Important Extracellular Interactions between Plasmodium Sporozoites and Host Cells Required for Infection

Dundas, Kirsten; Shears, Melanie J.; Sinnis, Photini; Wright, Gavin J.

doi:10.1016/j.pt.2018.11.008

Cited by 34 publications

(47 citation statements)

References 86 publications

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“…In both assays, challenge of mice used an engineered P. berghei parasite in which the natural CSP gene has been replaced by that of P. falciparum [34]. This challenge system may not fully replicate the desired biology of P. falciparum infection of the liver [35][36][37]; however, it can test P. falciparum interventions efficiently at relatively low cost in immunocompetent mice [34]. Assays using a similar approach with transgenic sporozoite expressing Plasmodium yoelii strain specific CSP have been published by other groups [38].…”

Section: Discussionmentioning

confidence: 99%

Characterization of two in vivo challenge models to measure functional activity of monoclonal antibodies to Plasmodium falciparum circumsporozoite protein

Raghunandan

Mayer

Flores-García

et al. 2020

Malar J

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Background: New strategies are needed to reduce the incidence of malaria, and promising approaches include the development of vaccines and monoclonal antibodies (mAbs) that target the circumsporozoite protein (CSP). To select the best candidates and speed development, it is essential to standardize preclinical assays to measure the potency of such interventions in animal models. Methods: Two assay configurations were studied using transgenic Plasmodium berghei expressing Plasmodium falciparum full-length circumsporozoite protein. The assays measured (1) reduction in parasite infection of the liver (liver burden) following an intravenous (i.v) administration of sporozoites and (2) protection from parasitaemia following mosquito bite challenge. Two human CSP mAbs, AB311 and AB317, were compared for their ability to inhibit infection. Multiple independent experiments were conducted to define assay variability and resultant impact on the ability to discriminate differences in mAb functional activity. Results: Overall, the assays produced highly consistent results in that all individual experiments showed greater functional activity for AB317 compared to AB311 as calculated by the dose required for 50% inhibition (ID50) as well as the serum concentration required for 50% inhibition (IC50). The data were then used to model experimental designs with adequate statistical power to rigorously screen, compare, and rank order novel anti-CSP mAbs. Conclusion: The results indicate that in vivo assays described here can provide reliable information for comparing the functional activity of mAbs. The results also provide guidance regarding selection of the appropriate experimental design, dose selection, and group sizes.

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Section: Discussionmentioning

confidence: 99%

Characterization of two in vivo challenge models to measure functional activity of monoclonal antibodies to Plasmodium falciparum circumsporozoite protein

Raghunandan

Mayer

Flores-García

et al. 2020

Malar J

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“…In the hepatocyte that sporozoites finally invade, asexual replication by schizogony occurs within a parasitophorous vacuolar membrane [115]. The coordinated steps of transmigration, invasion and parasitophorous vacuolar membrane formation depend on specific interactions between the host and parasite proteins (reviewed in [116]). If hepatocyte invasion and development succeed, the liver stage of infection culminates with Plasmodium egressing from the liver via merosomes [117], release of merozoites and invasion of RBCs already back in the capillaries [118], giving rise to the symptomatic stages of infection (blood stage).…”

Section: Mechanisms Of Tissue Tropismmentioning

confidence: 99%

Tissue tropism in parasitic diseases

et al. 2019

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Parasitic diseases, such as sleeping sickness, Chagas disease and malaria, remain a major cause of morbidity and mortality worldwide, but particularly in tropical, developing countries. Controlling these diseases requires a better understanding of host–parasite interactions, including a deep appreciation of parasite distribution in the host. The preferred accumulation of parasites in some tissues of the host has been known for many years, but recent technical advances have allowed a more systematic analysis and quantifications of such tissue tropisms. The functional consequences of tissue tropism remain poorly studied, although it has been associated with important aspects of disease, including transmission enhancement, treatment failure, relapse and clinical outcome. Here, we discuss current knowledge of tissue tropism in Trypanosoma infections in mammals, describe potential mechanisms of tissue entry, comparatively discuss relevant findings from other parasitology fields where tissue tropism has been extensively investigated, and reflect on new questions raised by recent discoveries and their potential impact on clinical treatment and disease control strategies.

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“…In both assays, challenge of mice used an engineered P. berghei parasite in which the natural CSP gene has been replaced by that of P. falciparum [34]. This challenge system may not fully replicate the desired biology of P. falciparum infection of the liver [35] [36] [37]; however, it can test P. falciparum interventions efficiently at relatively low cost in immunocompetent mice [34]. Assays using a similar approach with transgenic sporozoite expressing Plasmodium yoelii strain specific CSP have been published by other groups [38].…”

Section: Discussionmentioning

confidence: 99%

Characterization of two in vivo challenge models to measure functional activity of monoclonal antibodies to Plasmodium falciparum circumsporozoite protein

Raghunandan¹,

Mayer

Flores-García

et al. 2020

Preprint

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Background New strategies are needed to reduce the incidence of malaria, and promising approaches include the development of vaccines and monoclonal antibodies (mAbs) that target the circumsporozoite protein (CSP). To select the best candidates and speed development, it is essential to standardize preclinical assays to measure the potency of such interventions in animal models. Methods Two assay configurations were studied using transgenic Plasmodium berghei expressing Plasmodium falciparum full-length circumsporozoite protein. The assays measured 1) reduction in parasite infection of the liver (liver burden) following an intravenous (i.v) administration of sporozoites and 2) protection from parasitaemia following mosquito bite challenge. Two human CSP mAbs, AB311 and AB317, were compared for their ability to inhibit infection. Multiple independent experiments were conducted to define assay variability and resultant impact on the ability to discriminate differences in mAb functional activity. Results Overall, the assays produced highly consistent results in that all individual experiments showed greater functional activity for AB317 compared to AB311 as calculated by the dose required for 50% inhibition (ID50) as well as the serum concentration required for 50% inhibition (IC50). The data were then used to model experimental designs with adequate statistical power to rigorously screen, compare, and rank order novel anti-CSP mAbs. Conclusion The results indicate that in vivo assays described here can provide reliable information for comparing the functional activity of mAbs. The results also provide guidance regarding selection of the appropriate experimental design, dose selection, and group sizes.

show abstract

Important Extracellular Interactions between Plasmodium Sporozoites and Host Cells Required for Infection

Cited by 34 publications

References 86 publications

Characterization of two in vivo challenge models to measure functional activity of monoclonal antibodies to Plasmodium falciparum circumsporozoite protein

Characterization of two in vivo challenge models to measure functional activity of monoclonal antibodies to Plasmodium falciparum circumsporozoite protein

Tissue tropism in parasitic diseases

Characterization of two in vivo challenge models to measure functional activity of monoclonal antibodies to Plasmodium falciparum circumsporozoite protein

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