Shigella bacteria move between host cells by hijacking the cell’s own structural proteins to build a rocket-like actin tail that propels them through the cytoplasm and into neighboring cells. This process, called actin-based motility, lets Shigella spread laterally through the intestinal lining without ever leaving the protective interior of host cells, effectively hiding from the immune system while causing widespread tissue damage.
Building the Actin Tail
The entire process starts with a single bacterial surface protein called IcsA (also known as VirG). IcsA sits at just one pole of the bacterium, like a nozzle on a rocket. This protein is the only Shigella-specific factor needed for movement. Researchers confirmed this by engineering harmless E. coli bacteria to produce IcsA on their surface. Those modified bacteria moved through cell extracts at speeds comparable to actual Shigella, proving that IcsA alone is enough to drive the system.
What IcsA actually does is recruit the host cell’s own machinery for building actin filaments. It binds a host protein called N-WASP, which normally helps cells form finger-like projections during routine cellular tasks. IcsA mimics the way the cell’s own signaling molecule (Cdc42) activates N-WASP, essentially flipping a molecular switch that was designed for the cell’s use. Once activated, N-WASP pulls in a second host complex called Arp2/3, forming a three-part assembly (IcsA, N-WASP, and Arp2/3) that rapidly generates new actin filaments at the bacterial surface. When researchers depleted Arp2/3 from cell extracts, Shigella movement stopped completely.
The result is a polarized “comet tail” of actin filaments that grows continuously behind the bacterium, pushing it forward through the cell’s interior like a jet trail. N-WASP concentrates at the bacterial surface where IcsA sits, while the Arp2/3 complex distributes throughout the growing tail. Some accessory proteins, like profilin, can speed the process up but aren’t strictly required.
Targeting the Weak Spots Between Cells
Shigella doesn’t crash into neighboring cells at random. As bacteria propelled by their actin tails reach the edge of a cell, they preferentially head toward spots where three cells meet, called tricellular junctions. These junctions are marked by a protein called tricellulin, and they represent natural weak points in the tissue barrier. When researchers depleted tricellulin from cells, Shigella spread dropped more sharply than when they removed proteins found at the more common two-cell junctions. Interestingly, Listeria (another bacterium that uses actin-based motility) takes a different route, crossing into adjacent cells below the standard two-cell junctions instead.
Pushing Into the Next Cell
When a motile Shigella bacterium reaches the plasma membrane at a cell junction, it doesn’t stop. The force generated by actin polymerization pushes the membrane outward, creating a finger-like protrusion that extends into the neighboring cell. Think of pressing your finger into a balloon: the bacterium is your finger, and the balloon is the membrane of the adjacent cell.
These protrusions rely on the same IcsA and N-WASP/Arp2/3 machinery that powers movement in the cytoplasm, but additional host proteins join in. Formins, a family of actin-building proteins that work independently of Arp2/3, contribute to efficient protrusion formation. Motor proteins called myosins also play a role. Myosin X localizes along the sides of the protrusion, bridging the actin skeleton to the surrounding membrane and potentially ferrying molecular cargo to the protrusion tip. Myosin II and its regulator MLCK further support the process.
Escaping the Double Membrane
Once the protrusion is engulfed by the neighboring cell, the bacterium ends up trapped inside a pocket wrapped in two layers of membrane: one from the original host cell and one from the new cell. To complete the transfer, Shigella must break out of this double-membrane vacuole. It does so using its type III secretion system, a needle-like injection apparatus that delivers specialized proteins directly into the vacuole membranes. These proteins punch through both layers, freeing the bacterium into the fresh cytoplasm of the new host cell. From there, a new actin tail forms, and the cycle repeats.
How the Host Fights Back
Host cells aren’t entirely defenseless against this hijacking. Proteins called septins, part of the cell’s own structural skeleton, can recognize Shigella and trap individual bacteria in cage-like structures that block actin tail formation. Septins detect the curved bacterial surface using a specialized sensing domain and assemble as filaments directly on the bacterium. Another group of host defense proteins called GBPs can similarly prevent actin tail assembly. These defenses don’t always succeed, but they represent the cell’s attempt to stop lateral spread before it starts.
Temperature as an On Switch
Shigella only activates its spreading machinery under the right conditions. The genes controlling motility and invasion, including the gene encoding IcsA, are temperature-regulated. Bacteria grown at human body temperature (37°C) are fully invasive. At 30°C, they produce none of the required virulence proteins and cannot invade cells at all. At 33°C, invasion is only partial, and by 35°C, bacteria are as invasive as at 37°C. This built-in thermostat ensures Shigella conserves energy until it reaches the warm environment of the human gut, where spreading from cell to cell causes the mucosal ulceration, inflammation, and bleeding characteristic of shigellosis.
How Shigella Compares to Listeria
Shigella and Listeria monocytogenes both use actin-based motility to spread between cells, but they evolved the strategy independently and rely on different surface proteins. Listeria uses a protein called ActA, which directly mimics host signaling proteins to recruit actin-building machinery. Shigella’s IcsA takes a more indirect route, binding and activating N-WASP as an intermediary step before engaging the Arp2/3 complex. Despite these biochemical differences, the resulting actin tails are structurally identical, with matching filament dynamics. The two pathogens converged on the same physical solution through different molecular paths, a striking example of evolutionary convergence in bacterial virulence.