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Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19.

ABSTRACT: Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-κB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.

SUBMITTER: Wilk AJ

PROVIDER: S-EPMC8210586 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19.

Wilk Aaron J AJ Lee Madeline J MJ Wei Bei B Parks Benjamin B Pi Ruoxi R Martínez-Colón Giovanny J GJ Ranganath Thanmayi T Zhao Nancy Q NQ Taylor Shalina S Becker Winston W Jimenez-Morales David D Blomkalns Andra L AL O'Hara Ruth R Ashley Euan A EA Nadeau Kari C KC Yang Samuel S Holmes Susan S Rabinovitch Marlene M Rogers Angela J AJ Greenleaf William J WJ Blish Catherine A CA

The Journal of experimental medicine 20210615 8

Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunct ...[more]

PMID: 34128959

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Project description:Rationale: Children usually develop less severe symptoms responding to Coronavirus Disease 2019 (COVID-19) than adults. However, little is known about the molecular alterations and pathogenesis of COVID-19 in children. Methods: We conducted plasma proteomic and metabolomic profilings of the blood samples of a cohort containing 18 COVID-19-children with mild symptoms and 12 healthy children, which were enrolled from hospital admissions and outpatients, respectively. Statistical analyses were performed to identify molecules specifically altered in COVID-19-children. We also developed a machine learning-based pipeline named inference of biomolecular combinations with minimal bias (iBM) to prioritize proteins and metabolites strongly altered in COVID-19-children, and experimentally validated the predictions. Results: By comparing to the multi-omic data in adults, we identified 44 proteins and 249 metabolites differentially altered in COVID-19-children against healthy children or COVID-19-adults. Further analyses demonstrated that both deteriorative immune response/inflammation processes and protective antioxidant or anti-inflammatory processes were markedly induced in COVID-19-children. Using iBM, we prioritized two combinations that contained 5 proteins and 5 metabolites, respectively, each exhibiting a total area under curve (AUC) value of 100% to accurately distinguish COVID-19-children from healthy children or COVID-19-adults. Further experiments validated that all the 5 proteins were up-regulated upon coronavirus infection. Interestingly, we found that the prioritized metabolites inhibited the expression of pro-inflammatory factors, and two of them, methylmalonic acid (MMA) and mannitol, also suppressed coronaviral replication, implying a protective role of these metabolites in COVID-19-children. Conclusion: The finding of a strong antagonism of deteriorative and protective effects provided new insights on the mechanism and pathogenesis of COVID-19 in children that mostly underwent mild symptoms. The identified metabolites strongly altered in COVID-19-children could serve as potential therapeutic agents of COVID-19.

Project description:Coronavirus disease 2019 (COVID-19) poses significant risks for solid organ transplant (SOT) recipients, who have atypical but poorly characterized immune responses to SARS-CoV-2 infection. We sought to understand and the host immunologic and microbial features of COVID-19 in SOT recipients by leveraging a prospective multicenter cohort of 1164 hospitalized patients. Using multi-omic immuoprofiling, we studied 86 SOT recipients in this cohort, who were age- and sex-matched 2:1 with 172 non-SOT controls. PBMC and nasal transcriptional profiling unexpectedly demonstrated upregulation of innate immune pathways related to interferon (IFN) and Toll-like receptor signaling, and complement activation, in SOT recipients. Longitudinal analyses across the first 30-days post-hospitalization demonstrated persistent upregulation of these innate immunity pathways in SOT recipients. The levels of several proinflammatory serum chemokines, such as CX3CL1 and KITLG, were also higher in SOT recipients at the time of hospitalization, although IFN-gamma levels were lower. We observed differential dynamics of CXCL11, which remained persistently elevated in SOT recipients over the course of hospitalization. Nasal microbiome alpha diversity was higher in SOT recipients versus controls, but no differences in taxonomic abundance beyond SARS-CoV-2 were observed. SOT recipients had higher nasal SARS-CoV-2 viral loads and impaired viral clearance compared to controls. Antibody analysis demonstrated lower anti-SARS-CoV-2 spike IgG levels in SOT recipients upon hospitalization, but no distinctions over time compared to controls. Mass cytometry demonstrated marked differences in blood immune cell populations, with SOT recipients exhibiting decreased plasmablasts and transitional B cells, and increased senescent T cells. Severe disease in SOT recipients was characterized by a less robust induction of inflammatory chemokines, such as IL-6 and CCL7, and a more subtle proinflammatory transcriptional response in the blood and airway. Together, our study reveals distinct immune features and altered viral dynamics in SOT recipients compared to non-SOT controls. We unexpectedly find that SOT recipients exhibit an augmented, predominantly innate immune response in both the blood and upper respiratory tract that remains relatively stable across disease severity, in contrast to non-SOT controls. These findings may relate to the paradoxical observation that SOT recipients have similar COVID-19 mortality rates versus the general population, despite being more susceptible to SARS-CoV-2 infection, remaining infectious longer, and having higher rates of hospitalization. In summary, we find that COVID-19 in SOT recipients is characterized by a biologically distinct immune state, suggesting the potential for unique prognostic biomarkers and therapeutic approaches in this vulnerable population.

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Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19.

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Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19.

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