Existing Evidence for Influenza B Virus Adaptations to Drive Replication in Humans as the Primary Host

Abstract

Influenza B virus (IBV) is one of the two major types of influenza viruses that circulate each year. Unlike influenza A viruses, IBV does not harbor pandemic potential due to its lack of historical circulation in non-human hosts. Many studies and reviews have highlighted important factors for host determination of influenza A viruses. However, much less is known about the factors driving IBV replication in humans. We hypothesize that similar factors influence the host restriction of IBV. Here, we compile and review the current understanding of host factors crucial for the various stages of the IBV viral replication cycle. While we discovered the research in this area of IBV is limited, we review known host factors that may indicate possible host restriction of IBV to humans. These factors include the IBV hemagglutinin (HA) protein, host nuclear factors, and viral immune evasion proteins. Our review frames the current understanding of IBV adaptations to replication in humans. However, this review is limited by the amount of research previously completed on IBV host determinants and would benefit from additional future research in this area.

Keywords: host adaptation; immune evasion; influenza B virus; nuclear replication; viral evolution; virus–receptor interaction.

Figure 1

Schematic representation of the structure and organization of an IBV virion and gene segments with all 11 proteins represented. Schematic created in BioRender.

Figure 2

An overview of the possible host restriction factors that promote IBV circulation in humans. (A) B-HA binding preference for α2,6-linked sialic acid residues on glycoproteins more prevalent in the human respiratory tract. (B) IBV can utilize a broad range of host proteases found in abundance in the human respiratory tract and do not rely on TMPRSS2 for B-HA activation. (A–C) The physical environment in human respiratory epithelial cells and in the extracellular environment favors human replication, including human endosomal pH ranges and upper respiratory tract temperature. (D) IBV replication requires the human importin-α protein to be present to ensure functional replication takes place, but a role as a host restriction factor is currently unclear. (E) Human ANP32 proteins are required for optimal B-Pol efficiency, and a wider range of ANP32 proteins can support B-Pol activity compared to the IAV polymerase complex. (F) B-Pol subunit PB1 and B-NS1 disrupt the host IFN response by preventing expression of anti-viral transcription factors IRF-3 and STAT1, but this interaction has not been evaluated as a possible host restriction factor. (G) B-NS1 selectively prevents ISGylation of host proteins that promote anti-viral responses through sequestration of ISG15 target proteins. (H,I) IBV avoids T-cell recognition of infected cells through surface downregulation of host MHC class I presentation (H) and the lack of a broadly reactive CD8⁺ T-cell epitope found near the NES of B-M1 (I). Diagram created in BioRender.