A High Force of Plasmodium vivax Blood-Stage Infection Drives the Rapid Acquisition of Immunity in Papua New Guinean Children

AbstractThe gene encoding the Duffy blood group protein (Fy, CD234; additional designations Duffy Antigen Receptor of Chemokines [DARC] and Atypical Chemokine Receptor 1 [ACKR1]) is characterized by a SNP in a GATA-1 transcription factor binding site associated with the erythrocyte silent (ES) phenotype.FYEShomozygous people are viewed to be highly resistant to blood stage infection withPlasmodium vivax. Increasingly, however, studies are reportingP. vivaxinfections in Fy-negative individuals across malarious African countries whereFYESapproaches genetic fixation. This suggests thatP. vivaxhas evolved a Fy-independent RBC invasion pathway, or that the GATA-1 SNP does not abolish Fy expression. Here, we tested the second hypothesis through binding studies to erythroid lineage cells using recombinantP. vivaxDuffy binding protein, the parasite’s invasion ligand and Fy6-specific antibodies. We first observed variable Fy expression on circulating RBCs, irrespective ofFYgenotype;FYESRBCs were periodically Fy-positive. Furthermore, during thein vitroerythroid differentiation of CD34+ cells and onex vivobone marrow samples, we observed Fy expression on erythroid precursor cells fromFYESpeople. Finally, the Fy6-specific nanobody, CA111 was used to capture Fy from the surface ofFYESRBCs. Our findings reveal that the GATA-1 SNP does not fully abolish Fy expression and provide insight on potential susceptibility of Fy-negative people to vivax malaria.SignificanceDuffy blood group negativity results from a single nucleotide polymorphism (SNP) in the gene promoter, and reaches genetic fixation in many African ethnicities. Because the Duffy protein (Fy) is an important contact point duringPlasmodium vivaxhuman red blood cell invasion, Fy-negativity is considered to confer resistance toP. vivaxmalaria. With recent studies in African countries reportingP. vivaxinfection in Fy-negative people, we studied Fy expression across erythroid development. Here we report that theFYpromoter SNP does not abolish Fy protein expression in erythroid progenitors developing in the bone marrow. These results further emphasizes the importance of reticulocytes as targets forP. vivaxblood stage infection and propose a mechanism forP. vivaxinfections in Fy-negative people.

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Prevalence and Force of Plasmodium Vivax and Plasmodium Falciparum Blood Stage Infection and Associated Clinical Malaria Burden in the Brazilian Amazon

10.21203/rs.3.rs-51282/v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Wuelton Monteiro ◽

Stephan Karl ◽

Andrea Kuehn Kuehn ◽

Anne Almeida ◽

Michael White ◽

...

Keyword(s):

Plasmodium Vivax ◽

Brazilian Amazon ◽

Clinical Malaria ◽

Blood Stage ◽

Radical Cure ◽

Low Transmission ◽

Malaria Burden ◽

Blood Stage Infection ◽

Stage Infection ◽

Malaria Episodes

Abstract Background: Plasmodium vivax and Plamodium falciparum are co-endemic in much of the Brazilian Amazon, with P. vivax comprising greater than 80% of clinical cases, especially in low transmission settings. The molecular force of blood-stage infection of P. vivax (molFOB) can provide a detailed picture of P. vivax transmission in low transmission settings and help improve malaria measures control and elimination efforts. Methodology: Monthly samples were collected in a cohort of 1,274 individuals of all ages between April 2013 and March 2014 in three peri-urban communities in the Brazilian Amazon. Regression analyses were used to test how factors including age and community were associated with P. vivax molFOB, parasite positivity and clinical episodes. Principal Findings: Respectively, 77.8% and 97.2% of the population remained free of P. vivax and P. falciparum infection. Expected heterozygosity for P. vivax was 0.69 for MSP1_F3 and 0.86 for MS2. Multiplicity of infection in P. vivax was close to the value of 1 as determined with both markers (1.06 for MSP1_F3 and 1.04 for MS2). Season was associated with P. vivax positivity [adjusted hazard ration (aHR) 2.6 (1.9-5.7)] and clinical disease [aHR 10.6 (2.4-47.2)]. P. falciparum infection was associated with previous malarial episodes [HR 9.7 (4.5-20.9)]. Subjects who reported bednet possession [incidence rate ratio (IRR) 1.6 (1.2-2.2)] or previous malaria episodes [IRR 3.0 (2.0-4.5)] were found to have significantly higher P. vivax molFOB.Conclusions: Overall, P. vivax infection prevailed in the area and infections were mostly observed as monoclonal. High proportions of symptomatic and submicroscopic infections were found. Previous malaria episodes were associated with significantly higher P. vivax molFOB, likely indicating that effective radical cure is an important strategy to be addressed in these endemic communities.

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Resolving the cause of recurrent Plasmodium vivax malaria probabilistically

Nature Communications ◽

10.1038/s41467-019-13412-x ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 8

Author(s):

Aimee R. Taylor ◽

James A. Watson ◽

Cindy S. Chu ◽

Kanokpich Puaprasert ◽

Jureeporn Duanguppama ◽

...

Keyword(s):

Plasmodium Vivax ◽

Vivax Malaria ◽

Blood Stage ◽

High Dose ◽

Time To Event ◽

Liver Stage ◽

Plasmodium Vivax Malaria ◽

Blood Stage Infection ◽

Stage Infection

AbstractRelapses arising from dormant liver-stage Plasmodium vivax parasites (hypnozoites) are a major cause of vivax malaria. However, in endemic areas, a recurrent blood-stage infection following treatment can be hypnozoite-derived (relapse), a blood-stage treatment failure (recrudescence), or a newly acquired infection (reinfection). Each of these requires a different prevention strategy, but it was not previously possible to distinguish between them reliably. We show that individual vivax malaria recurrences can be characterised probabilistically by combined modelling of time-to-event and genetic data within a framework incorporating identity-by-descent. Analysis of pooled patient data on 1441 recurrent P. vivax infections in 1299 patients on the Thailand–Myanmar border observed over 1000 patient follow-up years shows that, without primaquine radical curative treatment, 3 in 4 patients relapse. In contrast, after supervised high-dose primaquine only 1 in 40 relapse. In this region of frequent relapsing P. vivax, failure rates after supervised high-dose primaquine are significantly lower (∼3%) than estimated previously.

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Plasmodium vivax Latent Liver Stage Infection and Relapse: Biological Insights and New Experimental Tools

Annual Review of Microbiology ◽

10.1146/annurev-micro-032421-061155 ◽

2021 ◽

Vol 75 (1) ◽

Author(s):

Carola Schäfer ◽

Gigliola Zanghi ◽

Ashley M. Vaughan ◽

Stefan H.I. Kappe

Keyword(s):

Plasmodium Vivax ◽

Blood Stage ◽

Annual Review ◽

Publication Date ◽

Liver Stage ◽

Human Malaria Parasite ◽

Treatment And Prevention ◽

Parasite Stage ◽

Blood Stage Infection ◽

Stage Infection

Plasmodium vivax is the most widespread human malaria parasite, in part because it can form latent liver stages known as hypnozoites after transmission by female anopheline mosquitoes to human hosts. These persistent stages can activate weeks, months, or even years after the primary clinical infection; replicate; and initiate relapses of blood stage infection, which causes disease and recurring transmission. Eliminating hypnozoites is a substantial obstacle for malaria treatment and eradication since the hypnozoite reservoir is undetectable and unaffected by most antimalarial drugs. Importantly, in some parts of the globe where P. vivax malaria is endemic, as many as 90% of P. vivax blood stage infections are thought to be relapses rather than primary infections, rendering the hypnozoite a major driver of P. vivax epidemiology. Here, we review the biology of the hypnozoite and recent discoveries concerning this enigmatic parasite stage. We discuss treatment and prevention challenges, novel animal models to study hypnozoites and relapse, and hypotheses related to hypnozoite formation and activation. Expected final online publication date for the Annual Review of Microbiology, Volume 75 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Plasmodium yoelii Sporozoites with Simultaneous Deletion of P52 and P36 Are Completely Attenuated and Confer Sterile Immunity against Infection

Infection and Immunity ◽

10.1128/iai.00225-07 ◽

2007 ◽

Vol 75 (8) ◽

pp. 3758-3768 ◽

Cited By ~ 114

Author(s):

Mehdi Labaied ◽

Anke Harupa ◽

Ronald F. Dumpit ◽

Isabelle Coppens ◽

Sebastian A. Mikolajczak ◽

...

Keyword(s):

Host Cell ◽

Genetic Manipulation ◽

Parasitophorous Vacuole ◽

Plasmodium Yoelii ◽

Blood Stage ◽

Mammalian Host ◽

Electron Microscopic ◽

Rodent Host ◽

Blood Stage Infection ◽

Stage Infection

ABSTRACT Malaria infection starts when sporozoites are transmitted to the mammalian host during a mosquito bite. Sporozoites enter the blood circulation, reach the liver, and infect hepatocytes. The formation of a parasitophorous vacuole (PV) establishes their intracellular niche. Recently, two members of the 6-Cys domain protein family, P52 and P36, were each shown to play an important albeit nonessential role in Plasmodium berghei sporozoite infectivity for the rodent host. Here, we generated p52/p36-deficient Plasmodium yoelii parasites by the simultaneous deletion of both genes using a single genetic manipulation. p52/p36-deficient parasites exhibited normal progression through the life cycle during blood-stage infection, transmission to mosquitoes, mosquito-stage development, and sporozoite infection of the salivary glands. p52/p36-deficient sporozoites also showed normal motility and cell traversal activity. However, immunofluorescence analysis and electron microscopic observations revealed that p52/p36-deficient parasites did not form a PV within hepatocytes in vitro and in vivo. The p52/p36-deficient parasites localized as free entities in the host cell cytoplasm or the host cell nucleoplasm and did not develop as liver stages. Consequently, they did not cause blood-stage infections even at high sporozoite inoculation doses. Mice immunized with p52/p36-deficient sporozoites were completely protected against infectious sporozoite challenge. Our results demonstrate for the first time the generation of two-locus gene deletion-attenuated parasites that infect the liver but do not progress to blood-stage infection. The study will critically guide the design of Plasmodium falciparum live attenuated malaria vaccines.

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