scholarly journals Malaria Immunoepidemiology in Low Transmission: Correlation of Infecting Genotype and Immune Response to Domains of Plasmodium falciparum Merozoite Surface Protein 3

2011 ◽  
Vol 79 (5) ◽  
pp. 2070-2078 ◽  
Author(s):  
Stephen J. Jordan ◽  
Ana L. Oliveira ◽  
Jean N. Hernandez ◽  
Robert A. Oster ◽  
Debasish Chattopadhyay ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Effective Vaccine ◽  
Serum Samples ◽  
Content Type ◽  
Low Transmission ◽  
Rational Development ◽  
Time Of Infection ◽  
Potential Vaccine

ABSTRACTMalaria caused byPlasmodium falciparumis a major cause of global infant mortality, and no effective vaccine currently exists. Multiple potential vaccine targets have been identified, and immunoepidemiology studies have played a major part in assessing those candidates. When such studies are carried out in high-transmission settings, individuals are often superinfected with complex mixtures of genetically distinctP. falciparumtypes, making it impossible to directly correlate the genotype of the infecting antigen with the antibody response. In contrast, in regions of low transmissionP. falciparuminfections are often genetically simple, and direct comparison of infecting genotype and antigen-specific immune responses is possible. As a test of the utility of this approach, responses against several domains and allelic variants of the vaccine candidateP. falciparummerozoite surface protein 3 (PfMSP3) were tested in serum samples collected near Iquitos, Peru. Antibodies recognizing both the conserved C-terminal and the more variable N-terminal domain were identified, but anti-N-terminal responses were more prevalent, of higher titers, and primarily of cytophilic subclasses. Comparing antibody responses to different PfMSP3 variants with thePfMSP3genotype present at the time of infection showed that anti-N-terminal responses were largely allele class specific, but there was some evidence for responses that cross-reacted across allele classes. Evidence for cross-reactive responses was much stronger when variants within one allele class were tested, which has implications for the rational development of genotype-transcending PfMSP3-based vaccines.

scholarly journals Plasmodium falciparum Malaria in the Peruvian Amazon, a Region of Low Transmission, Is Associated with Immunologic Memory

2012 ◽  
Vol 80 (4) ◽  
pp. 1583-1592 ◽  
Author(s):  
Eva H. Clark ◽  
Claudia J. Silva ◽  
Greta E. Weiss ◽  
Shanping Li ◽  
Carlos Padilla ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Surface Protein ◽  
Plasmodium Falciparum Malaria ◽  
Merozoite Surface Protein ◽  
Content Type ◽  
Low Transmission ◽  
Apical Membrane Antigen 1 ◽  
Specific Memory ◽  
Erythrocyte Binding ◽  
Transmission Region

ABSTRACTThe development of clinical immunity toPlasmodium falciparummalaria is thought to require years of parasite exposure, a delay often attributed to difficulties in developing protective antibody levels. In this study, we evaluated severalP. falciparumvaccine candidate antigens, including apical membrane antigen 1 (AMA-1), circumsporozoite protein (CSP), erythrocyte binding antigen 175 (EBA-175), and the 19-kDa region of merozoite surface protein 1 (MSP119). After observing a more robust antibody response to MSP119, we evaluated the magnitude and longevity of IgG responses specific to this antigen in Peruvian adults and children before, during, and afterP. falciparuminfection. In this low-transmission region, even one reported prior infection was sufficient to produce a positive anti-MSP119IgG response for >5 months in the absence of reinfection. We also observed an expansion of the total plasmablast (CD19+CD27+CD38high) population in the majority of individuals shortly after infection and detected MSP1-specific memory B cells in a subset of individuals at various postinfection time points. This evidence supports our hypothesis that effective antimalaria humoral immunity can develop in low-transmission regions.

scholarly journals Mosquito Bite-Induced Controlled Human Malaria Infection withPlasmodium vivaxorP. falciparumGenerates Immune Responses to Homologous and Heterologous Preerythrocytic and Erythrocytic Antigens

2018 ◽  
Vol 87 (3) ◽  
Author(s):  
Cysha E. Hall ◽  
Lisa M. Hagan ◽  
Elke Bergmann-Leitner ◽  
Donna M. Tosh ◽  
Jason W. Bennett ◽  
...  
Keyword(s):  
Malaria Infection ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Similar Proportion ◽  
Enzyme Linked Immunosorbent Assay ◽  
Serum Samples ◽  
Content Type ◽  
Human Malaria ◽  
Before And After ◽  
Controlled Human Malaria Infection

ABSTRACTSeroepidemiological studies on the prevalence of antibodies to malaria antigens are primarily conducted on individuals from regions of endemicity. It is therefore difficult to accurately correlate the antibody responses to the timing and number of prior malaria infections. This study was undertaken to assess the evolution of antibodies to the dominant surface antigens ofPlasmodium vivaxandP. falciparumfollowing controlled human malaria infection (CHMI) in malaria-naive individuals. Serum samples from malaria-naive adults, collected before and after CHMI with eitherP. vivax(n= 18) orP. falciparum(n= 18), were tested for the presence of antibodies to the circumsporozoite protein (CSP) and the 42-kDa fragment of merozoite surface protein 1 (MSP-142) ofP. vivaxandP. falciparumusing an enzyme-linked immunosorbent assay (ELISA). Approximately 1 month following CHMI with eitherP. vivaxorP. falciparum, >60% of subjects seroconverted to homologous CSP and MSP-1. More than 50% of the subjects demonstrated reactivity to heterologous CSP and MSP-142, and a similar proportion of subjects remained seropositive to homologous MSP-142>5 months after CHMI. Computational analysis provides insight into the presence of cross-reactive responses. The presence of long-lived and heterologous reactivity and its functional significance, if any, need to be taken into account while evaluating malaria exposure in field settings.

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 directed against merozoite surface protein-6 are induced by natural exposure to Plasmodium falciparum in a low transmission environment

2011 ◽  
Vol 33 (7) ◽  
pp. 401-410 ◽  
Author(s):  
S. J. JORDAN ◽  
A. L. OLIVEIRA ◽  
A. T. NEAL ◽  
J. N. HERNANDEZ ◽  
O. H. BRANCH ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Low Transmission ◽  
Natural Exposure

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 Antigenic Characterization of an Intrinsically Unstructured Protein, Plasmodium falciparum Merozoite Surface Protein 2

2012 ◽  
Vol 80 (12) ◽  
pp. 4177-4185 ◽  
Author(s):  
Christopher G. Adda ◽  
Christopher A. MacRaild ◽  
Linda Reiling ◽  
Kaye Wycherley ◽  
Michelle J. Boyle ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Surface Protein ◽  
Variable Region ◽  
Intrinsic Property ◽  
Merozoite Surface Protein ◽  
Surface Proteins ◽  
Structural Basis ◽  
Content Type ◽  
Intrinsically Unstructured Protein ◽  
Unstructured Protein

ABSTRACTMerozoite surface protein 2 (MSP2) is an abundant glycosylphosphatidylinositol (GPI)-anchored protein ofPlasmodium falciparum, which is a potential component of a malaria vaccine. As all forms of MSP2 can be categorized into two allelic families, a vaccine containing two representative forms of MSP2 may overcome the problem of diversity in this highly polymorphic protein. Monomeric recombinant MSP2 is an intrinsically unstructured protein, but its conformational properties on the merozoite surface are unknown. This question is addressed here by analyzing the 3D7 and FC27 forms of recombinant and parasite MSP2 using a panel of monoclonal antibodies raised against recombinant MSP2. The epitopes of all antibodies, mapped using both a peptide array and by nuclear magnetic resonance (NMR) spectroscopy on full-length recombinant MSP2, were shown to be linear. The antibodies revealed antigenic differences, which indicate that the conserved N- and C-terminal regions, but not the central variable region, are less accessible in the parasite antigen. This appears to be an intrinsic property of parasite MSP2 and is not dependent on interactions with other merozoite surface proteins as the loss of some conserved-region epitopes seen using the immunofluorescence assay (IFA) on parasite smears was also seen on Western blot analyses of parasite lysates. Further studies of the structural basis of these antigenic differences are required in order to optimize recombinant MSP2 constructs being evaluated as potential vaccine components.

scholarly journals A Chimeric Plasmodium falciparum Merozoite Surface Protein Vaccine Induces High Titers of Parasite Growth Inhibitory Antibodies

2013 ◽  
Vol 81 (10) ◽  
pp. 3843-3854 ◽  
Author(s):  
James R. Alaro ◽  
Andrea Partridge ◽  
Kazutoyo Miura ◽  
Ababacar Diouf ◽  
Ana M. Lopez ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
T Cell ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Plasmodium Yoelii ◽  
T Cell Response ◽  
Blood Stage ◽  
Fusion Partner ◽  
Content Type ◽  
Cpg Oligodeoxynucleotide

ABSTRACTThe C-terminal 19-kDa domain ofPlasmodium falciparummerozoite surface protein 1 (PfMSP119) is an established target of protective antibodies. However, clinical trials ofPfMSP142, a leading blood-stage vaccine candidate which contains the protective epitopes ofPfMSP119, revealed suboptimal immunogenicity and efficacy. Based on proof-of-concept studies in thePlasmodium yoeliimurine model, we produced a chimeric vaccine antigen containing recombinantPfMSP119(rPfMSP119) fused to the N terminus ofP. falciparummerozoite surface protein 8 that lacked its low-complexity Asn/Asp-rich domain, rPfMSP8 (ΔAsn/Asp). Immunization of mice with the chimeric rPfMSP1/8 vaccine elicited strong T cell responses to conserved epitopes associated with the rPfMSP8 (ΔAsn/Asp) fusion partner. While specific forPfMSP8, this T cell response was adequate to provide help for the production of high titers of antibodies to bothPfMSP119and rPfMSP8 (ΔAsn/Asp) components. This occurred with formulations adjuvanted with either Quil A or with Montanide ISA 720 plus CpG oligodeoxynucleotide (ODN) and was observed in both inbred and outbred strains of mice.PfMSP1/8-induced antibodies were highly reactive with two major alleles ofPfMSP119(FVO and 3D7). Of particular interest, immunization withPfMSP1/8 elicited higher titers ofPfMSP119-specific antibodies than a combined formulation of rPfMSP142and rPfMSP8 (ΔAsn/Asp). As a measure of functionality,PfMSP1/8-specific rabbit IgG was shown to potently inhibit thein vitrogrowth of blood-stage parasites of the FVO and 3D7 strains ofP. falciparum. These data support the further testing and evaluation of this chimericPfMSP1/8 antigen as a component of a multivalent vaccine forP. falciparummalaria.

scholarly journals Contrasting Patterns of Serologic and Functional Antibody Dynamics to Plasmodium falciparum Antigens in a Kenyan Birth Cohort

2015 ◽  
Vol 23 (2) ◽  
pp. 104-116 ◽  
Author(s):  
Arlene E. Dent ◽  
Indu Malhotra ◽  
Xuelie Wang ◽  
Denise Babineau ◽  
Kee Thai Yeo ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cord Blood ◽  
Natural Infection ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
In Utero ◽  
Content Type ◽  
Malaria Exposure ◽  
Increased Risk ◽  
Functional Antibodies

ABSTRACTIgG antibodies toPlasmodium falciparumare transferred from the maternal to fetal circulation during pregnancy, wane after birth, and are subsequently acquired in response to natural infection. We examined the dynamics of malaria antibody responses of 84 Kenyan infants from birth to 36 months of age by (i) serology, (ii) variant surface antigen (VSA) assay, (iii) growth inhibitory activity (GIA), and (iv) invasion inhibition assays (IIA) specific for merozoite surface protein 1 (MSP1) and sialic acid-dependent invasion pathway. Maternal antibodies in each of these four categories were detected in cord blood and decreased to their lowest level by approximately 6 months of age. Serologic antibodies to 3 preerythrocytic and 10 blood-stage antigens subsequently increased, reaching peak prevalence by 36 months. In contrast, antibodies measured by VSA, GIA, and IIA remained low even up to 36 months. Infants sensitized toP. falciparum in utero, defined by cord blood lymphocyte recall responses to malaria antigens, acquired antimalarial antibodies at the same rate as those who were not sensitizedin utero, indicating that fetal exposure to malaria antigens did not affect subsequent infant antimalarial responses. Infants with detectable serologic antibodies at 12 months of age had an increased risk ofP. falciparuminfection during the subsequent 24 months. We conclude that serologic measures of antimalarial antibodies in children 36 months of age or younger represent biomarkers of malaria exposure rather than protection and that functional antibodies develop after 36 months of age in this population.

scholarly journals Evaluation of the Immunogenicity and Vaccine Potential of Recombinant Plasmodium falciparum Merozoite Surface Protein 8

2012 ◽  
Vol 80 (7) ◽  
pp. 2473-2484 ◽  
Author(s):  
James R. Alaro ◽  
Evelina Angov ◽  
Ana M. Lopez ◽  
Hong Zhou ◽  
Carole A. Long ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
T Cell ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Plasmodium Yoelii ◽  
Full Length ◽  
T Cell Epitopes ◽  
Content Type ◽  
Rich Domain ◽  
Vaccine Potential

ABSTRACTThe C-terminal 19-kDa domain of merozoite surface protein 1 (MSP119) is the target of protective antibodies but alone is poorly immunogenic. Previously, using thePlasmodium yoeliimurine model, we fusedP. yoeliiMSP119(PyMSP119) with full-lengthP. yoeliimerozoite surface protein 8 (MSP8). Upon immunization, the MSP8-restricted T cell response provided help for the production of high and sustained levels of protectivePyMSP119- andPyMSP8-specific antibodies. Here, we assessed the vaccine potential of MSP8 of the human malaria parasite,Plasmodium falciparum. Distinct fromPyMSP8,P. falciparumMSP8 (PfMSP8) contains an N-terminal asparagine and aspartic acid (Asn/Asp)-rich domain whose function is unknown. Comparative analysis of recombinant full-lengthPfMSP8 and a truncated version devoid of the Asn/Asp-rich domain,PfMSP8(ΔAsn/Asp), showed that both proteins were immunogenic for T cells and B cells. All T cell epitopes utilized mapped within rPfMSP8(ΔAsn/Asp). The dominant B cell epitopes were conformational and common to both rPfMSP8 and rPfMSP8(ΔAsn/Asp). Analysis of nativePfMSP8 expression revealed thatPfMSP8 is present intracellularly in late schizonts and merozoites. Following invasion,PfMSP8 is found distributed on the surface of ring- and trophozoite-stage parasites. Consistent with a low and/or transient expression ofPfMSP8 on the surface of merozoites,PfMSP8-specific rabbit IgG did not inhibit thein vitrogrowth ofP. falciparumblood-stage parasites. These studies suggest that the further development ofPfMSP8 as a malaria vaccine component should focus on the use ofPfMSP8(ΔAsn/Asp) and its conserved, immunogenic T cell epitopes as a fusion partner for protective domains of poor immunogens, includingPfMSP119.

scholarly journals Detection of High Frequency of MAD20 Allelic Variants of Plasmodium Falciparum Merozoite Surface Protein 1 Gene from Adama and its Surroundings, Oromia, Ethiopia

2021 ◽  
Author(s):  
Temesgen File ◽  
Tsegaye Chekol ◽  
Gezahegn Solomon ◽  
Hunduma Dinka ◽  
Lemu Golassa
Keyword(s):  
Plasmodium Falciparum ◽  
Genetic Polymorphism ◽  
Malaria Control ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Allelic Variant ◽  
Clinical Isolates ◽  
Effective Vaccine ◽  
Multiple Infections ◽  
Size Polymorphism

Abstract Background: One of the major challenges in developing an effective vaccine against asexual stages of Plasmodium falciparum is genetic polymorphism within parasite population. Understanding the genetic polymorphism like block 2 region of merozoite surface protein (msp-1) genes of P. falciparum enlighten mechanisms underlining disease pathology, identification of the parasite clone profile from the isolates, transmission intensity and potential deficiencies of the ongoing malaria control and elimination effort in the locality. Detailed understanding of local genetic polymorphism is an input to pave the way for better management, control and elimination of malaria. The aim of this study was to detect the most frequent allelic variant of the merozoite surface protein (msp-1) gene of P. falciparum clinical isolates from selected health facilities in Adama town and its surroundings, Oromia, Ethiopia.Methods: A total of 139 clinical isolates were successfully amplified for msp-1 gene using specific sets of primer. Nested PCR amplification conducted, using specific primers targeting K1, MAD20, and R033 alleles followed by gel electrophoresis for fragment analysis. Based on the detection of a PCR fragment, infections were classified as monoclonal or multiple infections.Result: 19 different size polymorphism of msp-1 gene were identified in the study, with 67(48 %) MAD20, 18 (13 %) K-1 and 18 (13 %) RO33 allelic family. Whereas, the multiple infections were 21(15 %), 8(5.8 %), 4(2.9 %), 3(2.2 %) for MAD20+K-1, MAD20+RO33, K-1+ RO33, and MAD20+K-1, RO33, respectively. The overall Multiplicity of Infection (MOI) was 1.3 and the expected heterozygosity (He) was 0.58 indicating intermediate falciparum malaria transmission.Conclusion: The status of msp-1 allele size polymorphism, MOI and He observed in the study revealed an intermediate genetic diversity of P. falciparum clinical isolates, indicating that the ongoing malaria control and elimination effort should be intensified to effectively monitor the potential malaria resurgence in the study area. Moreover, deriving force that led to high predominance of MAD20 allelic variant revealed in such malaria declining region demands further research.

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