandong Laboratory, Jinan, People’s Republic of China; 3Key Laboratory of Clinical in Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, People’s Republic of China; 4Institute of Laboratory Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 5Department of Blood Transfusion, Shaoxing Maternity and Child Health Care Hospital, Shaoxing, People’s Republic of ChinaThese authors contributed equally to this workCorrespondence: Weizhen Chen, Email jadesonchen@gmail.com Shufa Zheng, Email zsfzheng@zju.edu.cnBackground: Invasive mechanical ventilation (IMV) is a critical intervention for severe respiratory failure and has been widely used in the clinical management of COVID-19 patients. The relationship between such microbiota changes and the host transcriptome in IMV patients remains poorly documented.Methods: We prospectively enrolled 69 critically ill COVID-19 patients, among whom 41 received IMV. Correlation analyses were conducted to investigate the relationship between the lung microbiome and host immune status in IMV COVID-19 patients.Results: Compared to the Non-mechanical ventilation (NMV) group, patients in the IMV group exhibited significantly reduced alpha diversity, while no significant difference was observed in beta diversity. The abundance of Streptococcus genus was significantly higher in the NMV group, primarily dominated by Streptococcus oralis and Streptococcus mitis. Transcriptomic enrichment analysis revealed significant upregulation of inflammation-related pathways in the IMV group, including “positive regulation of inflammatory response” and “cellular response to interleukin-1”. The decreased relative abundance of Streptococcus genus in the IMV group showed significant correlations with upregulation of genes including CXCL8, PLAU, SELENOK, SDC4, RPL17, RPS23, TOMM7, and PLK3. These upregulated genes promoted the recruitment of immune cells to inflammatory sites through activation of pathways including chemotaxis, leukocyte migration, and leukocyte cell-cell adhesion, ultimately triggering a robust innate immune response.Conclusion: IMV COVID-19 ARDS patients demonstrated significantly reduced pulmonary microbial diversity, with a marked decrease in the abundance of Streptococcus—primarily Streptococcus oralis and Streptococcus mitis. Transcriptomic profiling further revealed substantial upregulation of inflammatory pathways in IMV patients, including “positive regulation of inflammatory response”.Keywords: COVID-19, critically ill, mechanical ventilation, lower respiratory tract microbiota, blood transcriptome