Biomedical Engineering Reference
In-Depth Information
Taenia solium, and Mytilus edulis defined paramyosin as an inhibitor of the
classical complement pathway.
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Laclette et al. demonstrated that schistosome
paramyosin inhibited the haemolytic complement activity by binding to the
complement protein C1q, a component of the C1 complex. Shortly after these
results were published, Parizade et al. reported a 94 kDa complement-inhibiting
protein expressed on the surface of Schistosoma mansoni lung stage and adult
worms, called SCIP-1,
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which was later identified as a tegumental form of
paramyosin. Its ability to bind to the complement components C8 and C9
prevents their assembly into the membrane attack complex, a terminal pore-
forming complex of the complement system that inserts into the pathogen
surface resulting in cell lysis.
70,71
While paramyosin targets complement proteins at the beginning (C1q) and
the end (C8 and C9) of the cascade, schistosomes have also evolved strategies
targeting C3, a central component of the complement system. In an undis-
turbed situation, the cleavage of C3 by C3 convertases of the classical (C4b2a)
and alternative (C3bBb) pathways to its biologically active components C3a
and C3b triggers major immune events. C3a is an anaphylactic molecule that
attracts and activates inflammatory cells. The release of C3b leads to opsoni-
zation of a pathogen by phagocytic cells and generation of the C5 convertases
(C4b2a3b or C3b
2
Bb), which initiate the terminal pathway resulting in the
formation of the membrane attack complex.
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Activation of C3 is tightly
controlled, and schistosomes manipulate this regulation by using two strate-
gies: competitive inhibition using a schistosomal complement protein homolog
(CRIT) and acquisition of a host regulator (DAF).
Complement C2 Receptor Inhibitor Trispanning (CRIT) protects schisto-
somes from complement-mediated attack by competitively binding to the
complement component C2.
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CRIT has homology to C4b, the component that
would normally bind to C2. When bound to C4b, C2 is cleaved by another
complement protein to release C2b, resulting in the classical pathway C3
convertase C4b2a. CRIT's ability to bind to C2 prevents the formation of C3
convertase, thereby limiting downstream events that would result in comple-
ment-mediated damage of the parasite.
Human Decay Accelerating Factor (DAF) is a regulator of the complement
cascade that either prevents the assembly or accelerates the decay of alternative
pathway C3 convertase (C3bBb). Anchored to the surface of many types of
mammalian cells, DAF prevents activation of complement on the host's own
cells.
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Schistosomes incorporate host DAF into their membrane, thereby
preventing the activation of complement on the parasite surface.
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The use of DAF to protect the parasite is a strategy also used by Trypano-
soma cruzi, but unlike schistosomes, which acquire host DAF, T. cruzi pro-
duces its own. T. cruzi is a parasitic protozoan transmitted to human hosts via
infected insects. Within the insect vector, the parasite transforms from non-
infectious epimastigotes to infectious trypomastigotes, which are transmitted to
humans through the insect faeces. Within the human host, the infectious try-
pomastigotes are released into the bloodstream where the infection can spread.
The transition from epimastigotes to trypomastigotes coincides with the
