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a recent study demonstrated that a pest - like sequence present at the nh2 terminus of llo and absent in pfo is responsible for the rapid degradation of llo in the host cell cytosol ( decatur and portnoy , 2000 ) .
pest - like sequences are thought to target eukaryotic proteins for phosphorylation and degradation , and deletion or specific amino acid substitution of this sequence in llo led to increased cytotoxicity and lower virulence in a mouse model . when the sequence was introduced in pfo and the chimeric toxin expressed in l. monocytogenes ,
bacteria were less toxic than those expressing wild - type pfo and were able to multiply intracellularly in j774 macrophages .
thus , introduction of a pest motif in llo is a strategy used by l. monocytogenes to restrict the activity of this powerful toxin to the host cell vacuole , thereby preserving the intracellular niche for bacterial multiplication .
intriguingly , another report ( lety et al . , 2001 ) has also shown that l. monocytogenes mutants expressing a pest - deleted hly allele , although fully hemolytic , are strongly impaired in virulence in a mouse model .
however , in contrast to the previous report , in which j774 nonbactericidal macrophages were used , the authors of this second report used bone marrow  derived macrophages and showed that pest - deleted or -substituted mutants were unable to escape from the phagocytic vacuole raising the interesting possibility that the pest motif may play different roles in different cells .
direct evidence for a link between the optimum activity at low ph and compartment - specific pore - forming activity of llo has been provided by a recent study using a ph - sensitive and membrane - impermeant fluorophore 8-hydroxy - pyrene-1,3,6-trisulfonic acid ( hpts ) . it was shown that l. monocytogenes containing phagosomes ( average ph 5.9 ) rapidly acidify after bacterial uptake , followed by an increase in ph and dye release from the vacuole .
perforation of the vacuole was inhibited by lysosomotropic agents , such as ammonium chloride and bafilomycin a1 ( beauregard et al . , 1997 ) .
bafilomycin a1 was also shown to inhibit l. monocytogenes escape from the primary vacuole in epithelial cells ( conte et al . , 1996 ) .
these experiments indicate that llo activity is maximal in the phagosome lumen , requires this low ph for activity and leads to membrane disruption , increasing ph , and inactivation of llo activity , an auto - switch process . in their recent study ,
glomski et al . ( 2002 ) , by swapping dissimilar residues from the ph - insensitive ortholog perfringolysin o into llo , identified leucine 461 of llo as a key residue responsible for the low optimum ph activity of llo . changing this residue to threonine results in a molecule highly active at ph 7 .
if one assumes that llo shares with pfo , a general structure similarity , the l461 t mutation is located in the outer loop of the fourth domain ( fig .
1 ) . that a single amino acid residue is sufficient to increase the activity at ph 7.0 is quite astonishing , although it is important to note that activity at ph 5.0 is also increased in the mutant .
how this single amino acid change llo l461 t affects ph sensitivity thus awaits further biochemical analysis .
interestingly , the mutation that altered the optimum ph activity of pfo l462f described above was located in the conserved undecapeptide , which is very close to the region of the corresponding l461 t mutation ( jones et al . , 1996 ) .
it is particularly worth noting that while the llo l461 t mutant can efficiently permeabilize the host cell membrane from the cytosolic compartment , it only promotes efficient escape from the vacuolar compartment if this latter has been acidified , suggesting that additional bacterial or host factors activated by low ph are needed to act in concert with llo to mediate escape from the phagosomal compartment .
these findings could also reflect the difference in lipid composition of the internal versus external leaflets of the plasma membrane lipid bilayer , resulting in a difference in the behavior of llo depending on the nature of the first leaflet with which it is in contact . while it is clear that llo is largely responsible for mediating escape from the vacuole in most cell lines , two l. monocytogenes plcs also play a role .
mutants lacking both the broad - range plc ( plcb ) and a phosphatidylinositol - specific plc ( plca ) escape from a macrophage vacuole at 50% of the efficiency of the wild - type .
plcb can even replace llo in some cell lines , such as the human epithelial cell lines hela and henle 407 ( vazquez - boland et al .
optimal pore formation occurs between ph 5.5 and 6.0 , the ph of an early endosome .
one consequence of the pore formation is an elevation of the vacuolar ph , which may prevent vacuolar maturation , thus allowing the l. monocytogenes plcs , perhaps in concert with additional host factors , to mediate vacuolar dissolution .
llo activity is then progressively switched off and degraded and bacterial multiplication can take place in the host cytosol .
meanwhile , llo may have induced a series of signaling events since it is now well established that in addition to its role in escape from the phagosomal vacuole , llo is one of the most potent l. monocytogenes signal - inducing molecules ( vazquez - boland et al . , 2001 ) .
cholesterol - dependent cytolysins ( cdcs ) * are produced by a large number of pathogenic gram  positive bacteria . 
 a member of this family , listeriolysin o ( llo ) , is produced by the intracellular pathogen listeria monocytogenes . 
 a unique feature of llo is its low optimal ph activity ( 6 ) which permits escape of the bacterium from the phagosome into the host cell cytosol without damaging the plasma membrane of the infected cell . in a recent study ( glomski et al . , 2002 , this issue ) 
 , portnoy 's group has addressed the molecular mechanism underlying the ph sensitivity of llo . 
 unexpectedly , a single amino acid substitution in llo l461 t results in a molecule more active at neutral ph and promoting premature permeabilization of the infected cells , leading to attenuated virulence . 
 this finding highlights how subtle changes in proteins can be exploited by bacterial pathogens to establish and maintain the integrity of their specific niches .