Medical Biology - Theses

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Type: PhD thesis × Subject: Plasmodium falciparum × Subject: malaria × Author: Kennedy, Alexander Thomas ×

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    Complement evasion mechanisms of the deadly human pathogen Plasmodium falciparum
    Kennedy, Alexander Thomas ( 2016)
    The human complement system is a front-line defence system against invading pathogens. It has over 50 different protein components that are involved either in pathogen clearance or in the regulation of complement. The two main mechanisms of clearance are direct membrane lysis or opsonisation leading to enhanced phagocytosis. Despite the presence of this potent system, many pathogens thrive in human serum due to the evolution of complement evasion strategies. One common evasion strategy involves pathogens recruiting host regulators of complement activation to down- regulate complement attack on their surfaces. Merozoites, the invasive stage of malaria parasites are exposed to serum after egress from the host red blood cell. In this thesis, we examined whether merozoites recruit human regulators of complement activation to their surface to evade complement-mediated destruction. We found that merozoites recruit the human regulators Factor H, Factor H-like 1 and C1 esterase inhibitor to their surface. Factor H and Factor H-like 1 are recruited by an interaction between the merozoite surface protein Pf92, a member of the six cysteine family of merozoite surface proteins, and the complement control protein modules 5-6 of the Factor H and Factor H-like 1 proteins. When bound to the merozoite surface, Factor H and Factor H- like 1 retain cofactor activity, a key function that allows them to down-regulate the alternative pathway of complement activation. Deletion of the Pf92 gene resulted in a loss of Factor H and Factor H-like 1 recruitment and an increased susceptibility of merozoites to immune destruction. We also showed that C1 esterase inhibitor is recruited to the merozoite surface by an interaction between PfMSP3.1, a member of the MSP3 family of merozoite surface proteins, and the C1 esterase inhibitor serpin domain. Bound C1 esterase inhibitor retained the ability to complex with complement activating proteases C1s, MASP1 and MASP2, allowing it to down-regulate both the classical and lectin pathways of complement on the merozoite surface. Deletion of the PfMSP3.1 gene led to a loss of C1 esterase inhibitor recruitment and an increase in complement deposition on merozoites. However, this resulted in enhanced merozoite invasion in the presence of active complement rather than merozoite destruction. Overall, the ability of merozoites to sequester host complement regulators has important implications for the immune evasion strategy of malaria parasites amid a growing body of evidence for an important role of complement in protection.