Biomedical Engineering Reference
In-Depth Information
development of resistance to complement-mediated lysis.
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Investigations into
the resistance mechanism led to the identification of a trypomastigote DAF-like
protein (gp160) present on the surface of trypomastigotes. gp160 shares many
functional, biochemical, and genetic similarities with human DAF. Like DAF,
it binds to C3b, prevents its assembly into C3 convertase (C3bBb), and is
anchored to the parasite membrane by a glycosyl-phosphatidylinositol link-
age.
76
In addition to the alternative pathway-specific inhibitory activity of
gp160, T. cruzi produces a classical pathway inhibitory molecule, T. cruzi
calreticulin (TcCRT).
77
Calreticulin is present in the cells of all higher organ-
isms, and one of its many functions is the ability to inhibit C1q-dependent
complement activity.
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. TcCRT shares approximately 50% homology with
human calreticulin and up to 80% in certain functional regions.
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Like human
calreticulin, TcCRT has been shown to inhibit the classical pathway by inter-
fering with C1q.
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Similar to the DAF-like proteins, TcCRT interferes with the
assembly of a complement complex, in this case C1. The C1 complex comprises
a serine protease (C1r-C1s)
2
unit that binds to collagenous tail of C1q. The
positioning of C1r and C1s in this complex enables them to be activated and in
turn cleave downstream complement components C2 and C4.
80
TcCRT com-
petes with the (C1r-C1s)
2
unit for binding to C1q, preventing the assembly of a
functionally active C1 unit.
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Some parasites have taken a more direct approach and degrade or sequester
complement components, thereby preventing them from contributing to the
complement system. The cattle parasite Hypoderma lineatum inhibits comple-
ment by degrading the component C3. Newly hatched Hypoderma lineatum L1-
stage larvae penetrate the skin and migrate into host subcutaneous connective
tissues where they feed for several months and undergo a transition from the L1
to L3 stage.
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The L1 larvae release three serine proteases, hypodermin A, B,
and C, which enable them to migrate through the skin and combat immune
defenses.
83
Hypodermins A and B were shown to degrade the alpha and beta
chains of C3 and produce more cleavage products at a faster rate than normal
spontaneous degradation would generate.
84,85
C3 degradation by the host
machinery leads to the anaphylatoxin C3a and C3b. Subunits of these products
would attract and activate an inflammatory response. Intact fragments of these
units were not identified under hypodermin A or B degradation. It is believed
that the degradation of C3 is responsible for the reduced inflammatory
response observed in regions surrounding larvae.
82
Blood-feeding ticks must contend with the complement system both at the
site of feeding and in the gut. Tick salivary proteins have been shown to inhibit a
number of complement components including C5. Ornithodoros moubata
complement inhibitor (OmCI) is a salivary protein released by the soft tick
Ornithodoros moubata. OmCI has been shown to bind directly to C5, preventing
it from cleavage by C5 convertases of the classical or alternative pathways.
86
Unlike hypodermin A or B, OmCI does not degrade C5 but binds to it with high
anity, forming a stable complex.
87
The OmCI:C5 complex inhibits C5 from
cleavage into the anaphylatoxin C5a and C5b, a subunit of the membrane
attack complex. This inhibition protects the ticks from complement-mediated
