The pathways of host cell exit
Many bacterial, fungal and protozoan pathogens pass through a life-cycle phase, during which they persist or multiply inside host cells. While the intracellular life-style provides shelter to these microbes, they eventually need to exit the enveloping cell to ensure life-cycle progression. Hence, host cell exit is intimately linked to microbial pathogenesis and crucial for spread of the disease.
Initially viewed as a passive process, host cell exit is now seen as an orchestrated and temporally defined programme that has evolved during host-pathogen co-evolution and relies on the dynamic interplay between host and microbial factors. Although host cell exit is an essential step of the infection process, the detailed mechanisms and effector molecules involved remain largely unresolved.
Three distinct pathways of host cell exit have been postulated, which appear to have convergently evolved among the otherwise highly diverse groups of bacterial, fungal and protozoan pathogens. These pathways include
- the initiation of programmed cell death
- the active lytic destruction of the host cell
- the membrane-dependent exit without host cell lysis.
Increasing evidence indicates that the majority of intracellular pathogens utilize more than one of these pathways, dependent on life-cycle stage, environmental factors and/or host cell type. Molecules involved in the exit process are essential for microbial survival and spread and thus represent important antimicrobial targets, as illustrated for example by the recent finding that chemical inhibition of plasmodial proteases involved in the egress of the malaria parasite from the enveloping erythrocyte can block disease progression.
The priority programme aims at exploring the exit strategies used by important human pathogens, including the infectious agents of such devastating diseases as malaria, tuberculosis and typhoid fever. The priority programme will characterize in great detail the spectrum of convergently evolved exit pathways employed by human bacterial, parasitic and fungal pathogens, dissect the molecular mechanisms that trigger, regulate, mediate, and synchronize exit from their host cells and cellular compartments, and unveil the link between exit strategy and disease pathogenesis. We expect that findings of the priority programme will substantially advance our fundamental understanding of microbial pathogenesis and identify novel interventional targets to fight infections of worldwide importance.
Host cell exit by intracellular pathogens: The Achilles´ heel of intracellular life?
The currently available data suggest that host cell exit by intracellular pathogens represents a fundamental step during the infection process, which, shaped by evolutionary pressure, is crucial for microbial spread and might represent the Achilles´ heel of microbial pathogenesis.
A limited set of exit pathways appears to be shared by a high variety of phylogenetically different microbes with the involvement of similar classes of pathogen-derived proteins, particularly proteases, pore-forming proteins and phospholipases. This strongly suggests convergent evolution of the exit machineries and enhances the prospect of identifying molecules that are involved in host cell exit as promising targets for intervention strategies.
Although targeting microbial exit might not protect from primary infection, the cell-entrapment of microbes ensures immediate control of microbial tissue spread and disease progression, while still allowing the stimulation of a protective adaptive immune response thus providing therapeutic and prophylactic advantages.
Schematic depicting the host cell exit pathways
The figure depics the three pathways of the host cell exit by intracellular pathogens.
The first pathway comprises the induction of programmed cell death including non-lytic apoptosis and lytic necroptosis and pyroptosis.
The second pathway includes the active destruction of host cell membranes, here both vacuole and plasma membranes.
The third pathway comprises the induced, membrane-dependent exit without destroying the host cell, for example by actin-mediated protrusions, marked in yellow, or by budding, extrusion, exocytosis or ejection through the ejectosome, marked with a yellow box. Pathogens for which at least one of the pathways has been postulated are indicated.
The figure shown is from Flieger et al. 2018. Microb Cell 5:525-544.