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Molecular Mechanism of Complement Inhibition by the African Trypanosome Receptor ISG65


Core Concepts
ISG65, a receptor on the surface of African trypanosomes, binds to complement component C3b through two distinct interfaces, forming a conjugate that may dampen the complement response and promote trypanosome survival.
Abstract
The content describes the molecular mechanism by which the African trypanosome receptor ISG65 inhibits the complement system, a key component of the innate immune response. Key highlights: ISG65 binds to complement C3b through two distinct interfaces - one involving the TED domain and another involving the CUB domain of C3b. This dual binding enhances the affinity of ISG65 for C3b compared to the isolated TED domain (C3d). ISG65 does not prevent the conversion of C3 to the active C3b form or the formation of the C3 convertase enzyme complex (C3bBb). However, ISG65 forms a specific conjugate with newly formed C3b, potentially acting as a decoy to reduce C3b deposition on the trypanosome surface. The binding sites of ISG65 on C3b overlap with those for complement receptors CR2 and CR3, which are involved in immune cell recruitment and activation. By blocking these interactions, ISG65 may reduce complement-mediated clearance of trypanosomes by the host. The combined effects of enhancing C3b binding, forming a C3b conjugate, and blocking complement receptor interactions suggest that ISG65 employs multiple mechanisms to dampen the overall complement response and promote trypanosome survival.
Stats
Complement C3 is present at 600 nM concentration in the assays. Complement Factor B is present at 600 nM concentration in the assays. Complement C3b and Factor D are each present at 12 nM concentration in the assays. ISG65 is present at 2 μM concentration in the assays.
Quotes
"ISG65 does not prevent the conformational changes which occur as C3 is converted to C3b, with no difference in conformation of free C3b and ISG65-bound C3b." "ISG65 does not block the binding sites occupied by factors B or D, or the site proposed to be occupied by subsequent C3 molecules." "ISG65 forms a specific conjugate with newly formed C3b, potentially acting as a decoy to reduce C3b deposition on the trypanosome surface."

Deeper Inquiries

How might the formation of the ISG65-C3b conjugate impact the downstream activation of the complement cascade, such as the generation of the C5 convertase and the membrane attack complex

The formation of the ISG65-C3b conjugate can have significant implications for the downstream activation of the complement cascade. By preferentially conjugating with C3b on the trypanosome surface, ISG65 may interfere with the efficient assembly of the C5 convertase. The C5 convertase is crucial for the cleavage of complement factor C5, leading to the recruitment of factors C6, C7, C8, and C9 to form the membrane attack complex (MAC). The conjugation of ISG65 with C3b may disrupt the normal progression of the complement cascade, potentially reducing the formation of the C5 convertase and subsequent MAC assembly. This interference could impede the trypanosome's susceptibility to complement-mediated lysis, allowing it to evade the destructive effects of the MAC and prolong its survival in the host.

What other complement evasion strategies might African trypanosomes employ in addition to ISG65, and how do these mechanisms work together to promote long-term survival in the host

In addition to ISG65, African trypanosomes may employ other complement evasion strategies to promote long-term survival in the host. One such mechanism could involve the modulation of host complement regulators to prevent the amplification of the complement cascade. By interfering with the regulatory proteins that control complement activation, trypanosomes can evade immune detection and clearance. Furthermore, trypanosomes may also utilize surface molecules that mimic host proteins to evade complement recognition and attack. By expressing surface proteins that resemble host cell markers, trypanosomes can trick the immune system into tolerating their presence, allowing them to persist in the host without triggering a robust immune response. These complement evasion strategies, in conjunction with ISG65, work synergistically to create a multifaceted defense mechanism that shields trypanosomes from the host immune response. By employing a combination of tactics to dampen complement activation and evade immune surveillance, trypanosomes can establish chronic infections and evade clearance by the host immune system.

Given the diverse roles of complement receptors CR2 and CR3 in immune cell function, how might the blockade of these receptors by ISG65 impact the broader host immune response beyond just complement-mediated clearance of trypanosomes

The blockade of complement receptors CR2 and CR3 by ISG65 can have broad implications for the host immune response beyond just complement-mediated clearance of trypanosomes. CR2, also known as CD21, is primarily expressed on B cells and plays a crucial role in B cell activation and antibody production. By preventing the binding of C3b-conjugated trypanosomes to CR2, ISG65 may inhibit the activation of B cells and the production of specific antibodies against the pathogen. Similarly, CR3, also known as CD11b/CD18 or Mac-1, is expressed on various immune cells, including macrophages and neutrophils, and is involved in phagocytosis and immune cell activation. By blocking the interaction between C3b-conjugated trypanosomes and CR3, ISG65 may impede the recruitment and activation of phagocytic cells, reducing the host's ability to clear the infection through immune cell-mediated mechanisms. Overall, the blockade of CR2 and CR3 by ISG65 can disrupt critical immune cell functions, such as B cell activation and phagocytosis, leading to a broader impact on the host immune response beyond complement-mediated clearance. This interference with immune cell activities contributes to the overall immune evasion strategy of trypanosomes, allowing them to establish chronic infections and evade immune surveillance in the host.
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