Molecular basis of erythrocyte invasion by<i>Plasmodium</i>merozoites

Gaur, Deepak; Chitnis, Chetan E.; Chauhan, Virander S.

doi:10.1002/9781118493816.ch3

Cited by 4 publications

(6 citation statements)

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“…Plasmodium falciparum is primarily responsible for most worldwide malaria mortality [1]. The clinical symptoms and pathology of malaria are associated with the blood stages of the parasite life cycle, which involves a crucial and complex multistep process of erythrocyte invasion mediated by diverse ligand-receptor interactions [2][3][4]. Erythrocyte invasion is considered an attractive target for malaria vaccine development [5,6].…”

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confidence: 99%

“…However, the key challenge is the identification of essential, conserved target antigens that induce potent cross-strain parasiteneutralizing antibodies [5,6]. Merozoite surface proteins (MSPs) and reticulocyte binding-like homologous (RH) proteins play a critical role in P. falciparum erythrocyte invasion [2][3][4]. Merozoite surface protein-1 is an essential protein that mediates initial attachment of the parasite to the erythrocyte membrane [2][3][4].…”

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confidence: 99%

“…Merozoite surface proteins (MSPs) and reticulocyte binding-like homologous (RH) proteins play a critical role in P. falciparum erythrocyte invasion [2][3][4]. Merozoite surface protein-1 is an essential protein that mediates initial attachment of the parasite to the erythrocyte membrane [2][3][4]. Although, full-length MSP-1 is highly polymorphic, a C-terminal processed fragment, MSP-1 19 , is highly conserved and elicits potent invasion-inhibitory antibodies [14].…”

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confidence: 99%

“…The RH protein family (RH1, RH2, RH4, RH5) function downstream of the MSPs, exhibit limited polymorphism and primarily define the invasion phenotype of P. falciparum strains [2][3][4][21][22][23][24][25][26][27]. RH5, a leading blood-stage vaccine candidate, is the only indispensable member that plays an essential role in erythrocyte invasion [25,26] and elicits potent parasite-neutralizing antibodies [11,12,28].…”

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Antibody Combinations Targeting the Essential Antigens CyRPA, RH5, and MSP-119 Potently Neutralize Plasmodium falciparum Clinical Isolates From India and Africa

Singh

Mian

Pandey

et al. 2020

The Journal of Infectious Diseases

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Background Targeting multiple key antigens that mediate distinct P. falciparum erythrocyte invasion pathways is an attractive approach for the development of blood-stage malaria vaccines. However, the challenge is to identify antigen cocktails that elicit potent strain-transcending parasite-neutralizing antibodies efficacious at low IgG concentrations feasible to achieve through vaccination. Previous reports have screened inhibitory antibodies primarily against well-adapted laboratory parasite clones. However, validation of the parasite-neutralizing efficacy against clinical isolates with minimal in vitro cultivation is equally significant to better ascertain their prospective in vivo potency. Method We evaluated the parasite-neutralizing activity of different antibodies individually and in combinations against laboratory adapted clones and clinical isolates. Clinical isolates were collected from central India and Mozambique (Africa), characterized for their invasion properties and genetic diversity of invasion ligands. Results In our portfolio, we evaluated 25 triple antibody combinations and identified the MSP-Fu+CyRPA+RH5 antibody combination to elicit maximal parasite neutralization against P. falciparum clinical isolates with variable properties that underwent minimal in vitro cultivation. Conclusion The MSP-Fu+CyRPA+RH5 combination exhibited highly robust parasite-neutralization against P. falciparum clones and clinical-isolates, thus substantiating them as promising candidate antigens and establishing a proof of principle for the development of a combinatorial P. falciparum blood-stage malaria vaccine.

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Antibody Combinations Targeting the Essential Antigens CyRPA, RH5, and MSP-119 Potently Neutralize Plasmodium falciparum Clinical Isolates From India and Africa

Singh

Mian

Pandey

et al. 2020

The Journal of Infectious Diseases

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“…Clinical manifestations of the disease occur in the blood-stage infection of the parasite's lifecycle, where the parasite invades the host red blood cells (RBC), multiplies and invades other RBC to continue the asexual cycle. Invasion of the RBC by merozoites involves: (i) the initial contact by the merozoite, (ii) reorientation and deformation, (iii) binding of the merozoite to the RBC, (iv) formation of a moving junction, (v) internalization of the merozoite, and (vi) resealing the parasitophorous vacuole [3][4][5] . Various antigens such as merozoite surface proteins (MSP) 1 6 and 3 7 , erythrocyte binding antigen-175 8 , apical membrane antigen 1 (AMA1) 9 and reticulocyte-binding protein Homolog 5 (RH5) 10 are involved in these steps and have been the focus of asexual blood stage vaccine development.…”

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Bliss' and Loewe's additive and synergistic effects in Plasmodium falciparum growth inhibition by AMA1-RON2L, RH5, RIPR and CyRPA antibody combinations

Azasi

Gallagher

Diouf

et al. 2020

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Plasmodium invasion of red blood cells involves malaria proteins, such as reticulocyte-binding protein homolog 5 (RH5), RH5 interacting protein (RIPR), cysteine-rich protective antigen (CyRPA), apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2), all of which are bloodstage malaria vaccine candidates. So far, vaccines containing AMA1 alone have been unsuccessful in clinical trials. However, immunization with AMA1 bound with RON2L (AMA1-RON2L) induces better protection against P. falciparum malaria in Aotus monkeys. We therefore sought to determine whether combinations of RH5, RIPR, CyRPA and AMA1-RON2L antibodies improve their biological activities and sought to develop a robust method for determination of synergy or additivity in antibody combinations. Rabbit antibodies against AMA1-RON2L, RH5, RIPR or CyRPA were tested either alone or in combinations in P. falciparum growth inhibition assay to determine Bliss' and Loewe's additivities. The AMA1-RON2L/RH5 combination consistently demonstrated an additive effect while the CyRPA/RIPR combination showed a modest synergistic effect with Hewlett's S = 1.07 95%CI : 1.03, 1.19. Additionally, we provide a publicly-available, online tool to aid researchers in analyzing and planning their own synergy experiments. This study supports future blood-stage vaccine development by providing a solid methodology to evaluate additive and/or synergistic (or antagonistic) effect of vaccine-induced antibodies. Malaria remains a global health problem with over 200 million cases and more than 400,000 deaths annually 1. Most of these deaths are caused by the most virulent parasite Plasmodium falciparum. Ongoing interventions with insecticides, bed nets and artemisinin combination therapy had led to a decline of mortality and morbidity; however, the decline has stalled in recent years. It is still the hope that a malaria vaccine will facilitate the much-needed step towards eradication of the disease, especially in Sub-Saharan Africa where it is most relevant. There are many malaria vaccine candidates in development; these are targeted at the pre-erythrocytic-stage,

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Host age and expression of genes involved in red blood cell invasion in Plasmodium falciparum field isolates

Valmaseda

Bassat

Aíde

et al. 2017

Sci Rep

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Plasmodium falciparum proteins involved in erythrocyte invasion are main targets of acquired immunity and important vaccine candidates. We hypothesized that anti-parasite immunity acquired upon exposure would limit invasion-related gene (IRG) expression and affect the clinical impact of the infection. 11 IRG transcript levels were measured in P. falciparum isolates by RT-PCR, and IgG/IgM against invasion ligands by Luminex®, in 50 Mozambican adults, 25 children with severe malaria (SM) and 25 with uncomplicated malaria (UM). IRG expression differences among groups and associations between IRG expression and clinical/immunologic parameters were assessed. IRG expression diversity was higher in parasites infecting children than adults (p = 0.022). eba140 and ptramp expression decreased with age (p = 0.003 and 0.007, respectively) whereas p41 expression increased (p = 0.022). pfrh5 reduction in expression was abrupt early in life. Parasite density decreased with increasing pfrh5 expression (p < 0.001) and, only in children, parasite density increased with p41 expression (p = 0.007), and decreased with eba175 (p = 0.013). Antibody responses and IRG expression were not associated. In conclusion, IRG expression is associated with age and parasite density, but not with specific antibody responses in the acute phase of infection. Our results confirm the importance of multi-antigen vaccines development to avoid parasite immune escape when tested in malaria-exposed individuals.

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Molecular basis of erythrocyte invasion byPlasmodiummerozoites

Cited by 4 publications

References 206 publications

Antibody Combinations Targeting the Essential Antigens CyRPA, RH5, and MSP-119 Potently Neutralize Plasmodium falciparum Clinical Isolates From India and Africa

Antibody Combinations Targeting the Essential Antigens CyRPA, RH5, and MSP-119 Potently Neutralize Plasmodium falciparum Clinical Isolates From India and Africa

Bliss' and Loewe's additive and synergistic effects in Plasmodium falciparum growth inhibition by AMA1-RON2L, RH5, RIPR and CyRPA antibody combinations

Host age and expression of genes involved in red blood cell invasion in Plasmodium falciparum field isolates

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