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

doi:10.1016/j.isci.2023.108387

Early cellular and molecular signatures correlate with severity of West Nile virus infection

iScience. 2023 Nov 2;26(12):108387. doi: 10.1016/j.isci.2023.108387. eCollection 2023 Dec 15.

Authors

Ho-Joon Lee¹, Yujiao Zhao², Ira Fleming^{3

4

5}, Sameet Mehta¹, Xiaomei Wang², Brent Vander Wyk², Shannon E Ronca⁶, Heather Kang⁴, Chih-Hung Chou⁴, Benoit Fatou⁷, Kinga K Smolen⁷, Ofer Levy⁸, Clary B Clish⁴, Ramnik J Xavier^{4

9

10}, Hanno Steen⁶, David A Hafler¹¹, J Christopher Love^{3

4

5}, Alex K Shalek^{3

4

5}, Leying Guan¹², Kristy O Murray⁶, Steven H Kleinstein^{13

14}, Ruth R Montgomery²

Affiliations

¹ Department of Genetics and Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT 06520, USA.
² Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
³ The Institute of Medical Science and Engineering, Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ The Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
⁶ Department of Pediatrics, National School of Tropical Medicine, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA.
⁷ Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁸ Department of Infectious Disease, Precision Vaccines Program, Boston Children's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
⁹ Center for Computational and Integrative Biology and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
¹⁰ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹¹ Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA.
¹² Department of Biostatistics, Yale School of Public Health, New Haven, CT 06520, USA.
¹³ Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
¹⁴ Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.

Abstract

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.

Keywords: Diagnostics; Virology.

Abstract

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