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

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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A Humanized Mouse Model for Plasmodium vivax to Test Interventions that Block Liver Stage to Blood Stage Transition and Blood Stage Infection

iScience ◽

10.1016/j.isci.2020.101381 ◽

2020 ◽

Vol 23 (8) ◽

pp. 101381

Author(s):

Carola Schäfer ◽

Wanlapa Roobsoong ◽

Niwat Kangwanrangsan ◽

Martino Bardelli ◽

Thomas A. Rawlinson ◽

...

Keyword(s):

Mouse Model ◽

Plasmodium Vivax ◽

Blood Stage ◽

Humanized Mouse ◽

Humanized Mouse Model ◽

Liver Stage ◽

Blood Stage Infection ◽

Stage Transition ◽

Stage Infection

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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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Malaria Blood Stage Suppression of Liver Stage Immunity by Dendritic Cells

Journal of Experimental Medicine ◽

10.1084/jem.20021072 ◽

2003 ◽

Vol 197 (2) ◽

pp. 143-151 ◽

Cited By ~ 168

Author(s):

Carlos Ocaña-Morgner ◽

Maria M. Mota ◽

Ana Rodriguez

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

Cd8 T Cell ◽

Blood Stage ◽

Liver Stage ◽

Cell Responses ◽

Blood Stage Infection ◽

Stage Infection

Malaria starts with Plasmodium sporozoites infection of the host's liver, where development into blood stage parasites occurs. It is not clear why natural infections do not induce protection against the initial liver stage and generate low CD8+ T cell responses. Using a rodent malaria model, we show that Plasmodium blood stage infection suppresses CD8+ T cell immune responses that were induced against the initial liver stage. Blood stage Plasmodium affects dendritic cell (DC) functions, inhibiting maturation and the capacity to initiate immune responses and inverting the interleukin (IL)-12/IL-10 secretion pattern. The interaction of blood stage parasites with DCs induces the secretion of soluble factors that inhibit the activation of CD8+ T cells in vitro and the suppression of protective CD8+ T cell responses against the liver stage in vivo. We propose that blood stage infection induces DCs to suppress CD8+ T cell responses in natural malaria infections. This evasion mechanism leaves the host unprotected against reinfection by inhibiting the immune response against the initial liver stage of the disease.

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Phenotypic profiling of CD8+ T cells during Plasmodium vivax blood-stage infection

BMC Infectious Diseases ◽

10.1186/s12879-015-0762-x ◽

2015 ◽

Vol 15 (1) ◽

Cited By ~ 10

Author(s):

Natália Satchiko Hojo-Souza ◽

Dhelio Batista Pereira ◽

Lívia Silva Araújo Passos ◽

Pedro Henrique Gazzinelli-Guimarães ◽

Mariana Santos Cardoso ◽

...

Keyword(s):

T Cells ◽

Plasmodium Vivax ◽

Cd8 T Cells ◽

Blood Stage ◽

Blood Stage Infection ◽

Stage Infection

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Plasmodium vivax but Not Plasmodium falciparum Blood-Stage Infection in Humans Is Associated with the Expansion of a CD8+ T Cell Population with Cytotoxic Potential

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0005031 ◽

2016 ◽

Vol 10 (12) ◽

pp. e0005031 ◽

Cited By ~ 13

Author(s):

Julie G. Burel ◽

Simon H. Apte ◽

James S. McCarthy ◽

Denise L. Doolan

Keyword(s):

Plasmodium Falciparum ◽

T Cell ◽

Plasmodium Vivax ◽

Cell Population ◽

Cd8 T Cell ◽

Blood Stage ◽

Cytotoxic Potential ◽

Blood Stage Infection ◽

Stage Infection

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Proteomic Analysis ofPlasmodiumMerosomes: The Link Between Liver and Blood Stages in Malaria

10.1101/580266 ◽

2019 ◽

Author(s):

Melanie J Shears ◽

Raja Sekhar Nirujogi ◽

Kristian E Swearingen ◽

Santosh Renuse ◽

Satish Mishra ◽

...

Keyword(s):

Proteomic Analysis ◽

Life Cycle Stage ◽

Blood Stage ◽

Quantitative Detection ◽

List Type ◽

Liver Stage ◽

Core Set ◽

Blood Stage Infection ◽

Malaria Model ◽

Stage Infection

SummaryThe pre-erythrocytic liver stage of the malaria parasite, comprising sporozoites and the liver stages into which they develop, remains one of the least understood parts of the lifecycle, in part owing to the low numbers of parasites. Nonetheless, it is recognized as an important target for anti-malarial drugs and vaccines. Here we provide the first proteomic analysis of merosomes, which define the final phase of the liver stage and are responsible for initiating the blood stage of infection. We identify a total of 1879 parasite proteins, and a core set of 1188 proteins quantitatively detected in every biological replicate, providing an extensive picture of the protein repertoire of this stage. This unique dataset will allow us to explore key questions about the biology of merosomes and hepatic merozoites.HighlightsFirst proteome of the merosome stage of malaria parasitesQuantitative detection of 1188 parasite proteins across 3 biological replicatesComparison to blood stage proteomes identifies shared and unique proteinsDiscovery of cleaved PEXEL motifs highlights liver stage protein exportIn BriefThe merosome stage that links malaria liver and blood stage infection is poorly understood. Here we provide the first proteome of this life cycle stage using thePlasmodium bergheirodent malaria model.Graphical Abstract

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Duffy Antigen Expression in Erythroid Bone Marrow Precursor Cells of Genotypically Duffy Negative Individuals

10.1101/508481 ◽

2018 ◽

Author(s):

Célia Dechavanne ◽

Sebastien Dechavanne ◽

Sylvain Metral ◽

Brooke Roeper ◽

Sushma Krishnan ◽

...

Keyword(s):

Bone Marrow ◽

Plasmodium Vivax ◽

Blood Group ◽

Precursor Cells ◽

Blood Stage ◽

African Countries ◽

Duffy Blood Group ◽

Duffy Antigen ◽

Blood Stage Infection ◽

Stage Infection

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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