The battle between viruses and the host immune system is a complex and relentless arms race, with each side evolving new strategies to outmaneuver the other. Among the many viral families, bunyaviruses represent a formidable group of pathogens responsible for significant human and animal diseases worldwide. Central to their ability to cause disease and evade the host defenses is a viral protein known as NSs. This small but potent factor orchestrates a sophisticated multifaceted attack on the host’s innate immune responses, tipping the balance in favor of viral replication and pathogenesis.
The human immune system mounts its defense against invading pathogens using two broad strategies: innate and adaptive immunity. While much remains to be uncovered about adaptive responses to bunyaviruses, neutralizing antibodies targeting viral surface glycoproteins are rapidly emerging as a pivotal mechanism in controlling infection. Viral particles first encounter immune sentinels such as dermal dendritic cells and macrophages, both highly susceptible to bunyavirus invasion. These early infection events serve as a crucial battleground where the virus attempts to establish a foothold before the full immune arsenal is activated.
Innate immunity serves as the front line against early viral spread. It relies on a network of pattern recognition receptors (PRRs) within infected cells that detect conserved features of pathogens, such as viral RNA and proteins. Prominent among these sensors are RIG-I-like receptors, certain Toll-like receptors, and protein kinase R (PKR), each specializing in recognizing RNA and triggering downstream antiviral signaling cascades. When activated, these pathways converge on central transcription factors, including NF-κB and interferon regulatory factor 3 (IRF3), culminating in the production and release of type I interferons and a suite of proinflammatory cytokines designed to thwart viral replication.
Bunyaviruses, however, have not remained passive targets. Over evolutionary time, many bunyavirus species have developed deft means to undermine PRR signaling. The NSs protein of Rift Valley fever virus (RVFV) stands out as the most extensively studied viral antagonist in this context. NSs facilitates the assembly of amyloid-like fibrillar aggregates that localize within the host cell nucleus, a feature first observed over four decades ago yet only recently understood in structural and functional terms. These NSs fibrils recruit a specialized E3 ubiquitin ligase complex, composed of host factors Skp1, Cul1, FBXW11, and β-TRCP1, which together tag the antiviral sensor PKR for proteasomal degradation.
By accelerating PKR destruction, RVFV NSs effectively silences a key antiviral defense. PKR normally acts by binding viral RNA and phosphorylating the translation initiation factor eIF2α, shutting down protein synthesis to prevent viral replication. NSs intervention prevents this translational arrest, thereby enabling continuous viral protein production and replication within infected cells. This elegant immune evasion strategy underscores how NSs subverts intrinsic cellular defense pathways at multiple levels to facilitate viral survival and spread.
Other bunyaviruses adopt similar yet distinct molecular tactics through their own NSs proteins. Toscana virus (TOSV), for example, also appears to target PKR for proteasomal degradation, though the precise molecular intermediates mediating this effect have yet to be fully characterized. Meanwhile, Sandfly fever Sicilian virus takes a unique route by directly binding and modulating the translation factor eIF2B, counteracting PKR’s attempt to inhibit translation without triggering PKR degradation. This variation in NSs function highlights the evolutionary plasticity of bunyavirus immune antagonism.
Beyond PKR interference, NSs proteins of different bunyaviruses exploit diverse strategies to block interferon production at early signaling junctures. The NSs protein of Dabie bandavirus (DABV), a contributor to severe hemorrhagic disease, forms cytoplasmic inclusion bodies sequestering critical signaling molecules such as TRIM25. TRIM25 is an E3 ubiquitin ligase essential for RIG-I activation; by capturing TRIM25, DABV NSs effectively shuts down RIG-I sensing pathways, preventing the cascade of events leading to interferon induction. This “molecular trap” mechanism illustrates another mode by which NSs disables host antiviral sensors.
Similarly, TOSV’s NSs has been shown to promote RIG-I degradation, potentially bearing intrinsic E3 ubiquitin ligase activity, thus actively removing this principal viral RNA sensor from the cell. Conversely, in Andes hantavirus, a pathogen responsible for hantavirus pulmonary syndrome, the NSs protein interferes with interferon signaling downstream of RIG-I, potentially by disrupting mitochondrial antiviral-signaling protein (MAVS) complexes. However, the precise molecular mechanisms underlying this disruption remain an active area of research, emphasizing the complex interplay between viral virulence factors and the intricate host immune machinery.
The role of NSs in bunyavirus pathogenesis exemplifies the virus’s capacity to turn host cellular processes to its advantage. Through delicate manipulation of protein degradation pathways, translational control, and signaling sequestering, NSs ensures that the viral replication cycle proceeds unimpeded while simultaneously dampening alarm signals that would otherwise recruit potent immune effectors. This nuanced immune subversion is a hallmark of bunyavirus virulence and offers promising avenues for therapeutic intervention.
In parallel, arenaviruses—virus cousins to bunyaviruses—utilize related immune evasion strategies through different viral proteins. The arenavirus Z protein prevents the interaction of RIG-I and MDA5 with MAVS, thus blocking the activation of downstream transcription factors IRF3, IRF7, and NF-κB subunit p65. These actions cripple the host’s ability to mount an effective interferon response. Arenaviral nucleoproteins further degrade viral dsRNA replication intermediates, thereby fine-tuning viral RNA synthesis to evade detection while maintaining progeny production. Together, these findings highlight a convergent strategy among negative-strand RNA viruses to target shared immune checkpoints.
The growing recognition of NSs as a master manipulator of the host antiviral response has profound implications for our understanding of bunyavirus biology and pathogenesis. Structural studies revealing its amyloid-like aggregates provide new insight into the physical nature of viral immune antagonists, while biochemical analyses elucidate the recruitment of cellular ubiquitin ligases and suppression of translational brakes. These insights pave the way for novel antiviral strategies aimed at disrupting NSs function, thereby restoring innate immune control and limiting disease severity.
Furthermore, the discovery that individual bunyaviruses tailor NSs functions to different aspects of innate immunity—whether targeting PKR, RIG-I, or downstream signaling components—underscores the need for virus-specific therapeutic approaches. Broad-spectrum antivirals may require combinations of agents countering multiple NSs-mediated antagonisms, while vaccines could benefit from engineered NSs mutants that elicit robust immune responses without pathogenicity.
In conclusion, the NSs proteins of bunyaviruses are emblematic of viral ingenuity in immune evasion. By hijacking and neutralizing central pillars of the host’s innate defenses, they convert infected cells into viral factories shielded from immune destruction. The structural and functional diversity uncovered among NSs factors across bunyavirus species spotlights a dynamic battlefield where molecular adaptations govern infection outcomes. Continued research into these multifaceted virulence determinants holds promise for unlocking new paradigms in antiviral research and disease control.
Subject of Research: NSs protein as a multifunctional virulence factor in bunyaviruses and its role in innate immune evasion.
Article Title: NSs: the multifaceted bunyavirus virulence factor.
Article References:
Duboeuf, M., Legrand, AF., Lozach, PY. et al. NSs: the multifaceted bunyavirus virulence factor. npj Viruses 3, 65 (2025). https://doi.org/10.1038/s44298-025-00146-5
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