ABSTRACT
Infection with West Nile Virus (WNV) can drive 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 at 3 months and 1 year employing multiplexed single cell protein and transcriptional profiling (CyTOF and Seq-Well) complemented with matched serum proteomics and metabolomics. At the acute time point, we detected both an elevated proportion of pro-inflammatory markers in innate immune cell types and reduced frequency of regulatory T cell activity in participants with severe infection compared to those with asymptomatic infection. Single-cell transcriptomics of paired samples revealed that asymptomatic donors had higher expression of genes associated with innate immune pathways, in particular anti-inflammatory CD16+ monocytes at the acute time point. A multi-omics analysis identified factors--beyond those from individual analyses--that distinguished immune state trajectory between severity groups. Here we highlighted 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.
Competing Interest Statement
A.K.S. reports compensation for consulting and/or SAB membership from Merck, Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Ochre Bio, Third Rock Ventures, Hovione, Relation Therapeutics, FL82, and Dahlia Biosciences. J.C.L., A.K.S. and the Massachusetts Institute of Technology have filed patents related to the single-cell sequencing methods used in this work. J.C.L. has interests in Sunflower Therapeutics PBC, Honeycomb Biotechnologies, OneCyte Biotechnologies, Alloy Therapeutics, QuantumCyte, and Repligen. J.C.L.'s interests are reviewed and managed under Massachusetts Institute of Technology's policies for potential conflicts of interest. R.J.X. is a co-founder of Celsius Therapeutics and Jnana Therapeutics. S.H.K. receives consulting fees from Peraton.