scholarly journals Analysis of Antibodies to Newly Described Plasmodium falciparum Merozoite Antigens Supports MSPDBL2 as a Predicted Target of Naturally Acquired Immunity

2013 ◽  
Vol 81 (10) ◽  
pp. 3835-3842 ◽  
Author(s):  
Kevin K. A. Tetteh ◽  
Faith H. A. Osier ◽  
Ali Salanti ◽  
Gathoni Kamuyu ◽  
Laura Drought ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Risk Ratio ◽  
Statistical Significance ◽  
Clinical Malaria ◽  
Content Type ◽  
Type Antigen ◽  
Falciparum Merozoite ◽  
Merozoite Antigens ◽  
Allelic Type

ABSTRACTProspective studies continue to identify malaria parasite genes with particular patterns of polymorphism which indicate they may be under immune selection, and the encoded proteins require investigation. Sixteen new recombinant protein reagents were designed to characterize three such polymorphic proteins expressed inPlasmodium falciparumschizonts and merozoites: MSPDBL1 (also termed MSP3.4) and MSPDBL2 (MSP3.8), which possess Duffy binding-like (DBL) domains, and SURFIN4.2, encoded by a member of the surface-associated interspersed (surf) multigene family. After testing the antigenicities of these reagents by murine immunization and parasite immunofluorescence, we analyzed naturally acquired antibody responses to the antigens in two cohorts in coastal Kenya in which the parasite was endemic (Chonyi [n= 497] and Ngerenya [n= 461]). As expected, the prevalence and levels of serum antibodies increased with age. We then investigated correlations with subsequent risk of clinical malaria among children <11 years of age during 6 months follow-up surveillance. Antibodies to the polymorphic central region of MSPDBL2 were associated with reduced risk of malaria in both cohorts, with statistical significance remaining for the 3D7 allelic type after adjustment for individuals' ages in years and antibody reactivity to whole-schizont extract (Chonyi, risk ratio, 0.51, and 95% confidence interval [CI], 0.28 to 0.93; Ngerenya, risk ratio, 0.38, and 95% CI, 0.18 to 0.82). For the MSPDBL1 Palo Alto allelic-type antigen, there was a protective association in one cohort (Ngerenya, risk ratio, 0.53, and 95% CI, 0.32 to 0.89), whereas the other antigens showed no protective associations after adjustment. These findings support the prediction that antibodies to the polymorphic region of MSPDBL2 contribute to protective immunity.

scholarly journals Measuring antibody avidity to Plasmodium falciparum merozoite antigens using a multiplex immunoassay approach

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Diane Wallace Taylor ◽  
Naveen Bobbili ◽  
Alex Kayatani ◽  
Samuel Tassi Yunga ◽  
Winifrida Kidima ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antibody Avidity ◽  
Multiplex Immunoassay ◽  
Falciparum Merozoite ◽  
Merozoite Antigens

scholarly journals Changes in Antigen-Specific Cytokine and Chemokine Responses to Plasmodium falciparum Antigens in a Highland Area of Kenya after a Prolonged Absence of Malaria Exposure

2014 ◽  
Vol 82 (9) ◽  
pp. 3775-3782 ◽  
Author(s):  
Lyticia A. Ochola ◽  
Cyrus Ayieko ◽  
Lily Kisia ◽  
Ng'wena G. Magak ◽  
Estela Shabani ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Severe Disease ◽  
Clinical Malaria ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Highland Area ◽  
Cytokine Responses ◽  
Increased Risk ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACTIndividuals naturally exposed toPlasmodium falciparumlose clinical immunity after a prolonged lack of exposure.P. falciparumantigen-specific cytokine responses have been associated with protection from clinical malaria, but the longevity ofP. falciparumantigen-specific cytokine responses in the absence of exposure is not well characterized. A highland area of Kenya with low and unstable malaria transmission provided an opportunity to study this question. The levels of antigen-specific cytokines and chemokines associated in previous studies with protection from clinical malaria (gamma interferon [IFN-γ], interleukin-10 [IL-10], and tumor necrosis factor alpha [TNF-α]), with increased risk of clinical malaria (IL-6), or with pathogenesis of severe disease in malaria (IL-5 and RANTES) were assessed by cytometric bead assay in April 2008, October 2008, and April 2009 in 100 children and adults. During the 1-year study period, none had an episode of clinicalP. falciparummalaria. Two patterns of cytokine responses emerged, with some variation by antigen: a decrease at 6 months (IFN-γ and IL-5) or at both 6 and 12 months (IL-10 and TNF-α) or no change over time (IL-6 and RANTES). These findings document thatP. falciparumantigen-specific cytokine responses associated in prior studies with protection from malaria (IFN-γ, TNF-α, and IL-10) decrease significantly in the absence ofP. falciparumexposure, whereas those associated with increased risk of malaria (IL-6) do not. The study findings provide a strong rationale for future studies of antigen-specific IFN-γ, TNF-α, and IL-10 responses as biomarkers of increased population-level susceptibility to malaria after prolonged lack ofP. falciparumexposure.

scholarly journals Identification of Heparin Modifications and Polysaccharide Inhibitors of Plasmodium falciparum Merozoite Invasion That Have Potential for Novel Drug Development

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Michelle J. Boyle ◽  
Mark Skidmore ◽  
Benjamin Dickerman ◽  
Lynsay Cooper ◽  
Anthony Devlin ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Development ◽  
Inhibitory Activity ◽  
Sulfated Polysaccharides ◽  
Merozoite Invasion ◽  
Content Type ◽  
Molecular Weights ◽  
Falciparum Merozoite ◽  
Successful Control ◽  
Novel Drug

ABSTRACT Despite recent successful control efforts, malaria remains a leading global health burden. Alarmingly, resistance to current antimalarials is increasing and the development of new drug families is needed to maintain malaria control. Current antimalarials target the intraerythrocytic developmental stage of the Plasmodium falciparum life cycle. However, the invasive extracellular parasite form, the merozoite, is also an attractive target for drug development. We have previously demonstrated that heparin-like molecules, including those with low molecular weights and low anticoagulant activities, are potent and specific inhibitors of merozoite invasion and blood-stage replication. Here we tested a large panel of heparin-like molecules and sulfated polysaccharides together with various modified chemical forms for their inhibitory activity against P. falciparum merozoite invasion. We identified chemical modifications that improve inhibitory activity and identified several additional sulfated polysaccharides with strong inhibitory activity. These studies have important implications for the further development of heparin-like molecules as antimalarial drugs and for understanding merozoite invasion.

scholarly journals Plasmodium falciparum Line-Dependent Association ofIn VitroGrowth-Inhibitory Activity and Risk of Malaria

2012 ◽  
Vol 80 (5) ◽  
pp. 1900-1908 ◽  
Author(s):  
Josea Rono ◽  
Anna Färnert ◽  
Daniel Olsson ◽  
Faith Osier ◽  
Ingegerd Rooth ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Activity ◽  
Content Type ◽  
Phenotypic Differences ◽  
Erythrocyte Invasion ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Control Study

ABSTRACTPlasmodium falciparum's ability to invade erythrocytes is essential for its survival within the human host. Immune mechanisms that impair this ability are therefore expected to contribute to immunity against the parasite. Plasma of humans who are naturally exposed to malaria has been shown to have growth-inhibitory activity (GIA)in vitro. However, the importance of GIA in relation to protection from malaria has been unclear. In a case-control study nested within a longitudinally followed population in Tanzania, plasma samples collected at baseline from 171 individuals (55 cases and 116 age-matched controls) were assayed for GIA using threeP. falciparumlines (3D7, K1, and W2mef) chosen based on their erythrocyte invasion phenotypes. Distribution of GIA differed between the lines, with most samples inhibiting the growth of 3D7 and K1 and enhancing the growth of W2mef. GIA to 3D7 was associated with a reduced risk of malaria within 40 weeks of follow-up (odds ratio, 0.45; 95% confidence interval [CI], 0.21 to 0.96;P= 0.04), whereas GIA to K1 and W2mef was not. These results show that GIA, as well as its association with protection from malaria, is dependent on theP. falciparumline and can be explained by differences in erythrocyte invasion phenotypes between parasite lines. Our study contributes knowledge on the biological importance of growth inhibition and the potential influence ofP. falciparumerythrocyte invasion phenotypic differences on its relationship to protective immunity against malaria.

scholarly journals Comparative Immunogenicities of Full-Length Plasmodium falciparum Merozoite Surface Protein 3 and a 24-Kilodalton N-Terminal Fragment

2011 ◽  
Vol 18 (8) ◽  
pp. 1221-1228 ◽  
Author(s):  
Maryam Imam ◽  
Yengkhom Sangeeta Devi ◽  
Akhilesh K. Verma ◽  
Virander Singh Chauhan
Keyword(s):  
Plasmodium Falciparum ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Terminal Region ◽  
Content Type ◽  
Conserved Domain ◽  
Terminal Fragment ◽  
Falciparum Merozoite ◽  
Form Part ◽  
Parasite Lysate

ABSTRACTRecombinantPlasmodium falciparummerozoite surface protein 3 (PfMSP3F) and a 24-kDa fragment from its N terminus (MSP3N) that includes the essential conserved domain, which elicits the maximum antibody (Ab)-dependent cellular inhibition (ADCI), were expressed as soluble proteins inEscherichia coli. Both proteins were found to be stable in both soluble and lyophilized forms. Immunization with MSP3F and MSP3N formulated separately with two human-compatible adjuvants, aluminum hydroxide (Alhydrogel) and Montanide ISA 720, produced significant antibody responses in mice and rabbits. Polyclonal Abs against both antigens recognized native MSP3 in the parasite lysate. These two Abs also recognized two synthetic peptides, previously characterized to possess B cell epitopes from the N-terminal region. Antibody depletion assay showed that most of the IgG response is directed toward the N-terminal region of the full protein. Anti-MSP3F and anti-MSP3N rabbit antibodies did not inhibit merozoite invasion or intraerythrocytic development but significantly reduced parasitemia in the presence of human monocytes. The ADCI demonstrated by anti-MSP3N antibodies was comparable to that exhibited by anti-MSP3F antibodies (both generated in rabbit). These results suggest that the N-terminal fragment of MSP3 can be considered a vaccine candidate that can form part of a multigenic vaccine against malaria.

scholarly journals Antibodies to Peptides in Semiconserved Domains of RIFINs and STEVORs Correlate with Malaria Exposure

mSphere ◽  
2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Albert E. Zhou ◽  
Andrea A. Berry ◽  
Jason A. Bailey ◽  
Andrew Pike ◽  
Antoine Dara ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Severe Malaria ◽  
Surface Antigen ◽  
Immune Evasion ◽  
Clinical Malaria ◽  
Malaria Episode ◽  
Natural Immunity ◽  
Content Type ◽  
Variant Surface Antigen ◽  
Malaria Exposure

ABSTRACT The repetitive interspersed family (RIFIN) and the subtelomeric variable open reading frame (STEVOR) family represent two of three major Plasmodium falciparum variant surface antigen families involved in malaria pathogenesis and immune evasion and are potential targets in the development of natural immunity. Protein and peptide microarrays populated with RIFINs and STEVORs associated with severe malaria vulnerability in Malian children were probed with adult and pediatric sera to identify epitopes that reflect malaria exposure. Adult sera recognized and reacted with greater intensity to all STEVOR proteins than pediatric sera did. Serorecognition of and seroreactivity to peptides within the semiconserved domain of STEVORs increased with age and seasonal malaria exposure, while serorecognition and seroreactivity increased for the semiconserved and second hypervariable domains of RIFINs only with age. Serologic responses to RIFIN and STEVOR peptides within the semiconserved domains may play a role in natural immunity to severe malaria. IMPORTANCE Malaria, an infectious disease caused by the parasite Plasmodium falciparum, causes nearly 435,000 deaths annually worldwide. RIFINs and STEVORs are two variant surface antigen families that are involved in malaria pathogenesis and immune evasion. Recent work has shown that a lack of humoral immunity to these proteins is associated with severe malaria vulnerability in Malian children. This is the first study to have compared serologic responses of children and adults to RIFINs and STEVORs in settings of malaria endemicity and to examine such serologic responses before and after a clinical malaria episode. Using microarrays, we determined that the semiconserved domains in these two parasite variant surface antigen families harbor peptides whose seroreactivity reflects malaria exposure. A similar approach has the potential to illuminate the role of variant surface antigens in the development of natural immunity to clinical malaria. Potential vaccines for severe malaria should include consideration of peptides within the semiconserved domains of RIFINs and STEVORs.

scholarly journals Increasedpfmdr1Copy Number and Sequence Polymorphisms in Plasmodium falciparum Isolates from Sudanese Malaria Patients Treated with Artemether-Lumefantrine

2011 ◽  
Vol 55 (11) ◽  
pp. 5408-5411 ◽  
Author(s):  
Nahla B. Gadalla ◽  
Ishag Adam ◽  
Salah-Eldin Elzaki ◽  
Sahar Bashir ◽  
Izdihar Mukhtar ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Markers ◽  
Dna Sequencing ◽  
Gene Amplification ◽  
Recurrent Infection ◽  
Efficacy Study ◽  
Content Type ◽  
Sequence Polymorphisms ◽  
Eastern Sudan

ABSTRACTMolecular markers for surveillance ofPlasmodium falciparumresistance to current antimalarials are sorely needed. A 28-day efficacy study of artemether-lumefantrine in eastern Sudan identified 5 treatment failures among 100 evaluable patients; 9 further individuals were parasite positive by PCR during follow-up. Polymorphisms inpfatpase6andpfmdr1were evaluated by DNA sequencing. One individual carried parasites with a novelpfmdr1polymorphism (F1044L).pfmdr1gene amplification in parasites prior to treatment occurred in three individuals who had recurrent infection during follow-up.

Significance of proliferating cell nuclear antigen in predicting recurrence of intracranial meningioma

1996 ◽  
Vol 84 (1) ◽  
pp. 85-90 ◽  
Author(s):  
Mark A. Cobb ◽  
Muhammad Husain ◽  
Bruce J. Andersen ◽  
Ossama Al-Mefty
Keyword(s):  
Proliferating Cell Nuclear Antigen ◽  
Statistical Significance ◽  
Tumor Biology ◽  
Nuclear Antigen ◽  
Intracranial Meningioma ◽  
Content Type ◽  
Tumor Histology ◽  
Proliferating Cell ◽  
Fine Print

✓ It is well known that the histological appearance of meningiomas often fails to predict accurately the clinical behavior of the tumor. Therefore, attention has turned from tumor histology to tumor biology. Proliferating cell nuclear antigen (PCNA), a cell cycle-regulated protein, has been recently characterized as the cofactor of DNA polymerase-δ, an enzyme required for DNA replication. The rate of synthesis of PCNA directly correlates with the proliferative state of cells. Immunohistochemical labeling of this antigen is now possible with monoclonal antibodies that allow for its demonstration in routinely fixed, paraffin-embedded specimens. In this study, the PCNA labeling index (LI) was determined for 83 meningiomas, including tumors with both benign and malignant clinical courses and with benign, atypical, and malignant histologies, apparent after total or subtotal resections. No statistical difference was found between the LI on recurrence and that found at initial presentation. In addition, stepwise multivariate regression analysis failed to identify any combination of factors (age, gender, race, age of specimen, tumor histology, Simpson grade of resection) that contributes to the predictive strength of the PCNA LI for tumor recurrence. However, for LIs less than 2%, only one of 26 gross totally resected tumors recurred (mean follow up 53 months); for LIs more than 7%, five of 13 gross totally resected tumors recurred (mean follow up 55 months). The difference in recurrence rates between gross totally resected meningiomas with PCNA LIs less than 2% and those with PCNA LIs more than 7% achieved statistical significance with a Fisher's exact probability equaling 0.011. The authors conclude that quantitative PCNA labeling of meningiomas is a promising technique that can provide meaningful prognostic information.

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