Deep immune profiling of COVID-19 patients reveals patient heterogeneity and distinct immunotypes with implications for therapeutic interventions

Mathew, Divij; Giles, Josephine R.; Baxter, Amy E.; Greenplate, Allison R.; Wu, Jennifer E.; Alanio, Cécile; Oldridge, Derek A.; Kuri-Cervantes, Leticia; Pampena, María Betina; Manne, Sasikanth; Chen, Zeyu; Huang, Yinghui; Reilly, John P.; Weisman, A.R.; Ittner, C.A.G.; Kuthuru, Oliva; Dougherty, Jeanette; Nzingha, Kito; Han, Nicholas; Kim, Justin; Pattekar, Ajinkya; Goodwin, Eileen; Anderson, Elizabeth M.; Weirick, Madison E.; Gouma, Sigrid; Arevalo, Claudia P.; Bolton, Marcus J.; Chen, Fang; Lacey, Simone F; Hensley, Scott E.; Apostolidis, Sokratis A.; Huang, Alexander C.; Betts, Michael R.; Meyer, Nuala J.; Wherry, E. John

doi:10.1101/2020.05.20.106401

Cited by 141 publications

(216 citation statements)

References 62 publications

Supporting

Mentioning

170

Contrasting

Unclassified

Order By: Relevance

“…Compositional changes were not as readily apparent in PBMCs, although we observed an expansion of multiple plasma cell types in severe donors compared to healthy control subjects, consistent with previous reports [23,33,34,44].…”

Section: Indicated Expansion Of Nk Cells T Cells (General T Cell Popsupporting

confidence: 91%

Dissecting the common and compartment-specific features of COVID-19 severity in the lung and periphery with single-cell resolution

Overholt

Krog

Bryson

2020

Preprint

View full text Add to dashboard Cite

As the global COVID-19 pandemic continues to escalate, no effective treatment has yet been developed for the severe respiratory complications of this disease. This may be due in large part to the unclear immunopathological basis for the development of immune dysregulation and acute respiratory distress syndrome (ARDS) in severe and critical patients. Specifically, it remains unknown whether the immunological features of the disease that have been identified so far are compartment-specific responses or general features of COVID-19. Additionally, readily detectable biological markers correlated with strata of disease severity that could be used to triage patients and inform treatment options have not yet been identified. Here, we leveraged publicly available single-cell RNA sequencing data to elucidate the common and compartment-specific immunological features of clinically severe COVID-19. We identified a number of transcriptional programs that are altered across the spectrum of disease severity, few of which are common between the lung and peripheral immune environments. In the lung, comparing severe and moderate patients revealed severity-specific responses of enhanced interferon, A20/IκB, IL-2, and IL-6 pathway signatures along with broad signaling activity of IFNG, SPP1, CCL3, CCL8, and IL18 across cell types. These signatures contrasted with features unique to ARDS observed in the blood compartment, which included depletion of interferon and A20/IκB signatures and a lack of IL-6 response. The cell surface marker S1PR1 was strongly upregulated in patients diagnosed with ARDS compared to non-ARDS patients in γδ T cells of the blood compartment, and we nominate S1PR1 as a potential marker for immunophenotyping ARDS in COVID-19 patients using flow cytometry.HIGHLIGHTSCOVID-19 disease severity is associated with a number of compositional shifts in the cellular makeup of the blood and lung environments.Transcriptional data suggest differentially expressed cell surface proteins as markers for COVID-19 immunophenotyping from BALF and PBMC samples.Severity-specific features COVID-19 manifest at the pathway level, suggesting distinct changes to epithelia and differences between local and systemic immune dynamics.Immune-epithelial cellular communication analysis identifies ligands implicated in transcriptional regulation of proto-oncogenes in the lung epithelia of severe COVID-19 patients.Network analysis suggests broadly-acting dysregulatory ligands in the pulmonary microenvironment as candidate therapeutic targets for the treatment of severe COVID-19.

show abstract

Section: Indicated Expansion Of Nk Cells T Cells (General T Cell Popsupporting

confidence: 91%

Dissecting the common and compartment-specific features of COVID-19 severity in the lung and periphery with single-cell resolution

Overholt

Krog

Bryson

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…We also quantified the genes, surface proteins, and pathway enrichment scores in CD4 + T cells and their correlation with disease severity. Consistent with recent literature (Chen et al, 2020;Mathew et al, 2020), an increase of FAS pathway genes, proliferation genes, activation/effector surface markers CX3CR1, B7-H4, the Th1 differentiation pathway score, and the Type I interferon response gene signature were positively correlated with disease severity ( Figure 3I). By contrast, naïve T cell signatures and the earlyactivation marker CD27 were negatively correlated ( Figure 3I).…”

Section: Cd4 + T Cell Proliferation Cytotoxic Activity and Clonal Esupporting

confidence: 90%

“…Recorded signatures of immune dysregulation include lymphopenia that is commonly associated with reduced numbers of T cells, natural killer cells, and other lymphocytes (Cao, 2020;Ruan et al, 2020;Tan et al, 2020), as well as elevated exhaustion markers on immune cells (Zheng et al, 2020). Elevated levels of circulating inflammatory cytokines (Mathew et al, 2020) have been reported, although the primary source of such cytokines, as well as the roles of circulating T cells and monocytes, has been debated (Wilk et al, 2020;Zhou et al, 2020). A condition bearing similarities to IL-6-mediated cytokine release syndrome (CRS) (Yang et al, 2020) has also been reported in severely ill COVID-19 patients, although unlike in CRS in cancer patients receiving CAR-T immunotherapies, associated toxicity are less severe, and benefit of IL-6 blockade was less consistent (Vardhana and Wolchok, 2020).…”

Section: Introductionmentioning

confidence: 99%

Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories

Chen

Lausted

et al. 2020

Preprint

View full text Add to dashboard Cite

Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were co-analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8+ and CD4+ T cells, and cytotoxic CD4+ T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development.

show abstract

“…T cells are crucial for viral clearance and development of immunologic memory (Wherry and Ahmed, 2004) and are plausible contributors to immunopathology following viral infection (Channappanavar and Perlman, 2017). Both SARS-CoV-2 reactive CD4 and CD8 T cells have been detected in patients with COVID-19 (Chour et al, 2020;Grifoni et al, 2020a;Weiskopf et al, 2020a), though early studies suggest the relationship between T cell responses and the severity of COVID-19 is complex (Mathew et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, genetic susceptibilities to viral infection have been tied to variation in the major histocompatibility complex (MHC) genes that encode HLA proteins (Dutta et al, 2018;Hill, 2001). Meanwhile, functional differences in viral antigen-specific T cell responses in symptomatic and asymptomatic patients may also contribute to the biology of at-risk populations (Mathew et al, 2020;Weiskopf et al, 2020a).…”

Section: Introductionmentioning

confidence: 99%

Prioritization of SARS-CoV-2 epitopes using a pan-HLA and global population inference approach

Campbell

Steiner

Wells

et al. 2020

Preprint

View full text Add to dashboard Cite

SummarySARS-CoV-2 T cell response assessment and vaccine development may benefit from an approach that considers the global landscape of the human leukocyte antigen (HLA) proteins. We predicted the binding affinity between 9-mer and 15-mer peptides from the SARS-CoV-2 peptidome for 9,360 class I and 8,445 class II HLA alleles, respectively. We identified 368,145 unique combinations of peptide-HLA complexes (pMHCs) with a predicted binding affinity less than 500nM, and observed significant overlap between class I and II predicted pMHCs. Using simulated populations derived from worldwide HLA frequency data, we identified sets of epitopes predicted in at least 90% of the population in 57 countries. We also developed a method to prioritize pMHCs for specific populations. Collectively, this public dataset and accessible user interface (Shiny app: https://rstudio-connect.parkerici.org/content/13/) can be used to explore the SARS-CoV-2 epitope landscape in the context of diverse HLA types across global populations.

show abstract

Deep immune profiling of COVID-19 patients reveals patient heterogeneity and distinct immunotypes with implications for therapeutic interventions

Cited by 141 publications

References 62 publications

Dissecting the common and compartment-specific features of COVID-19 severity in the lung and periphery with single-cell resolution

Dissecting the common and compartment-specific features of COVID-19 severity in the lung and periphery with single-cell resolution

Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories

Prioritization of SARS-CoV-2 epitopes using a pan-HLA and global population inference approach

Contact Info

Product

Resources

About