Figure 23–22 Choices that an intracellular pathogen faces. After entry into a host cell, generally through phagocytosis into a membrane-enclosed compartment, intracellular pathogens can use one of three strategies to survive and replicate. Pathogens that follow strategy (1) include all viruses, Trypanosoma cruzi, Listeria monocytogenes, and Shigella flexneri. Those that follow strategy (2) include Mycobacterium tuberculosis and Legionella pneumophila. Those that follow strategy (3) include Salmonella enterica, Coxiella burnetii, and Leishmania.
Some Intracellular Pathogens Escape from the Phagosome into the Cytosol
The intracellular parasites just discussed raise a general problem that faces all intracellular pathogens, including viruses, bacteria, and eukaryotic parasites: they must find a cell compartment in which they can replicate. After their endocytosis by a host cell, they usually find themselves in an endosomal compartment, which normally would fuse with lysosomes to form a phagolysosome—a dangerous place for pathogens. To survive, pathogens use a variety of strategies. Some escape from the endosomal compartment before such fusion. Others remain in the endosomal compartments but modify it so that it no longer fuses with lysosomes. Still others have evolved to weather the harsh conditions in the phagolysosome (Figure 23–22).
Trypanosoma cruzi uses the escape route by secreting a pore-forming toxin that lyses the lysosome membrane, releasing the parasite into the host cell’s cytosol (see Figure 23–21). The bacterium Listeria monocytogenes uses a similar strategy. Following phagocytosis by the zipper mechanism, it secretes a protein called listeriolysin O, which disrupts the phagosomal membrane, releasing the bacteria into the cytosol (Figure 23–23).
Many Pathogens Alter Membrane Traffic in the Host Cell to Survive and Replicate
The survival and reproduction of many intracellular pathogens requires that they modify membrane (vesicular) traffic in the host cell. They may, for example, prevent the normal fusing of endosomes with lysosomes, or adapt themselves to 1 2 uptake by zipper mechanism 3 listeriolysin secretion 4 listeriolysin-mediated membrane disruption 5 bacterial release and replication 6 secreted listeriolysin now destroyed in host proteasomes phagosome proteasome pH <6.0 pH >6.0
Figure 23–23 escape of Listeria monocytogenes by selective destruction of the phagosomal membrane. The bacterium attaches to E-cadherin on the surface of host epithelial cells and induces its own uptake by the zipper mechanism (see Figure 23–19A). Within the phagosome, the bacterium secretes the protein listeriolysin O, which is activated at pH <6 and forms oligomers in the phagosome membrane, thereby creating large pores and eventually disrupting the membrane. Once in the host-cell cytosol, the bacteria begin to replicate and continue to secrete listeriolysin O; because the pH in the cytosol is >6, however, the listeriolysin O there is inactive and is also rapidly degraded by proteasomes. Thus, the host cell’s plasma membrane remains intact.
resist the lysosome’s antimicrobial armaments. Intracellular pathogens must also provide a pathway for importing nutrients from the host cytosol into their compartment of choice.