A Systems Virology Framework for Understanding Lassa Mammarenavirus Pathogenesis in Nigerian Haemorrhagic Fever Patients: Integrating Transcriptomics, Proteomics, and Immunophenotyping

Lassa fever pathogenesis in severe human infection remains incompletely characterised at the molecular level, limiting the development of host-directed therapeutics and prognostic biomarkers. This study develops a systems virology framework for understanding Lassa mammarenavirus pathogenesis in Nigerian patients, integrating multi-omic approaches across matched cohorts of severe, mild, and convalescent cases. Whole blood RNA-sequencing (bulk and single-cell), plasma proteomics by tandem mass spectrometry, and mass cytometry-based deep immunophenotyping will be performed on longitudinal samples collected from Lassa fever patients at the Irrua Specialist Teaching Hospital, Edo State, and Ondo State Hospital. Transcriptomic analysis will identify differentially expressed host genes in innate immune and coagulation pathways. Proteomic datasets will characterise plasma biomarker signatures distinguishing fatal from non-fatal outcomes. CyTOF immunophenotyping will resolve NK cell, T cell, and monocyte subset dynamics during acute infection versus convalescence. An integrative multi-omic network model will be constructed using systems biology tools to identify hub genes and pathway intersections driving immunopathology. This study addresses a critical gap: existing Lassa fever pathogenesis data are largely from animal models that poorly recapitulate human disease. By anchoring all analyses in authenticated Nigerian patient samples, this research provides the most contextually valid systems-level portrait of Lassa fever pathogenesis generated to date, with direct implications for therapeutic target prioritisation and biomarker-guided clinical management in endemic West African settings. Keywords: Lassa fever, systems virology, transcriptomics, proteomics, immunopathogenesis