Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19

Unterman, Avraham; Sumida, Tomokazu; Nouri, Nima; Yan, Xiting; Zhao, Amy; Gasque, Victor; Schupp, Jonas C.; Asashima, Hiromitsu; Liu, Yunqing; Cosme, Carlos; Deng, Wenxuan; Chen, Ming; Raredon, Micha Sam Brickman; Hoehn, Kenneth B.; Wang, Guilin; Wang, Zuoheng; DeIuliis, Giuseppe; Ravindra, Neal G.; Li, Ningshan; Castaldi, Christopher; Wong, Patrick; Fournier, John; Bermejo, Santos; Sharma, Lokesh; Casanovas‐Massana, Arnau; Vogels, Chantal B.F.; Grubaugh, Nathan D.; Melillo, Anthony; Meng, Hailong; Stein, Yan; Minasyan, Maksym; Mohanty, Subhasis; Ruff, William; Cohen, Inessa; Raddassi, Khadir; Nelson, Allison; Shepard, Denise; Rainone, Michael; Peng, Xiaohua; Niklason, Laura E.; Ko, Albert I.; Montgomery, Ruth R.; Farhadian, Shelli; Iwasaki, Akiko; Shaw, Albert C.; Dijk, David van; Zhao, Hongyu; Kleinstein, Steven H.; Hafler, David A.; Kaminski, Naftali; Cruz, Charles S. Dela

doi:10.1038/s41467-021-27716-4

Cited by 110 publications

(128 citation statements)

References 133 publications

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“…Single cell data for comparisons of patients with stable vs progressive COVID-19 were obtained from GEO (GSE155224 ( 67 )). The dataset consisted of 42,293 cells loaded using the Seurat v4.0.2 package ( 111 ).…”

Section: Methodsmentioning

confidence: 99%

ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection

et al. 2022

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), continues to cause significant morbidity and mortality in the ongoing global pandemic. Understanding the fundamental mechanisms that govern innate immune and inflammatory responses during SARS-CoV-2 infection is critical for developing effective therapeutic strategies. While IFN-based therapies are generally expected to be beneficial during viral infection, clinical trials in COVID-19 have shown limited efficacy and potential detrimental effects of IFN treatment during SARS-CoV-2 infection. However, the underlying mechanisms responsible for this failure remain unknown. In this study, we found that IFN induced ZBP1-mediated inflammatory cell death, PANoptosis, in human and murine macrophages and in the lungs of mice infected with β-coronaviruses, including SARS-CoV-2 and mouse hepatitis virus (MHV). In patients with COVID-19, expression of the innate immune sensor ZBP1 was increased in immune cells from those who succumbed to the disease compared with those who recovered, further suggesting a link between ZBP1 and pathology. In mice, IFN-β treatment following β-coronavirus infection increased lethality, and genetic deletion of Zbp1 or its Zα domain suppressed cell death and protected the mice from IFN-mediated lethality during β-coronavirus infection. Overall, our results identify that ZBP1 induced during coronavirus infection limits the efficacy of IFN therapy by driving inflammatory cell death and lethality. Therefore, inhibiting ZBP1 activity may improve the efficacy of IFN therapy, paving the way for the development of new and critically needed therapeutics for COVID-19 as well as other infections and inflammatory conditions where IFN-mediated cell death and pathology occur.

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Section: Methodsmentioning

confidence: 99%

ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection

et al. 2022

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“…Sequences were connected if they meet the following criteria (a) same V and J gene usage; (b) from different individuals; (c) same CDRH3 amino acid length, and (d) ≥ 85% CDRH3 amino acid identity. The same criteria have been applied in published studies investigating convergent clonotypes across SARS-CoV-2 B-cell repertoires ( 35 , 36 ). To allow interpretation of possible targets of sequences in convergent network clusters, known binders were included in constructing the network.…”

Section: Methodsmentioning

confidence: 99%

Pandemic, Epidemic, Endemic: B Cell Repertoire Analysis Reveals Unique Anti-Viral Responses to SARS-CoV-2, Ebola and Respiratory Syncytial Virus

Stewart

Sinclair

et al. 2022

Front. Immunol.

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Immunoglobulin gene heterogeneity reflects the diversity and focus of the humoral immune response towards different infections, enabling inference of B cell development processes. Detailed compositional and lineage analysis of long read IGH repertoire sequencing, combining examples of pandemic, epidemic and endemic viral infections with control and vaccination samples, demonstrates general responses including increased use of IGHV4-39 in both Zaire Ebolavirus (EBOV) and COVID-19 patient cohorts. We also show unique characteristics absent in Respiratory Syncytial Virus or yellow fever vaccine samples: EBOV survivors show unprecedented high levels of class switching events while COVID-19 repertoires from acute disease appear underdeveloped. Despite the high levels of clonal expansion in COVID-19 IgG1 repertoires there is a striking lack of evidence of germinal centre mutation and selection. Given the differences in COVID-19 morbidity and mortality with age, it is also pertinent that we find significant differences in repertoire characteristics between young and old patients. Our data supports the hypothesis that a primary viral challenge can result in a strong but immature humoral response where failures in selection of the repertoire risk off-target effects.

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“…Recently, this multi-omic approach has also been applied to the developing single-cell technology, as it could allow to capture multiple omic layers from the same cell. For instance, Unterman et al performed a multi-omics single-cell analysis to investigate the immune responses in hospitalized patients with stable or progressive COVID-19 and the cellular effects to tocilizumab [ 138 ]. Of interest, single-cell multi-omics might make it easier to establish associations between variations in multiple omic layers within the same single cells, as defined relationships are unambiguous.…”

Section: New Perspectivesmentioning

confidence: 99%

Multi-Omics Integrative Approach of Extracellular Vesicles: A Future Challenging Milestone

et al. 2022

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In the era of multi-omic sciences, dogma on singular cause-effect in physio-pathological processes is overcome and system biology approaches have been providing new perspectives to see through. In this context, extracellular vesicles (EVs) are offering a new level of complexity, given their role in cellular communication and their activity as mediators of specific signals to target cells or tissues. Indeed, their heterogeneity in terms of content, function, origin and potentiality contribute to the cross-interaction of almost every molecular process occurring in a complex system. Such features make EVs proper biological systems being, therefore, optimal targets of omic sciences. Currently, most studies focus on dissecting EVs content in order to either characterize it or to explore its role in various pathogenic processes at transcriptomic, proteomic, metabolomic, lipidomic and genomic levels. Despite valuable results being provided by individual omic studies, the categorization of EVs biological data might represent a limit to be overcome. For this reason, a multi-omic integrative approach might contribute to explore EVs function, their tissue-specific origin and their potentiality. This review summarizes the state-of-the-art of EVs omic studies, addressing recent research on the integration of EVs multi-level biological data and challenging developments in EVs origin.

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Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19

Cited by 110 publications

References 133 publications

ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection

ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection

Pandemic, Epidemic, Endemic: B Cell Repertoire Analysis Reveals Unique Anti-Viral Responses to SARS-CoV-2, Ebola and Respiratory Syncytial Virus

Multi-Omics Integrative Approach of Extracellular Vesicles: A Future Challenging Milestone

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