Transcriptional and proteomic insights into the host response in fatal COVID-19 cases

Meng Wu,Dehua Yang,Chao Cheng,Isaac M Chiu,Neeraj K Surana,Tian Xia,Liang Liu,Sanpeng Xu,Yaobing Chen,Philip P Ahern,Fenghu Ji,Dennis L Kasper,Guoping Wang,Han Xia,Chin Yee Tan,Yufeng Liu,Xunhui Cai,Yuanlin Guan,Dong Kuang,Ran Liu,Yaqi Duan,Qin Xia,Changli Wang,Mingwei Wang ,Haodong Cai ,Ping Xiong

doi:10.1073/pnas.2018030117

Abstract

Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted thus far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear. Clinical and immunological features of patients with COVID-19 have highlighted a potential role for changes in immune activity in regulating disease severity. However, little is known about the responses in human lung tissue, the primary site of infection. Here we show that pathways related to neutrophil activation and pulmonary fibrosis are among the major up-regulated transcriptional signatures in lung tissue obtained from patients who died of COVID-19 in Wuhan, China. Strikingly, the viral burden was low in all samples, which suggests that the patient deaths may be related to the host response rather than an active fulminant infection. Examination of the colonic transcriptome of these patients suggested that SARS-CoV-2 impacted host responses even at a site with no obvious pathogenesis. Further proteomics analysis validated our transcriptome findings and identified several key proteins, such as the SARS-CoV-2 entry-associated protease cathepsins B and L and the inflammatory response modulator S100A8/A9, that are highly expressed in fatal cases, revealing potential drug targets for COVID-19.

Highlights

Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear
Previous studies have noted profound SARS-CoV-2-induced transcriptional and immunological changes in cell culture and animal models [2, 3], as well as in human blood [4], nasopharyngeal samples [5], and bronchoalveolar lavage fluid [6]. It is notable how little is known about the host response to SARS-CoV-2 in human lung tissue given that COVID19 deaths are primarily due to pneumonia-related complications
We have performed a detailed assessment of the host response to SARS-CoV-2 in human lung, a site of critical importance in SARS-CoV-2 pathogenesis, given the worldwide burden of morbidity and mortality stemming from COVID-19 pneumoniarelated complications

Summary

Introduction

Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear. Previous studies have noted profound SARS-CoV-2-induced transcriptional and immunological changes in cell culture and animal models [2, 3], as well as in human blood [4], nasopharyngeal samples [5], and bronchoalveolar lavage fluid [6]. It is notable how little is known about the host response to SARS-CoV-2 in human lung tissue given that COVID19 deaths are primarily due to pneumonia-related complications

Methods

Results

Conclusion