Page 403 - Clinical Immunology_ Principles and Practice ( PDFDrive )

384 PARt tHREE Host Defenses to Infectious Agents

mechanism of evasion is determined by the receptor that is used are Rab3, -4, -5, -9, -7, -11, and -14. These proteins are associ-
for pathogen entry into the host cell. Internalization via CRs ated with different maturation stages of the phagosome and
inhibits the production of IL-12, a cytokine critical in facilitating chiefly orchestrate membrane fusion events to allow delivery of
macrophage activation. Engulfment by this receptor also bypasses vesicular protein cargo to the phagosomal compartment. The
activation of the oxidative burst, thereby avoiding ROI production. mycobacteria-containing phagosome acquires Rab5a but not the
Similarly, engaging mismatch repair (MMR) and DC-specific late endosomal marker Rab7a, which ultimately mediates fusion of
intercellular adhesion (DC-SIGN) molecules for uptake triggers the bacterial-containing phagosome with lysosomes that contain
secretion of the suppressive cytokines IL-10 and TGF-β. Several proteolytic enzymes active at low pH. By enabling arrest of this
intracellular bacteria also produce ROI detoxifiers, including maturation, M. tuberculosis maintains its compartment at an
superoxide dismutase and catalase, which nullify oxygen (O 2 ) early endosomal stage. This compartment does not acidify, partly
+
and hydrogen peroxide (H 2 O 2 ), respectively. Finally, a number because of a paucity of vacuolar H adenosine triphosphatase
of small bacterial products, such as the phenolic glycolipid and (ATPase); at the same time, it exchanges molecules with the
LAM of mycobacteria, scavenge ROIs. Many of the strategies plasma membrane, such as the transferrin receptor, to access
used to counteract the effects of ROIs also overlap in their effects iron. Activation of macrophages with IFN-γ restores the normal
on RNIs. A modification of lipid A renders gram-negative bacteria, maturation of the mycobacterial phagosome, resulting in a drop
including salmonellae, resistant to the effects of host antimicrobial in mycobacterial viability. Francisellae and brucellae are engulfed
peptides. by phagosomes that acquire the early endosomal markers EEA1
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and Rab5a. The Francisella-containing vacuole acquires late
Intraphagosomal Survival endosomal markers, but the pathogen escapes into the cytosol
Inhibition of phagolysosome fusion represents a major intracel- by perforating the late endosomal membrane. After a transient
lular survival strategy for a number of intracellular bacteria, phagosomal stage, brucellae enter compartments enclosed by
including M. tuberculosis, Francisella spp., Brucella spp., and L. endoplasmic reticulum (ER) membranes to escape delivery to
monocytogenes (Fig. 26.2). After engulfment, these pathogens phagolysosomes.
manipulate the endocytic fate of the phagosome that contains
them. This is achieved in part by manipulation of Rab GTPases, Phenotypic Plasticity of the Infected Cell
proteins required for normal endocytic trafficking, positioned The ability of intracellular bacteria to influence the phenotypic fate
30
in the phagosome membrane. Rab GTPases associated with of both the cell in which it dwells and the cells within lesions that
phagosome maturation of the pathogen-containing phagosome form as a result of unresolved infection is becoming increasingly

Brucella
Francisella
Early endosome
Golgi Early BCV markers
EEA1 EEA1
Rab5 Rab5

Late endosome
ER Intermediate BCV markers Actin
Lamp-1, 2
Lamp-1 Rab5

ER
Replicative BCVs
Listeria

Rab5
Modified
phagosome
Mycobacterium
FIG 26.2 Inhibition of Phagolysosome Fusion Represents a Major Survival Strategy for a
Number of Intracellular Bacteria, Including Mycobacterium Tuberculosis, Francisella spp.,
Brucella spp., and Listeria Monocytogenes. The mycobacteria-containing phagosome acquires
Rab5 but not the late endosomal markers Lamp-1 and 2, enabling arrest of maturation of this
compartment at an early endosomal stage. Francisella spp. and Brucella spp. are engulfed by
phagosomes that acquire the early endosomal markers EEA1 and Rab5. The Francisella-containing
vacuole acquires late endosomal markers but escapes into the cytosol by perforating the late
endosomal membrane. A similar strategy is adopted by L. monocytogenes. After a transient
phagosomal stage, brucellae enter compartments enclosed by endoplasmic reticulum (ER)
membranes to escape delivery to phagolysosomes. BCV, Brucella-containing vacuole.