Mostafa Rezapour, David A Ornelles, Stephen J Walker, Colin E Bishop, Sean V Murphy, Metin Nafi Gurcan, Patrick M McNutt, Anthony Atala
RSVA showed the strongest temporal expansion and developed a late response centered on intracellular transport, localization, and organelle organization. RSVB remained the most restricted response, shifting from early inflammatory and signaling-associated activity to a later interferon-stimulated profile. IAV maintained a broad antiviral response, whereas hMPV combined limited induction with extensive late downregulation of stress, catabolic, metabolic, and transport-related processes. A shared antiviral component was present across infections, while downregulated responses were largely virus dependent. Under five-fold outer and four-fold inner nested cross-validation, the selected genes achieved a mean outer-test Macro F1 of 0.859 and balanced accuracy of 0.888, compared with 0.604 and 0.616 for the all-gene comparator.
INTRODUCTION: Respiratory syncytial virus A (RSVA) and respiratory syncytial virus B (RSVB) may induce distinct airway host responses. We compared them with influenza A virus (IAV) and human metapneumovirus (hMPV) in airway organ tissue equivalents (OTEs) and developed the Relaxed Magnitude Altitude Score with Hub-Centric Network Analysis framework (RMAS-HCNA).
METHODS: OTEs were infected with RSVA-GFP5 or RSVB-GFP3 at low multiplicity of infection and profiled at 24 and 72 h using the NanoString nCounter Host Response Panel. Previous IAV and hMPV profiles were integrated. Analyses included source-matched differential expression, cross-virus ranking, network-based module selection, nested cross-validation, and Gene Ontology Biological Process enrichment.
RESULTS: RSVA showed the strongest temporal expansion and developed a late response centered on intracellular transport, localization, and organelle organization. RSVB remained the most restricted response, shifting from early inflammatory and signaling-associated activity to a later interferon-stimulated profile. IAV maintained a broad antiviral response, whereas hMPV combined limited induction with extensive late downregulation of stress, catabolic, metabolic, and transport-related processes. A shared antiviral component was present across infections, while downregulated responses were largely virus dependent. Under five-fold outer and four-fold inner nested cross-validation, the selected genes achieved a mean outer-test Macro F1 of 0.859 and balanced accuracy of 0.888, compared with 0.604 and 0.616 for the all-gene comparator.
DISCUSSION: The four viruses shared an antiviral foundation but followed distinct temporal and functional trajectories. The framework identified compact, biologically representative panels that generalized better than the complete measured gene set, although independent genome-wide and in vivo validation remains necessary.