People critically ill with COVID-19 exhibit peripheral immune profiles predictive of mortality and reflective of SARS-CoV-2 lung viral burden

Anthony R Cillo; Ashwin Somasundaram; Feng Shan; Carly Cardello; Creg J Workman; Georgios D Kitsios; Ayana T Ruffin; Sheryl Kunning; Caleb Lampenfeld; Sayali Onkar; Stephanie Grebinoski; Gaurav Deshmukh; Barbara Methe; Chang Liu; Sham Nambulli; Lawrence P Andrews; W Paul Duprex; Alok V Joglekar; Panayiotis V Benos; Prabir Ray; Anuradha Ray; Bryan J McVerry; Yingze Zhang; Janet S Lee; Jishnu Das; Harinder Singh; Alison Morris; Tullia C Bruno; Dario A A Vignali

doi:10.1016/j.xcrm.2021.100476

People critically ill with COVID-19 exhibit peripheral immune profiles predictive of mortality and reflective of SARS-CoV-2 lung viral burden

Cell Rep Med. 2021 Dec 21;2(12):100476. doi: 10.1016/j.xcrm.2021.100476. Epub 2021 Dec 2.

Authors

Anthony R Cillo^{1

2}, Ashwin Somasundaram^{1

2}, Feng Shan^{1

2

3}, Carly Cardello^{1

2}, Creg J Workman^{1

2}, Georgios D Kitsios⁴, Ayana T Ruffin^{1

2

5}, Sheryl Kunning^{1

2}, Caleb Lampenfeld^{1

2}, Sayali Onkar^{1

2

5}, Stephanie Grebinoski^{1

2

5}, Gaurav Deshmukh⁶, Barbara Methe⁴, Chang Liu^{1

2}, Sham Nambulli^{7

8}, Lawrence P Andrews^{1

2}, W Paul Duprex^{7

8}, Alok V Joglekar^{1

9}, Panayiotis V Benos^{10

11}, Prabir Ray^{1

12}, Anuradha Ray^{1

12}, Bryan J McVerry⁴, Yingze Zhang⁴, Janet S Lee^{4

13}, Jishnu Das^{1

9}, Harinder Singh^{1

9}, Alison Morris^{1

4}, Tullia C Bruno^{1

2

14}, Dario A A Vignali^{1

2

14}

Affiliations

¹ Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.
² Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA.
³ Integrative Systems Biology (ISB) Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
⁴ Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
⁵ Graduate Program of Microbiology and Immunology (PMI), University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
⁶ Meso Scale Discovery, A division of Meso Scale Diagnostics, LLC, 1601 Research Boulevard, Rockville, MD 20850-3173, USA.
⁷ Center for Vaccine Research, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15261, USA.
⁸ Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
⁹ Center for Systems Immunology, Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
¹⁰ Department of Computer Science, University of Pittsburgh, 4200 Fifth Avenue, Pittsburgh, PA 15260, USA.
¹¹ Department of Computational and Systems Biology, University of Pittsburgh, 3420 Forbes Avenue, Pittsburgh, PA 15213, USA.
¹² University of Pittsburgh Asthma Institute at the University of Pittsburgh Medical Center, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.
¹³ Acute Lung Injury Center of Excellence, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁴ Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA.

Abstract

Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in people critically ill with COVID-19. Here, we present high-dimensional profiling of blood and respiratory samples from people with severe COVID-19 to examine the association between cell-linked molecular features and mortality outcomes. Peripheral transcriptional profiles by single-cell RNA sequencing (RNA-seq)-based deconvolution of immune states are associated with COVID-19 mortality. Further, persistently high levels of an interferon signaling module in monocytes over time lead to subsequent concerted upregulation of inflammatory cytokines. SARS-CoV-2-infected myeloid cells in the lower respiratory tract upregulate CXCL10, leading to a higher risk of death. Our analysis suggests a pivotal role for viral-infected myeloid cells and protracted interferon signaling in severe COVID-19.

Keywords: COVID-19; COVID-19 outcome; gene modules; inflammatory cytokines; inflammatory monocytes; machine learning; severe COVID-19; single-cell RNA-seq; type I interferon.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
COVID-19 / blood
COVID-19 / immunology*
COVID-19 / mortality*
COVID-19 / virology
Critical Illness
Cytokines / blood
Gene Regulatory Networks
Humans
Inflammation
Lung / immunology*
Lung / virology
Models, Theoretical
Monocytes / immunology
Myeloid Cells / immunology
Reproducibility of Results
SARS-CoV-2 / pathogenicity*
Viral Load

Substances

Cytokines

Abstract

Publication types

MeSH terms

Substances

Grants and funding