scholarly journals Naturally Acquired Immune Responses to Plasmodium falciparum Sexual Stage Antigens Pfs48/45 and Pfs230 in an Area of Seasonal Transmission

2011 ◽  
Vol 79 (12) ◽  
pp. 4957-4964 ◽  
Author(s):  
André Lin Ouédraogo ◽  
Will Roeffen ◽  
Adrian J. F. Luty ◽  
Sake J. de Vlas ◽  
Issa Nebie ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Immune Responses ◽  
Cumulative Exposure ◽  
Acquired Immunity ◽  
Sexual Stage ◽  
Wet Season ◽  
Asexual Blood Stage ◽  
Cross Sectional ◽  
Content Type ◽  
Sexual Stages

ABSTRACTAcquisition of immunity toPlasmodium falciparumsexual stages is a key determinant for reducing human-mosquito transmission by preventing the fertilization and the development of the parasite in the mosquito midgut. Naturally acquired immunity against sexual stages may therefore form the basis for the development of transmission-blocking vaccines, but studies conducted to date offer little in the way of consistent findings. Here, we describe the acquisition of antigametocyte immune responses in malaria-exposed individuals in Burkina Faso. A total of 719 blood samples were collected in a series of three cross-sectional surveys at the start, peak, and end of the wet season. The seroprevalence of antibodies with specificity for the sexual stage antigens Pfs48/45 and Pfs230 was 2-fold lower (22 to 28%) than that for an asexual blood stage antigen glutamate-rich protein (GLURP) (65%) or for the preerythrocytic stage antigen circumsporozoite protein (CSP) (54%). The youngest children responded at frequencies similar to those for all four antigens but, in contrast with the immune responses to GLURP and CSP that increased with age independently of season and area of residence, there was no evidence for a clear age dependence of responses to Pfs48/45 and Pfs230. Anti-Pfs230 antibodies were most prevalent at the peak of the wet season (P< 0.001). Our findings suggest that naturally acquired immunity against Pfs48/45 and Pfs230 is a function of recent exposure rather than of cumulative exposure to gametocytes.

scholarly journals Immune Responses to the Sexual Stages of Plasmodium falciparum Parasites

2019 ◽  
Vol 10 ◽  
Author(s):  
Jonas A. Kengne-Ouafo ◽  
Colin J. Sutherland ◽  
Fred N. Binka ◽  
Gordon A. Awandare ◽  
Britta C. Urban ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Immune Responses ◽  
Sexual Stages

scholarly journals Identification of MMV Malaria Box Inhibitors of Plasmodium falciparum Early-Stage Gametocytes Using a Luciferase-Based High-Throughput Assay

2013 ◽  
Vol 57 (12) ◽  
pp. 6050-6062 ◽  
Author(s):  
Leonardo Lucantoni ◽  
Sandra Duffy ◽  
Sophie H. Adjalley ◽  
David A. Fidock ◽  
Vicky M. Avery
Keyword(s):  
Plasmodium Falciparum ◽  
High Throughput ◽  
Early Stage ◽  
Blood Stage ◽  
Stage I ◽  
Mosquito Vector ◽  
Asexual Blood Stage ◽  
Content Type ◽  
Malaria Box ◽  
Gametocytocidal Activity

ABSTRACTThe design of new antimalarial combinations to treatPlasmodium falciparuminfections requires drugs that, in addition to resolving disease symptoms caused by asexual blood stage parasites, can also interrupt transmission to the mosquito vector. Gametocytes, which are essential for transmission, develop as sexual blood stage parasites in the human host over 8 to 12 days and are the most accessible developmental stage for transmission-blocking drugs. Considerable effort is currently being devoted to identifying compounds active against mature gametocytes. However, investigations on the drug sensitivity of developing gametocytes, as well as screening methods for identifying inhibitors of early gametocytogenesis, remain scarce. We have developed a luciferase-based high-throughput screening (HTS) assay using tightly synchronous stage I to III gametocytes from a recombinantP. falciparumline expressing green fluorescent protein (GFP)-luciferase. The assay has been used to evaluate the early-stage gametocytocidal activity of the MMV Malaria Box, a collection of 400 compounds with known antimalarial (asexual blood stage) activity. Screening this collection against early-stage (I to III) gametocytes yielded 64 gametocytocidal compounds with 50% inhibitory concentrations (IC50s) below 2.5 μM. This assay is reproducible and suitable for the screening of large compound libraries, with an average percent coefficient of variance (%CV) of ≤5%, an average signal-to-noise ratio (S:N) of >30, and a Z′ of ∼0.8. Our findings highlight the need for screening efforts directed specifically against early gametocytogenesis and indicate the importance of experimental verification of early-stage gametocytocidal activity in the development of new antimalarial candidates for combination therapy.

scholarly journals Submicroscopic Infections with Plasmodium falciparum during Pregnancy and Their Association with Circulating Cytokine, Chemokine, and Cellular Profiles

2014 ◽  
Vol 21 (6) ◽  
pp. 859-866 ◽  
Author(s):  
Samad A. Ibitokou ◽  
Stéphanie Boström ◽  
Laurent Brutus ◽  
Nicaise Tuikue Ndam ◽  
Bertin Vianou ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Multivariate Analyses ◽  
Cell Types ◽  
Interleukin 10 ◽  
Peripheral Blood Mononuclear ◽  
Cross Sectional ◽  
Content Type ◽  
Blood Smears ◽  
Inducible Protein ◽  
A Prospective Study

ABSTRACTThe immunological consequences of pregnancy-associated malaria (PAM) due toPlasmodium falciparumhave been extensively investigated in cross-sectional studies conducted at delivery, but there have been very few longitudinal studies of changes due to PAM during pregnancy. We conducted a prospective study in Benin to investigate the changes associated with PAM in groups of 131 and 111 women at inclusion in the second trimester and at delivery, respectively. Infected women were identified by standard microscopic examinations of blood smears and by quantitative PCR (qPCR) assays and were matched to uninfected control women by age, gestational age, and gravidity. We quantified plasma levels of a panel of soluble immunological mediators and other mediators, as well as the frequencies of peripheral blood mononuclear cell types. Comparisons of these variables in infected and uninfected women used multivariate analyses, and we also assessed the predictive value of variables measured at inclusion for pregnancy outcomes at delivery. In multivariate analyses, peripheral plasma interleukin 10 (IL-10) and gamma interferon-inducible protein 10 (IP-10) levels were associated with PAM at inclusion and at delivery, while higher IL-10 levels distinguished qPCR-detectable submicroscopic infections at inclusion but not at delivery. Maternal anemia at delivery was associated with markers of proinflammatory (increased frequency of monocytes) and anti-inflammatory (increased IL-10 levels and increased activation of regulatory T cells) activity measured at inclusion. Elevated concentrations of IL-10 are associated with the majority ofP. falciparuminfections during pregnancy, but this marker alone does not identify all submicroscopic infections. Reliably identifying such occult infections will require more sensitive and specific methods.

scholarly journals Looking for Needles in the Plasmodial Haystack

mSphere ◽  
2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Lars Hviid
Keyword(s):  
Infectious Disease ◽  
Plasmodium Falciparum ◽  
Protective Immunity ◽  
Protein Microarray ◽  
Acquired Immunity ◽  
Small Subset ◽  
Microarray Technology ◽  
Content Type ◽  
Vaccine Candidates ◽  
Parasite Exposure

ABSTRACT Plasmodium falciparum malaria remains a globally leading infectious disease problem. Despite decades of intense investigation, an efficacious and practical vaccine offering durable protection to people living in areas with transmission of malaria parasites remains an elusive goal. Our fragmentary understanding of the mechanisms of protective immunity to the disease is a major obstacle, and the almost complete focus on a very small subset of P. falciparum proteins as vaccine candidates has left most parasite antigens essentially unexplored as targets of acquired immunity. However, with the protein microarray technology, it is now possible to interrogate the entire parasite proteome for new vaccine candidates and for markers of parasite exposure. Recent mSphere papers describe the results of such research.

scholarly journals The Plasmodium falciparum Cell-Traversal Protein for Ookinetes and Sporozoites as a Candidate for Preerythrocytic and Transmission-Blocking Vaccines

2016 ◽  
Vol 85 (2) ◽  
Author(s):  
Diego A. Espinosa ◽  
Joel Vega-Rodriguez ◽  
Yevel Flores-Garcia ◽  
Amy R. Noe ◽  
Christian Muñoz ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Monoclonal Antibodies ◽  
Immune Responses ◽  
Passive Immunization ◽  
Content Type ◽  
Adjuvant System ◽  
Neutralizing Capacity ◽  
Important Evidence ◽  
Transmission Blocking Vaccines

ABSTRACT Recent studies have shown that immune responses against the cell-traversal protein for Plasmodium ookinetes and sporozoites (CelTOS) can inhibit parasite infection. While these studies provide important evidence toward the development of vaccines targeting this protein, it remains unknown whether these responses could engage the Plasmodium falciparum CelTOS in vivo. Using a newly developed rodent malaria chimeric parasite expressing the P. falciparum CelTOS (PfCelTOS), we evaluated the protective effect of in vivo immune responses elicited by vaccination and assessed the neutralizing capacity of monoclonal antibodies specific against PfCelTOS. Mice immunized with recombinant P. falciparum CelTOS in combination with the glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE) or glucopyranosyl lipid adjuvant-liposome-QS21 (GLA-LSQ) adjuvant system significantly inhibited sporozoite hepatocyte infection. Notably, monoclonal antibodies against PfCelTOS strongly inhibited oocyst development of P. falciparum and Plasmodium berghei expressing PfCelTOS in Anopheles gambiae mosquitoes. Taken together, our results demonstrate that anti-CelTOS responses elicited by vaccination or passive immunization can inhibit sporozoite and ookinete infection and impair vector transmission.

The multiplicity of Plasmodium falciparum infections is associated with acquired immunity to asexual blood stage antigens

2009 ◽  
Vol 11 (1) ◽  
pp. 108-114 ◽  
Author(s):  
P MAYENGUE ◽  
A LUTY ◽  
C ROGIER ◽  
M BARAGATTI ◽  
P KREMSNER ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Blood Stage ◽  
Acquired Immunity ◽  
Asexual Blood Stage

scholarly journals Systematic Genetic Analysis of the Plasmodium falciparum MSP7-Like Family Reveals Differences in Protein Expression, Location, and Importance in Asexual Growth of the Blood-Stage Parasite

2010 ◽  
Vol 9 (7) ◽  
pp. 1064-1074 ◽  
Author(s):  
Madhusudan Kadekoppala ◽  
Solabomi A. Ogun ◽  
Steven Howell ◽  
Ruwani S. Gunaratne ◽  
Anthony A. Holder
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Expression ◽  
Surface Protein ◽  
Gene Families ◽  
Merozoite Surface Protein ◽  
Blood Stage ◽  
Asexual Blood Stage ◽  
Content Type ◽  
Specific Proteins ◽  
Proteolytic Cleavages

ABSTRACT Proteins located on Plasmodium falciparum merozoites, the invasive form of the parasite's asexual blood stage, are of considerable interest in vaccine research. Merozoite surface protein 7 (MSP7) forms a complex with MSP1 and is encoded by a member of a multigene family located on chromosome 13. The family codes for MSP7 and five MSP7-related proteins (MSRPs). In the present study, we have investigated the expression and the effect of msrp gene deletion at the asexual blood stage. In addition to msp7, msrp2, msrp3, and msrp5 are transcribed, and mRNA was easily detected by hybridization analysis, whereas mRNA for msrp1 and msrp4 could be detected only by reverse transcription (RT)-PCR. Notwithstanding evidence of transcription, antibodies to recombinant MSRPs failed to detect specific proteins, except for antibodies to MSRP2. Sequential proteolytic cleavages of MSRP2 resulted in 28- and 25-kDa forms. However, MSRP2 was absent from merozoites; the 25-kDa MSRP2 protein (MSRP225) was soluble and secreted upon merozoite egress. The msrp genes were deleted by targeted disruption in the 3D7 line, leading to ablation of full-length transcripts. MSRP deletion mutants had no detectable phenotype, with growth and invasion characteristics comparable to those of the parental parasite; only the deletion of MSP7 led to a detectable growth phenotype. Thus, within this family some of the genes are transcribed at a significant level in asexual blood stages, but the corresponding proteins may or may not be detectable. Interactions of the expressed proteins with the merozoite also differ. These results highlight the potential for unexpected differences of protein expression levels within gene families.

scholarly journals Multicenter Pivotal Clinical Trial of Urine Malaria Test for Rapid Diagnosis of Plasmodium falciparum Malaria

2016 ◽  
Vol 55 (1) ◽  
pp. 253-263 ◽  
Author(s):  
Wellington A. Oyibo ◽  
Nnenna Ezeigwe ◽  
Godwin Ntadom ◽  
Oladipo O. Oladosu ◽  
Kaitlin Rainwater-Loveth ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Clinical Performance ◽  
Characteristic Curve ◽  
Malaria Diagnosis ◽  
Plasmodium Falciparum Malaria ◽  
Receiver Operator Characteristic Curve ◽  
Axillary Temperature ◽  
Cross Sectional ◽  
Content Type ◽  
Malaria Test

ABSTRACTThe need to expand malaria diagnosis capabilities alongside policy requirements for mandatory testing before treatment motivates exploration of noninvasive rapid diagnostic tests (RDTs). We report the outcome of the first cross-sectional, single-blind clinical performance evaluation of a urine malaria test (UMT) for diagnosis ofPlasmodium falciparummalaria in febrile patients. Matched urine and finger-prick blood samples from participants ≥2 years of age with fever (axillary temperature of ≥37.5°C) or with a history of fever in the preceding 48 h were tested with UMT and microscopy (as the gold standard). BinaxNOW (Pf and Pan versions) blood RDTs were done to assess relative performance. Urinalysis and rheumatoid factor (RF) tests were conducted to evaluate possible interference. Diagnostic performance characteristics were computed at 95% confidence intervals (CIs). Of 1,800 participants screened, 1,691 were enrolled; of these 566 (34%) were febrile, and 1,125 (66%) were afebrile. Among enrolled participants, 341 (20%) tested positive by microscopy, 419 (25%) were positive by UMT, 676 (40%) were positive by BinaxNOW Pf, and 368 (22%) were positive by BinaxNow Pan. UMT sensitivity among febrile patients (for whom the test was indicated) was 85%, and specificity was 84%. Among febrile children ≤5 years of age, UMT sensitivity was 93%, and specificity was 83%. The area under the receiver-operator characteristic curve (AUC) of UMT (0.84) was not significantly different from that of BinaxNOW Pf (0.86) or of BinaxNOW Pan (0.87), indicating that the tests do not differ in overall performance. Gender, seasons, and RF did not impact UMT performance. Leukocytes, hematuria, and urobilinogen concentrations in urine were associated with lower UMT specificities. UMT performance was comparable to that of the BinaxNOW Pf/Pan tests, making UMT a promising tool to expand malaria testing in public and private health care settings where there are challenges to blood-based malaria diagnosis testing.

scholarly journals Plasmodium falciparum Apicomplexan-Specific Glucosamine-6-Phosphate N-Acetyltransferase Is Key for Amino Sugar Metabolism and Asexual Blood Stage Development

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Jordi Chi ◽  
Marta Cova ◽  
Matilde de las Rivas ◽  
Ana Medina ◽  
Rafael Junqueira Borges ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Apicomplexan Parasite ◽  
Blood Stage ◽  
Host Cells ◽  
Asexual Blood Stage ◽  
Content Type ◽  
Apicomplexan Parasites ◽  
Hexosamine Pathway ◽  
Depth Analysis ◽  
Stage Development

ABSTRACT UDP-N-acetylglucosamine (UDP-GlcNAc), the main product of the hexosamine biosynthetic pathway, is an important metabolite in protozoan parasites since its sugar moiety is incorporated into glycosylphosphatidylinositol (GPI) glycolipids and N- and O-linked glycans. Apicomplexan parasites have a hexosamine pathway comparable to other eukaryotic organisms, with the exception of the glucosamine-phosphate N-acetyltransferase (GNA1) enzymatic step that has an independent evolutionary origin and significant differences from nonapicomplexan GNA1s. By using conditional genetic engineering, we demonstrate the requirement of GNA1 for the generation of a pool of UDP-GlcNAc and for the development of intraerythrocytic asexual Plasmodium falciparum parasites. Furthermore, we present the 1.95 Å resolution structure of the GNA1 ortholog from Cryptosporidium parvum, an apicomplexan parasite which is a leading cause of diarrhea in developing countries, as a surrogate for P. falciparum GNA1. The in-depth analysis of the crystal shows the presence of specific residues relevant for GNA1 enzymatic activity that are further investigated by the creation of site-specific mutants. The experiments reveal distinct features in apicomplexan GNA1 enzymes that could be exploitable for the generation of selective inhibitors against these parasites, by targeting the hexosamine pathway. This work underscores the potential of apicomplexan GNA1 as a drug target against malaria. IMPORTANCE Apicomplexan parasites cause a major burden on global health and economy. The absence of treatments, the emergence of resistances against available therapies, and the parasite’s ability to manipulate host cells and evade immune systems highlight the urgent need to characterize new drug targets to treat infections caused by these parasites. We demonstrate that glucosamine-6-phosphate N-acetyltransferase (GNA1), required for the biosynthesis of UDP-N-acetylglucosamine (UDP-GlcNAc), is essential for P. falciparum asexual blood stage development and that the disruption of the gene encoding this enzyme quickly causes the death of the parasite within a life cycle. The high-resolution crystal structure of the GNA1 ortholog from the apicomplexan parasite C. parvum, used here as a surrogate, highlights significant differences from human GNA1. These divergences can be exploited for the design of specific inhibitors against the malaria parasite.

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