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Intracellular pathogens inhabit specific cellular niches determined by the degree of compartment-specific immune surveillance and the pathogen’s need for host cell activities and nutrients. Most intracellular bacteria dwell in vacuoles while only few have conquered the cytosol, a perhaps counterintuitive situation considering the abundant energy sources available in the cytosol for bacterial growth. Potent cytosolic defense mechanisms must therefore exist. I will discuss the role of cell-autonomous immunity in defending the cytosol from bacterial invasion, in particular how ‘eat-me’ signals including galectins and ubiquitin become associated with cytosol-invading bacteria, how cells transform the bacterial surface into an anti-bacterial and pro-inflammatory signaling platform, and how cargo-selecting autophagy receptors target cytosolic bacteria for destruction by autophagy.
