The vacuole guard hypothesis: how intravacuolar pathogens fight to maintain the integrity of their beloved home

Abstract

Intravacuolar bacterial pathogens establish intracellular niches by constructing membrane-encompassed compartments. The vacuoles surrounding the bacteria are remarkably stable, facilitating microbial replication and preventing exposure to host cytoplasmically localized innate immune sensing mechanisms. To maintain integrity of the membrane compartment, the pathogen is armed with defensive weapons that prevent loss of vacuole integrity and potential exposure to host innate signaling. In some cases, the microbial components that maintain vacuolar integrity have been identified, but the basis for why the compartment degrades in their absence is unclear. In this review, we point out that lessons from the microbial-programmed degradation of the vacuole by the cytoplasmically localized Shigella flexneri provide crucial insights into how degradation of pathogen vacuoles occurs. We propose that in the absence of bacterial-encoded guard proteins, aberrant trafficking of host membrane-associated components results in a dysfunctional pathogen compartment. As a consequence, the vacuole is poisoned and replication is terminated.

Figure 1.. Host cell attacks on the replication vacuole.

Membrane traffic damage: Membrane traffic from host cells directed at the pathogen-containing compartment results in destabilization of the vacuolar membrane. The process that allows the host cell to recognize the vacuole is unknown. Xenophagic clearing. Replication compartments marked as derived from pathogens are recognized by the host as foreign. One strategy used is to ubiquitinate the vacuole, allowing recognition by autophagy adaptors followed by clearing, in a process called xenophagy. Specialized bacterial secretion systems can mark the replication vacuole as foreign. Interferon-regulated vacuole disruption. In response to pathogen attack, interferons are release, inducing expression of interferon-stimulated genes (ISGs). A subset of ISGs are believed to recognize pathogen compartments as foreign disrupting the compartment and releasing the pathogen into the cytosol. An interferon-dependent attack on the pathogen then occurs to clear of the infected cell.