Contemporary Victoria and Yamagata Influenza B Viruses Elicit Lineage-Specific Differences in Innate Immunity
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The two influenza B virus (FLUBV) lineages, Victoria and Yamagata, have continued to diverge since their separation in the 1970s, resulting in distinct antigenic characteristics and differences in immunity and cross-protection. Human epidemiological observations and experimental studies have identified lineage-specific differences in adaptive immune responses elicited by contemporary viruses, suggesting that innate immune signaling may contribute to these divergent outcomes. To understand in-depth immunity to contemporary influenza B viruses, we compared viral replication, cytokine production, gene expression, and cellular tropism following infection with representative Victoria- and Yamagata-lineage viruses. We found that, despite broadly similar cytokine profiles in the ferret upper respiratory tract, the two lineages exhibited distinct innate immune kinetics. Yamagata viruses induced rapid early expression of antiviral and inflammatory genes, including SOCS1 and multiple interferon-stimulated genes, whereas Victoria viruses displayed delayed innate immune activation accompanied by greater viral replication. Consistent with the ferret data, Yamagata viruses also induced elevated SOCS1 expression in human PBMCs early after infection. In addition, Yamagata viruses exhibited broader cellular tropism, infecting a wider range of immune cell populations than Victoria viruses. Together, these findings demonstrate that contemporary influenza B virus lineages distinctly engage the host immune system and provide new insight into how lineage-specific innate immune responses may contribute to differences in immunity, cross-protection, and the divergent evolutionary trajectories of Victoria and Yamagata viruses
Author Summary
Influenza B viruses cause substantial seasonal disease, yet the biological differences between the Victoria and Yamagata lineages that may contribute to their distinct epidemiology and immune responses remain incompletely understood. Recent studies comparing lineage-specific immunity have focused primarily on adaptive responses, leaving differences in early host–virus interactions comparatively unexplored. Here, we show that representative Victoria and Yamagata viruses differ during the earliest stages of infection. Using ferret and human immune cell models, we found differences in how the viruses trigger antiviral defenses, how efficiently they replicate, and which immune cells they infect. These findings suggest that early interactions between influenza B viruses and the immune system may help shape the distinct immunity observed between the lineages. Understanding these differences provides new insight into influenza B virus biology and may help inform our understanding of viral evolution, immunity, and future influenza vaccine development.
