Bacterial Pathogenesis, Molecular Basis of
569
majority of the cells that enter a phagocytic
host cell are destroyed. However, some
pathogens have evolved mechanisms that
allow them to survive within this environ-
ment. For those pathogens that do not
invade professional phagocytes, the task
of survival is somewhat facilitated in that
their host cells do not maintain an ar-
senal of host defense mechanisms as do
the phagocytes. Survival within host cells
is accomplished by a number of strate-
gies. Upon ingestion of the pathogen,
the host cell stimulates fusion of the vac-
uole harboring the pathogen (endosome)
with vacuoles that contain degradative en-
zymes (lysosomes). Some organisms such
as
Mycobacterium spp.
are able to inhibit
the fusion of the endosome to the lyso-
some, thereby eluding the toxic enzymes.
Other pathogens (e.g.
Rickettsia
and
Lis-
teria monocytogenes
) are able to dissolve
the endosomal membrane and escape di-
rectly into the cytoplasm of the cell. Still
others (e.g.
L. pneumophila
) utilize outer-
membrane proteins designated Mip that
interact with speci±c receptors on the host
cell surface to stimulate engulfment via
pathways that expose the pathogen to fewer
killing mechanisms. As an added bene±t,
L. pneumophila
is also able to inhibit the
fusion of the endosome to the lysosome.
5.6
Dissemination
Many pathogens remain localized to the
initial site of attachment, while others
are capable of dissemination within the
host. The ability to disseminate allows
th
ep
a
th
o
g
ent
om
o
v
et
oen
v
i
r
onm
en
t
s
of greater nutrient availability as well
as to increase the probability of locat-
ing a preferred niche (see preceding
text). Dissemination may involve move-
ment through cells or between cells in
the extracellular matrix. Many pathogens
are capable of eroding tissue through the
secretion of extracellular products.
Pseu-
domonas aeruginosa
and
Staph. aureus
may
secrete a large number of extracellular
products including toxins, which can have
an exfoliative effect, and collagenases and
elastases, which degrade major connective
tissue components.
Listeria monocytogenes
can take intracellular invasion one step
further to aid in dissemination. This or-
ganism makes use of various virulence
factors, including a membrane-disrupting
toxin known as Listeriolysin O, and phos-
pholipases to escape from the endosome
into the cytoplasm. Once in the cyto-
plasm, it begins to disrupt normal cellular
processes, resulting in the deposition of
ac
t
inonthebac
te
r
ia
lce
l
lsu
r
face
.These
‘‘actin tails’’ are further extended and
the organism uses these tails to move
about. The reorganization of the host cell
cytoskeleton also permits the formation
of ‘‘philopodia’’ or extensions of the in-
fected host cell. By moving through these
philopodia, the pathogen can gain access
to neighboring cells and invade them. In
this manner,
Listeria monocytogenes
is not
required to exit the host cells and re-
mains protected from the host immune
defenses.
6
Resistance to Antimicrobials
The increasing resistance of many bacte-
rial pathogens to a wider range of antimi-
crobial agents is an intriguing yet alarming
observation. Clearly, the increased use of
antibiotics by the medical profession has
contributed to the problem by placing
pressure on bacterial populations to se-
lect individual cells that can survive in
the presence of these agents. As a result,
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