Bacterial immune system Clover attacks viruses without harming host cell

Bacterial defense system balances virus fight and self-harm

Scientists have discovered a sophisticated bacterial immune system, named Clover, that can attack viruses without poisoning its own host cell. The system solves a fundamental problem in antiviral defense: disrupting a cell's nucleotide pool starves viruses of building blocks but also causes toxic side effects for the cell itself.

The research, published in Nature, reveals a two-protein machine. The effector protein, CloA, is a dGTPase enzyme that destroys a key viral nucleotide. Its partner, the regulatory protein CloB, acts as a safety switch to prevent self-inflicted damage.

How the Clover system activates

CloA remains inactive until it detects a specific sign of viral infection. The study found that many phages—viruses that infect bacteria—produce enzymes that cause a spike in cellular levels of a nucleotide called dTTP.

This phage-induced dTTP surge is the trigger. It binds to CloA at an allosteric site, activating the enzyme. Once active, CloA begins hydrolyzing, or breaking down, the nucleotide dGTP, depleting the pool a virus needs to replicate.

The built-in safety mechanism

Left unchecked, CloA's destruction of dGTP would be toxic to the bacterial cell. This is where CloB provides critical regulation. In the absence of an active phage infection, CloB synthesizes a unique inhibitory signal molecule.

This molecule, named p3diT (5′-triphosphothymidyl-3′5′-thymidine), is structurally related to dTTP. It binds to a different site on CloA, suppressing its activity and preventing the immune system from attacking the cell it's meant to protect.

The system creates a precise balance. A strong viral dTTP signal overpowers the inhibitory p3diT signal, flipping CloA into its active, antiviral state. When the infection is gone, CloB's p3diT signal keeps the defense on standby.

Structural biology reveals the switch

The team used cryo-electron microscopy to visualize the CloA protein in both its active and suppressed states. The structures show how the two nucleotide signals act like keys in different locks to control the enzyme's function.

The viral dTTP activates CloA by binding to one allosteric site, changing the protein's shape to enable dGTP hydrolysis. The self-produced p3diT inhibitor binds to a separate site, locking CloA in an inactive conformation.

"The structures reveal how these two nucleotides compete to regulate the effector function," the authors note. This direct visualization explains the precise molecular switch that prevents autoimmune toxicity.

A new model for immune regulation

The discovery of Clover provides a new model for how immune systems can be powerful yet safe. It highlights that successful defense requires coordination of both activation and inhibition signals.

Key features of the Clover system include:

• Dual-signal regulation: Activation by a viral cue (dTTP) and inhibition by a self-cue (p3diT).
• Dynamic response: The system's state changes based on the relative concentrations of the two signaling molecules.
• Overcoming the trade-off: It achieves broad antiviral defense without the typical cost of nucleotide pool disruption.

The research defines a new mechanism where nucleotide signals coordinate the entire cycle of an immune response. It explains how cells can balance effective defense against pathogens with the need to avoid self-destruction, a principle likely relevant beyond bacterial immunity.