Immune-Evasive Proline-283 Substitution In Influenza Nucleoprotein Shows That The Virus Is Evolving To Hijack Host Chaperones
Nikhil Prasad Fact checked by:Thailand Medical News Team Apr 29, 2024 7 months, 1 week, 5 days, 17 hours, 13 minutes ago
Influenza News: Influenza, a perennial respiratory menace, continually evolves to outwit the human immune system. A pivotal player in this evolutionary dance is the nucleoprotein (NP), a linchpin in viral replication and host immune evasion.
The immune-evasive proline-283 substitution in influenza nucleoprotein increases aggregation propensity without altering the key structure. X-ray crystal structures of Pro283 and Ser283 NP are highly similar. (A) Overlay of the Cα traces from the Pro283 and Ser283 NP crystal structures. Site 283 is marked as red. (B) Overlay of the main chain atoms for the α helix containing site 283 (spanning Ala278 to Ser287). For both (A) and (B), site 283 is marked in red. (C) RMSD per residue mapped onto the crystal structure of Ser283 NP. Site 283 is marked with a dashed line. (D) Stick representation of all atoms in the α helix containing site 283 (Ala278 to Ser287), with the predicted i + 4 ➔ i hydrogen bonds shown as yellow dashed lines. Select residues are indicated for orientation clarity. The table shows all possible i + 4 ➔ i hydrogen bonds within the α helix containing site 283 and their distances in each of the crystal structure.
A recent study by scientist from Massachusetts Institute of Technology, Cambridge-USA that is covered in this
Influenza News report, has spotlighted the Proline-283 (Pro283) substitution in NP as a key element in influenza's adaptation strategy, allowing it to evade the host's antiviral defenses, particularly the myxovirus resistance protein 1 (MxA). However, this adaptation comes at a cost to viral fitness, especially under conditions of elevated temperature and depleted host chaperones. Delving deeper into the biophysical underpinnings of Pro283's effects unveils a complex interplay between viral survival strategies and cellular machinery.
The Intricacies of Influenza NP: Structure and Function
Influenza, with its segmented RNA genome, relies on NP for packaging and trafficking viral RNA, essential for its replication and assembly into infectious virions. NP also serves as a battleground where the host's immune sentinels like MxA clash with viral invaders. MxA targets NP, seeking to block viral replication by forming complexes that hinder ribonucleoprotein access to the host cell's nucleus. This evolutionary arms race has sculpted NP, leading to critical mutations like Pro283, which render the virus resistant to MxA but impair its fitness.
Unveiling the Impact of Pro283: Biophysical Insights
Studies into Pro283's effects on NP folding and stability reveal a nuanced picture. While the substitution increases NP's propensity for aggregation during folding, it surprisingly leaves the native protein structure largely intact. This dichotomy suggests a strategic adaptation by influenza, leveraging host chaperones to navigate folding challenges and evade immune surveillance. The intric
ate dance between viral proteins and cellular chaperones underscores the dynamic nature of host-pathogen interactions.
Pro283 and Viral Fitness: A Balancing Act
The fitness landscape of Pro283 NP–encoding influenza is shaped by multifaceted pressures. While the substitution grants immune evasion capabilities, it also imposes fitness costs exacerbated by temperature variations and chaperone availability. This delicate balance highlights the intricate trade-offs inherent in viral evolution, where each adaptation comes with its set of advantages and limitations.
Chaperones as Allies: Navigating Folding Challenges
Host chaperones emerge as crucial allies in influenza's quest for survival. By stabilizing aggregation-prone conformations or guiding folding pathways, chaperones mitigate the biophysical defects induced by Pro283 substitution. The precise mechanisms by which chaperones rescue Pro283 NP underscore the sophistication of viral adaptation strategies and the interplay between viral proteins and cellular machinery.
Key Findings
This essential proline-283 substitution impairs influenza growth, a fitness defect that becomes particularly prominent at febrile temperature (39°C) when host chaperones are depleted. The study team biophysically characterize proline-283 NP and serine-283 NP to test whether the fitness defect is caused by the proline-283 substitution introducing folding defects. The study findings showed that the proline-283 substitution changes the folding pathway of NP, making NP more aggregation prone during folding, but does not alter the native structure of the protein. These findings suggest that influenza has evolved to hijack host chaperones to promote the folding of otherwise biophysically incompetent viral proteins that enable innate immune system escape.
Implications for Antiviral Strategies and Evolutionary Dynamics
Understanding the molecular basis of Pro283's impact on NP folding sheds light on potential antiviral strategies. Targeting chaperone-mediated rescue pathways could offer novel avenues for therapeutic intervention, disrupting viral survival strategies and bolstering the host's immune defenses. Furthermore, probing the evolutionary trajectories of Pro283 variants in diverse environmental contexts elucidates the intricate dance of selection pressures shaping influenza evolution.
Conclusion: Deciphering the Evolutionary Chessboard of Influenza
In the intricate interplay of host-pathogen interactions, influenza emerges as a master tactician, constantly evolving to navigate immune defenses and exploit cellular machinery. The Pro283 substitution in NP epitomizes this evolutionary strategy, offering immune evasion capabilities while posing fitness challenges. Unraveling the biophysical nuances of Pro283's impact on NP folding unveils the intricate dynamics of viral adaptation and underscores the pivotal role of host chaperones in viral survival. As we delve deeper into the molecular chessboard of influenza evolution, we gain crucial insights into potential therapeutic strategies and the ever-evolving arms race between viruses and their hosts.
The study findings were published in the peer reviewed journal: Science Advances.
https://www.science.org/doi/10.1126/sciadv.adl6144
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