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

Wilk, Aaron J.; Lee, Madeline; Wei, Bei; Parks, Benjamin; Pi, Ruoxi; Martínez-Colón, Giovanny J.; Ranganath, Thanmayi; Zhao, Nancy Q.; Taylor, Shalina; Becker, Winston R.; Vergara, Rosemary; McKechnie, Julia L.; Parte, Lauren de la; Dantzler, Kathleen W.; Ty, Maureen; Kathale, Nimish; Rustagi, Arjun; Ivison, Geoff; Brewer, Rachel; Hollis, Taylor; Baird, Andrea; Ugur, Michele; Tal, Michal Caspi; Bogusch, Drina; Nahass, Georgie; Haider, Kazim; Tran, Kim Q.T.; Simpson, Laura J.; Din, Hena; Roque, Jonasel; Mann, Rosen; Chang, Iris; Do, Evan; Fernandes, Andrea; Lyu, Shu‐Chen; Zhang, Wenming; Manohar, Monali; Krempski, James; Visweswaran, Anita; Zudock, Elizabeth J.; Jee, Kathryn; Kumar, Komal; Newberry, Jennifer A; Quinn, James V.; Schreiber, Donald; Ashley, Euan A.; Blish, Catherine A.; Blomkalns, Andra L.; Nadeau, Kari; O’Hara, Ruth; Rogers, Angela; Yang, Samuel; Jimenez-Morales, David; Holmes, Susan; Rabinovitch, Marlene; Rogers, Angela J.; Greenleaf, William J.; Blish, Catherine A.

doi:10.1084/jem.20210582

Cited by 167 publications

(187 citation statements)

References 145 publications

(232 reference statements)

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“…Such NDNs have been already described in cancer patients ( 40 , 79 ) and patients with severe COVID–19, where the presence of dysfunctional neutrophils, including LDNs, was linked to emergency myelopoiesis ( 35 ). Several studies have identified emergency myelopoiesis as a hallmark of fatal COVID–19 ( 42 , 80 ) and particularly neutrophil counts were found to be significantly elevated in patients with COVID–19 and correlated with disease severity ( 81 , 82 ). In this context, it is worth mentioning that in differential analysis, both LDNs/MN–MDSCs and NDNs are counted as peripheral blood neutrophils, affecting the neutrophil–to–lymphocyte ratio in COVID–19 patients.…”

Section: Discussionmentioning

confidence: 99%

Mild and Asymptomatic COVID-19 Convalescents Present Long-Term Endotype of Immunosuppression Associated With Neutrophil Subsets Possessing Regulatory Functions

et al. 2021

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The SARS-CoV-2 infection [coronavirus disease 2019 (COVID-19)] is associated with severe lymphopenia and impaired immune response, including expansion of myeloid cells with regulatory functions, e.g., so-called low-density neutrophils, containing granulocytic myeloid-derived suppressor cells (LDNs/PMN-MDSCs). These cells have been described in both infections and cancer and are known for their immunosuppressive activity. In the case of COVID-19, long-term complications have been frequently observed (long-COVID). In this context, we aimed to investigate the immune response of COVID-19 convalescents after a mild or asymptomatic course of disease. We enrolled 13 convalescents who underwent a mild or asymptomatic infection with SARS-CoV-2, confirmed by a positive result of the PCR test, and 13 healthy donors without SARS-CoV-2 infection in the past. Whole blood was used for T-cell subpopulation and LDNs/PMN-MDSCs analysis. LDNs/PMN-MDSCs and normal density neutrophils (NDNs) were sorted out by FACS and used for T-cell proliferation assay with autologous T cells activated with anti-CD3 mAb. Serum samples were used for the detection of anti-SARS-CoV-2 neutralizing IgG and GM-CSF concentration. Our results showed that in convalescents, even 3 months after infection, an elevated level of LDNs/PMN-MDSCs is still maintained in the blood, which correlates negatively with the level of CD8+ and double-negative T cells. Moreover, LDNs/PMN-MDSCs and NDNs showed a tendency for affecting the production of anti-SARS-CoV-2 S1 neutralizing antibodies. Surprisingly, our data showed that in addition to LDNs/PMN-MDSCs, NDNs from convalescents also inhibit proliferation of autologous T cells. Additionally, in the convalescent sera, we detected significantly higher concentrations of GM-CSF, indicating the role of emergency granulopoiesis. We conclude that in mild or asymptomatic COVID-19 convalescents, the neutrophil dysfunction, including propagation of PD-L1-positive LDNs/PMN-MDSCs and NDNs, is responsible for long-term endotype of immunosuppression.

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Section: Discussionmentioning

confidence: 99%

Mild and Asymptomatic COVID-19 Convalescents Present Long-Term Endotype of Immunosuppression Associated With Neutrophil Subsets Possessing Regulatory Functions

et al. 2021

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“…PG active neutrophils were distinguished by preferential splicing of PTGS2/COX2 (as well as expression for prostaglandin transport LST1) and included a subset that expressed high levels of IL1β decoy receptor IL1R2 33 . Lastly, IL7R + neutrophils (a small but distinct subset that maybe of thymic origin 60 expressed high levels of ribosomal subunit genes (e.g.…”

Section: Immunocytochemistry and Immunohistochemistrymentioning

confidence: 99%

“…Comparing scRNA-Seq findings with published datasets. To test whether dexamethasone-suppressed neutrophil genes at t1 and t2 (Extended Data Table 4) predicted COVID-19 mortality, we repurposed methods described in 33 and employed whole blood bulk RNA-Seq datasets generated by 34 as a validation cohort of 103 samples (where 17 were fatal). Briefly, each of the 103 samples were scored by the aggregated expression of dexamethasone-suppressed neutrophil consensus genes at t1 and t2 using Seurat's AddModuleScore().…”

Section: Statistical Approach For Comparing Cell Proportionsmentioning

confidence: 99%

“…To assess the generalizability of the dexamethasone regulated DEGs identified in our cohort, we asked whether they accurately predicted mortality due to COVID-19 in a larger validation cohort. By leveraging a whole blood bulk RNA-Seq dataset from 103 COVID-19 patients 33, 34 , we scored each sample by the aggregated expression of dexamethasone suppressed DEGs at t1 and t2 (Extended Data Table 3). Interestingly, suppressed DEGs at t2 (but not t1) proved to be a far superior predictor of 28-day mortality (AUC: 0.78, CI: 0.67 −0.89) compared to clinical severity scales such as sequential organ failure assessment (SOFA) (AUC: 0.67, CI: 0.51-0.82) across all classification thresholds (Fig 4c).…”

Section: Dexamethasone Therapy Intensifies Neutrophil Immunosuppressive Functionmentioning

confidence: 99%

“…IFN active neutrophils were defined by preferential mRNA splicing (positive velocity) and expression of IFN-stimulated genes such as IFITM1/2, IFIT1/2/3, ISG15/20, and IFI6/27/44/44L 6,44,59 . PG active neutrophils were distinguished by preferential splicing of PTGS2/COX2 (as well as expression for prostaglandin transport LST1) 44 and included a subset that expressed high levels of IL1β decoy receptor IL1R2 33 . Lastly, IL7R + neutrophils (a small but distinct subset that maybe of thymic origin 60 expressed high levels of ribosomal subunit genes (e.g.…”

Section: Immunocytochemistry and Immunohistochemistrymentioning

confidence: 99%

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An Immune Cell Atlas Reveals Dynamic COVID-19 Specific Neutrophil Programming Amenable to Dexamethasone Therapy

Sinha

Rosin

Arora

et al. 2021

Preprint

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SARS-CoV-2 is a novel coronavirus that causes acute respiratory distress syndrome (ARDS), death and long-term sequelae. Innate immune cells are critical for host defense but are also the primary drivers of ARDS. The relationships between innate cellular responses in ARDS resulting from COVID-19 compared to other causes of ARDS, such as bacterial sepsis is unclear. Moreover, the beneficial effects of dexamethasone therapy during severe COVID-19 remain speculative but understanding the mechanistic effects could improve evidence-based therapeutic interventions. To interrogate these relationships, we developed an scRNAseq atlas that is freely accessible (biernaskielab.ca/COVID_neutrophil). We discovered that compared to bacterial ARDS, COVID-19 was associated with distinct neutrophil polarization characterized by either interferon (IFN) or prostaglandin (PG) active states. Neutrophils from bacterial ARDS had higher expression of antibacterial molecules such as PLAC8 and CD83. Dexamethasone therapy in COVID patients rapidly altered the IFNactive state, downregulated interferon responsive genes, and activated the IL1R2+ve neutrophils. Dexamethasone also induced the emergence of immature neutrophils expressing immunosuppressive molecules ARG1 and ANXA1, which were not present in healthy controls. Moreover, dexamethasone remodeled global cellular interactions by changing neutrophils from information receivers into information providers. Importantly, male patients had higher proportions of IFN-active neutrophils and a greater degree of steroid-induced immature neutrophil expansion. Indeed, the highest proportion of IFN-active neutrophils was associated with mortality. These results define neutrophil states unique to COVID-19 when contextualized to other life-threatening infections, thereby enhancing the relevance of our findings at the bedside. Furthermore, the molecular benefits of dexamethasone therapy are also defined. The identified molecular pathways can now be targeted to develop improved therapeutics.

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Distinct and dynamic activation profiles of circulating dendritic cells and monocytes in mild COVID‐19 and after yellow fever vaccination

Winheim¹,

Eser

Deák

et al. 2022

Eur J Immunol

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Dysregulation of the myeloid cell compartment is a feature of severe disease in hospitalized COVID‐19 patients. Here, we investigated the response of circulating dendritic cell (DC) and monocyte subpopulations in SARS‐CoV‐2 infected outpatients with mild disease and compared it to the response of healthy individuals to yellow fever vaccine virus YF17D as a model of a well‐coordinated response to viral infection. In SARS‐CoV‐2‐infected outpatients circulating DCs were persistently reduced for several weeks whereas after YF17D vaccination DC numbers were decreased temporarily and rapidly replenished by increased proliferation until 14 days after vaccination. The majority of COVID‐19 outpatients showed high expression of CD86 and PD‐L1 in monocytes and DCs early on, resembling the dynamic after YF17D vaccination. In a subgroup of patients, low CD86 and high PD‐L1 expression were detected in monocytes and DCs coinciding with symptoms, higher age, and lower lymphocyte counts. This phenotype was similar to that observed in severely ill COVID‐19 patients, but less pronounced. Thus, prolonged reduction and dysregulated activation of blood DCs and monocytes were seen in a subgroup of symptomatic non‐hospitalized COVID‐19 patients while a transient coordinated activation was characteristic for the majority of patients with mild COVID‐19 and the response to YF17D vaccination.

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

Cited by 167 publications

References 145 publications

Mild and Asymptomatic COVID-19 Convalescents Present Long-Term Endotype of Immunosuppression Associated With Neutrophil Subsets Possessing Regulatory Functions

Mild and Asymptomatic COVID-19 Convalescents Present Long-Term Endotype of Immunosuppression Associated With Neutrophil Subsets Possessing Regulatory Functions

An Immune Cell Atlas Reveals Dynamic COVID-19 Specific Neutrophil Programming Amenable to Dexamethasone Therapy

Distinct and dynamic activation profiles of circulating dendritic cells and monocytes in mild COVID‐19 and after yellow fever vaccination

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