What makes a host inhospitable? Is it when they don't offer you a drink when you arrive at their home? Clearly, this is not what makes a host inhospitable to Shigella, although the factor that makes host neutrophils unwelcoming has now been identified. In Nature, Zychlinsky and colleagues show that neutrophil elastase (NE) attacks Shigella virulence factors, making this bacterium extremely unwelcome.

In macrophages and epithelial cells, Shigella escape to the cytoplasm from phagosomes, where they would otherwise be destroyed. Neutrophils, however, trap bacterial cells inside phagosomes. So what is the difference between these host cells?

Zychlinsky and co-workers investigated the effect of human neutrophil extract enriched in granule proteins (hNEGP) on Shigella. High concentrations of hNEGP killed Shigella, and sublethal concentrations specifically decreased the levels of the secreted type III virulence factors IpaA, IpaB and IpaC, which are required for invasion of the host's cytoplasm. The level of the outer-membrane virulence protein IcsA — which is required for intracellular movement — was also specifically decreased.

Using chemical inhibitors, the authors identified NE as the perpetrator of this degradation, and showed that NE degrades virulence factors at 1,000-fold lower concentrations than those required to degrade other bacterial proteins. Zychlinsky and colleagues further illustrated the specificity of NE by showing that virulence factors were cleaved in preference to, for example, virulence-associated proteins, even though the latter were present in larger amounts in the cultures used.

In intact neutrophils, the authors found that IpaA, IpaB and IcsA were specifically degraded on Shigella infection, an event that did not occur in cells treated with an NE-specific inhibitor. So what happens to Shigella when NE is absent in vivo? In both chemically inhibited human neutrophils and NE-null mice, the authors found that bacterial cells could escape to the cytoplasm, and that this escape correlated with increased Shigella survival. By contrast, Shigella remained in the phagosomes of wild-type cells.

The authors also found that NE targets the virulence proteins of two other pathogens — Salmonella and Yersinia — and future work will investigate the NE susceptibility of other bacteria. This work establishes NE as the first neutrophil factor that targets bacterial virulence proteins. So, now we know what makes neutrophils such inhospitable hosts.