Polymorphism of BIK as a Host Risk Factor for Severe Influenza

Influenza A viruses (IAVs) represent a significant and persistent threat to global public health (Lampejo, 2020). Despite the availability of antiviral drugs and vaccines (Hayden, 2001), the ongoing emergence of new strains, the potential for drug resistance, and the variable efficacy of vaccines highlight the urgent need for new therapeutic and preventative strategies (Bright et al., 2006) (Novel Swine-Origin Influenza et al., 2009). A crucial and often overlooked aspect of viral pathogenesis is the complex interplay between the virus and the host’s cellular machinery. The severity of an influenza infection is not solely determined by the viral strain but is heavily influenced by host-specific factors, particularly those that the virus can manipulate for its own benefit. Our recent findings, published in the Proceedings of the National Academy of Sciences (PNAS), uncover a novel host-virus axis involving the host protein Bcl-2-interacting killer (BIK) and the proteasome and reveal a key genetic variation that serves as a powerful predictor for severe influenza outcomes (Soni et al., 2025). Within the complex landscape of host-virus interactions, two key cellular components, BIK and the ubiquitin-proteasome system (UPS), have emerged as significant players in viral pathogenesis (Luo, 2016) (Soni et al., 2023) (Soni et al., 2025). BIK is a proapoptotic protein belonging to the Bcl-2 family, known for its role in initiating programmed cell death (Soni et al., 2023). The UPS, on the other hand, is a critical cellular pathway responsible for regulating protein degradation, thereby controlling the abundance and activity of a vast array of cellular proteins (Luo, 2016). This essay will elaborate on the central finding of our PNAS article (Soni et al., 2025), the discovery of a novel IAV-BIK-β5 axis that is pivotal in governing viral replication. This axis reveals a sophisticated mechanism by which IAVs exploit host cellular processes to enhance their infectivity and virulence.

In our in vitro studies, using human airway epithelial cells (AECs)-the primary site of influenza infection-we found that BIK is essential for efficient IAV replication. When we engineered AECs to be BIK-deficient, viral replication was significantly impaired. Conversely, in cells where BIK expression was restored or overexpressed, viral replication was markedly enhanced. This direct correlation demonstrated that BIK is not a simple bystander but an active participant in the viral life cycle.

To validate these findings in a more biologically relevant system, we moved to in vivo mouse models. Mice with airway-specific BIK overexpression exhibited a dramatic increase in viral load, exacerbated lung inflammation, and heightened mortality when challenged with IAV. This confirmed BIK’s role in promoting disease severity. In a complementary experiment, we demonstrated that BIK suppression conferred a protective effect, reducing viral replication and alleviating disease symptoms. These animal model data provide compelling evidence that BIK is a critical host factor that can be exploited by the virus to drive severe pathology.

Perhaps the most critical and clinically relevant finding of our study was the discovery of a genetic variation that underpins this proviral mechanism. We recently identified a single nucleotide polymorphism (SNP), rs738276, in the promoter region of the BIK gene (Mebratu et al., 2023). This SNP directly influences the basal expression levels of BIK in human cells. The most compelling evidence for the clinical relevance of this genetic discovery comes from the direct correlation observed between the rs738276 SNP and human influenza disease severity. The study analyzed data from the FLU09 cohort, a longitudinal study of naturally acquired influenza infection, where illness severity was meticulously defined using clinical and symptom data. Through an in-depth analysis of this cohort, we found that individuals with the specific AA genotype of rs738276, which is associated with naturally higher BIK expression, exhibited increased IAV replication in their airway cells. Critically, this genotype correlated with a higher risk of developing severe influenza infections, validating our in vitro and in vivo findings in a real-world clinical context (Soni et al., 2025). This genetic link establishes a clear host-specific risk factor for disease severity and highlights the importance of host genetics in the differential response to viral infections.

The final, and arguably most important, piece of the puzzle lay in deciphering the precise molecular mechanism by which IAV exploits this BIK-proteasome axis. We discovered that the IAV nucleoprotein (NP), a key viral component, plays a central role. The NP directly suppresses the β5 subunit of the host cell’s proteasome. This is a cunning strategy, as the suppression of β5 leads to the inhibition of BIK degradation, resulting in a stabilization and accumulation of BIK protein within the infected cell. This stabilized BIK then interacts with the viral NP, disrupting the normal protective interaction between NP and Bcl-2. By increasing the available BIK protein, the virus effectively creates a more hospitable environment for its own replication, leading to higher viral loads and more severe disease (Fig. 1). This intricate dance between viral and host proteins reveals a sophisticated mechanism of viral manipulation, demonstrating that the virus doesn’t just destroy the cell but actively remodels its internal machinery to enhance its own success.

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FIG. 1.

The BIK-IAV interaction axis and its genetic regulation as a determinant of influenza severity. (A) Influenza A virus (IAV) induces BIK which binds to viral NP to disrupt the protective Bcl2-nucleoprotein (NP) interaction. This shift enhances NP stability viral ribonucleoprotein (vRNP) assembly and stability, which enhances IAV replication resulting in increased viral loads. Pharmacologic inhibition of the BIK-NP interaction could prevent vRNP assembly and block viral replication. (B) A single nucleotide polymorphism (SNP) in the BIK promoter (rs738276) regulates basal BIK expression and influences disease outcome. Individuals with the AA genotype exhibit high BIK expression, leading to enhanced viral replication and increased risk of severe influenza. In contrast, the GG genotype is associated with low BIK expression, reduced viral replication, and protection against severe disease. This highlights BIK as both a host genetic risk factor and a potential therapeutic target for influenza.

The discovery of the IAV-BIK-β5 axis has profound implications for both influenza research and clinical practice. First, it identifies BIK as a promising new therapeutic target. While current antivirals target viral proteins, this work opens the door to developing host-directed antiviral therapies. Compounds that either inhibit BIK or restore β5 activity could be developed to treat or prevent influenza by disrupting the very cellular machinery the virus depends on. This approach could be more effective against a broader range of viral strains, as it targets a host factor rather than a rapidly mutating viral protein. This makes it a more durable strategy and potentially less susceptible to the emergence of drug resistance.

Second, the identification of the rs738276 SNP in the BIK gene offers a pathway toward personalized medicine in the context of influenza. Genetic screening for this SNP could be used to identify individuals at high risk for severe outcomes, allowing for targeted preventive measures or a more aggressive treatment plan at the onset of symptoms (Fig. 1). For example, a high-risk individual could be prioritized for early antiviral administration or provided with closer medical monitoring during an outbreak. This shift from a “one-size-fits-all” approach to a more tailored strategy holds immense promise for improving patient outcomes. Furthermore, this research provides a powerful illustration of how host genetics can predispose an individual to more severe disease, paving the way for similar discoveries in the context of other infectious diseases.

In conclusion, our study provides a new and vital perspective on host-virus interactions. By unveiling a novel molecular axis through which IAVs enhance their replication, we have not only identified a significant and quantifiable host risk factor but have also illuminated a new avenue for antiviral drug development. Understanding and targeting the host’s vulnerabilities, as opposed to just the virus itself, may be the key to developing more effective, durable, and personalized solutions for a disease that continues to challenge global health. Looking ahead, this work opens several exciting avenues for future investigation. Further research could focus on high-throughput screening of small molecules to identify specific inhibitors of BIK’s proviral function or activators of the β5 subunit. Additionally, a deeper exploration of the molecular details of the BIK-NP interaction could pave the way for designing peptides or small molecules that specifically block this crucial protein-protein interaction. Clinically, large-scale, multi-center studies are needed to further validate the rs738276 SNP as a reliable biomarker for influenza severity across diverse populations (Fig. 1). Ultimately, the insights gained from this study could be applied to other viral diseases, such as those caused by coronaviruses or respiratory syncytial virus, where host factors similarly play a critical role in pathogenesis. The foundation of this research points to a new era of antiviral strategies built upon the nuanced understanding of host-virus dynamics.