Single-cell transcriptome identifies FCGR3B upregulated subtype of alveolar macrophages in patients with critical COVID-19

Nasna Nassir,Ghausia Begum,Mahmood Yaseen Hachim,Seyed Ali Safizadeh Shabestari,Reem Abdel Hameid,Zulfa Deesi,Binte Zehra,Proton Rahman,Omar Almidani,Tom Loney,Mellissa Gaudet,Noushad Karuvantevida,Saba Al Heialy,Abdulmajeed Alkhajeh,Ahmad Abou Tayoun,Mohammed Uddin,Awab Ahmed,Hosneara Akter,Bakhrom K Berdiev,Wolfgang M Kuebler,Richa Tambi,Norbert Nowotny,Asma Bankapur,Marc Woodbury‐Smith ,Abu Zafor Md Touhidul Islam ,Jean‐Laurent Casanova ,Richard K Kandasamy ,K M Furkan Uddin ,Alawi A Alsheikh‐Ali ,Hamda Khansaheb

doi:10.1016/j.isci.2021.103030

Abstract

SummaryUnderstanding host cell heterogeneity is critical for unraveling disease mechanism. Utilizing large-scale single-cell transcriptomics, we analyzed multiple tissue specimens from patients with life-threatening COVID-19 pneumonia, compared with healthy controls. We identified a subtype of monocyte-derived alveolar macrophages (MoAMs) where genes associated with severe COVID-19 comorbidities are significantly upregulated in bronchoalveolar lavage fluid of critical cases. FCGR3B consistently demarcated MoAM subset in different samples from severe COVID-19 cohorts and in CCL3L1-upregulated cells from nasopharyngeal swabs. In silico findings were validated by upregulation of FCGR3B in nasopharyngeal swabs of severe ICU COVID-19 cases, particularly in older patients and those with comorbidities. Additional lines of evidence from transcriptomic data and in vivo of severe COVID-19 cases suggest that FCGR3B may identify a specific subtype of MoAM in patients with severe COVID-19 that may present a novel biomarker for screening and prognosis, as well as a potential therapeutic target.

Highlights

Most individuals infected with SARS-CoV-2 remain asymptomatic or develop mild forms of the disease, a significant proportion of infected cases develops severe COVID-19 pneumonia and a smaller proportion (0.5%) critical pneumonia (Hu et al, 2020; Uddin et al, 2020)
We identified a subtype of monocyte-derived alveolar macrophages (MoAMs) where genes associated with severe COVID-19 comorbidities are significantly upregulated in bronchoalveolar lavage fluid of critical cases
In silico findings were validated by upregulation of FCGR3B in nasopharyngeal swabs of severe ICU COVID-19 cases, in older patients and those with comorbidities

Summary

Introduction

Most individuals infected with SARS-CoV-2 remain asymptomatic or develop mild forms of the disease, a significant proportion (approximately 5%) of infected cases develops severe COVID-19 pneumonia and a smaller proportion (0.5%) critical pneumonia (Hu et al, 2020; Uddin et al, 2020). Major international initiatives are underway to unravel the pathogenesis of severe COVID-19. Despite these efforts, our knowledge of COVID-19 pathophysiology is very limited and has been compounded by the complex interplay with a range of comorbid conditions. At least 10% of critical COVID-19 cases can be explained by the presence of their autoimmune phenocopy, in the form of neutralizing autoantibodies to type I IFNs (Bastard et al, 2020; Zhang et al, 2020c, 2020d). From the international COVID-19 Host Genetics Initiative, thirteen loci have been found to be associated with severe COVID-19, with OR < 2, and were subsequently replicated in other independent population cohorts

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