Early cellular and molecular signatures correlate with severity of West Nile virus infection
Ho-Joon Lee,
Yujiao Zhao,
Ira Fleming,
Sameet Mehta,
Xiaomei Wang,
Brent Vander Wyk,
Shannon E. Ronca,
Heather Kang,
Chih-Hung Chou,
Benoit Fatou,
Kinga K. Smolen,
Ofer Levy,
Clary B. Clish,
Ramnik J. Xavier,
Hanno Steen,
David A. Hafler,
J. Christopher Love,
Alex K. Shalek,
Leying Guan,
Kristy O. Murray,
Steven H. Kleinstein,
Ruth R. Montgomery
Affiliations
Ho-Joon Lee
Department of Genetics and Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT 06520, USA
Yujiao Zhao
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA
Ira Fleming
The Institute of Medical Science and Engineering, Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; The Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
Sameet Mehta
Department of Genetics and Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT 06520, USA
Xiaomei Wang
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA
Brent Vander Wyk
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA
Shannon E. Ronca
Department of Pediatrics, National School of Tropical Medicine, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX 77030, USA
Heather Kang
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Chih-Hung Chou
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Benoit Fatou
Department of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Kinga K. Smolen
Department of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Ofer Levy
Department of Infectious Disease, Precision Vaccines Program, Boston Children’s Hospital, and Harvard Medical School, Boston, MA 02115, USA
Clary B. Clish
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Ramnik J. Xavier
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Hanno Steen
Department of Pediatrics, National School of Tropical Medicine, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX 77030, USA
David A. Hafler
Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA
J. Christopher Love
The Institute of Medical Science and Engineering, Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; The Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
Alex K. Shalek
The Institute of Medical Science and Engineering, Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; The Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
Leying Guan
Department of Biostatistics, Yale School of Public Health, New Haven, CT 06520, USA
Kristy O. Murray
Department of Pediatrics, National School of Tropical Medicine, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX 77030, USA
Steven H. Kleinstein
Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA; Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA
Ruth R. Montgomery
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Corresponding author
Summary: Infection with West Nile virus (WNV) drives a wide range of responses, from asymptomatic to flu-like symptoms/fever or severe cases of encephalitis and death. To identify cellular and molecular signatures distinguishing WNV severity, we employed systems profiling of peripheral blood from asymptomatic and severely ill individuals infected with WNV. We interrogated immune responses longitudinally from acute infection through convalescence employing single-cell protein and transcriptional profiling complemented with matched serum proteomics and metabolomics as well as multi-omics analysis. At the acute time point, we detected both elevation of pro-inflammatory markers in innate immune cell types and reduction of regulatory T cell activity in participants with severe infection, whereas asymptomatic donors had higher expression of genes associated with anti-inflammatory CD16+ monocytes. Therefore, we demonstrated the potential of systems immunology using multiple cell-type and cell-state-specific analyses to identify correlates of infection severity and host cellular activity contributing to an effective anti-viral response.
