Risk of Burkitt Lymphoma Correlates with Breadth and Strength of Antibody Response to Plasmodium Falciparum Malaria Stage-Specific Antigens

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. LBA-3-LBA-3
Author(s):  
Peter Aka ◽  
Maria Vila ◽  
Amar Jariwala ◽  
Francis Nkrumah ◽  
Benjamin Emmanuel ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Confidence Intervals ◽  
Burkitt Lymphoma ◽  
Protective Immunity ◽  
Conflicts Of Interest ◽  
Hematologic Malignancy ◽  
Merozoite Surface Protein ◽  
Blood Stage ◽  
Malaria Parasites

Abstract Abstract LBA-3 The incidence of endemic Burkitt lymphoma (eBL) is high in areas where Plasmodium falciparum (Pf) malaria is endemic, which suggests a role of malaria in eBL etiology. Previous data suggest that children with eBL are 5–12 times more likely to have elevated antibody titers to the whole schizont extract, a surrogate of exposure to malaria, compared to controls of comparable age and sex without eBL. However, the corollary studies to understand the role of protective malarial antibodies in eBL have not been conducted. We hypothesized that the risk for eBL might be different according to the breadth and strength of protective immunity to clinical malaria in children exposed to Pf malaria parasites. We investigated this hypothesis in children with and without eBL cases using samples from the National Cancer Institutes (NCI) Ghana Burkitt Lymphoma Study. Cases were children aged 0–15 years enrolled at the Korle-Bu Teaching Hospital, Accra, Ghana, during 1965–1994. Controls were children enrolled contemporaneously from the same villages as the cases or children who were referred to Korle-Bu as BL but diagnosed with benign or a non-hematologic malignancy. Antibodies to recombinant Pf serine repeat antigen 36 (SE 36) and merozoite surface protein-1 (MSP-1), which are blood stage vaccine candidates, and antibodies to histidine-rich protein-II (HRP-II), an exposure antigen expressed during the blood stage, and the peptide 6NANP, which is a circumsporozoite protein (CSP) expressed in the pre-hepatic stage, were measured using sub-class-specific enzyme-linked absorbent immunoassays (ELISAs). Antibodies to tetanus toxoid were measured as an irrelevant antigen control. Markers were included if the within (W)- and between (B)-plate coefficients of variation for the sub-class-specific IgG results was <30% (Figure 1). The independent association of each malaria marker with eBL was determined by calculating the odds ratio (ORs) and 95% confidence intervals (95% CIs) using unconditional multivariable logistic regression adjusted for sex, age, calendar year, and for all the other malaria markers, which were hypothesized to be contributory. In adjusted results, eBL was inversely associated with IgG1 seropositivity to SE36 (OR 0.54 [95% CI 0.34–0.86], p=0.01) and positively associated with HRPII (OR 1.47 [95% CI 1.06–2.02], p=0.019). The ORs for eBL were significantly decreased for low, medium, and high titers, but without a trend (0.44, 0.47, and 0.58 for low, medium, and high, respectively [ptrend=0.216]) (Figure 2: Odds ratios and 95% confidence intervals of association of eBL with different malaria markers). They increased significantly with increasing titers of IgG3 antibodies to HRPII (ORs 1.83, 1.91, to 2.25 for low, medium, and high titers, respectively [ptrend<0.002]) and showed a trend. Having antibodies to 6NANP was associated with eBL (OR 1.48 [95% CI 0.90–2.43]), but among the positives, having medium and high IgG3 antibodies to 6NANP as opposed to being sero-negative was associated with decreased risk of BL (ORs 0.79 and OR 0.60, respectively [ptrend=0.002]). Models with three markers (IgG1 to SE36, IgG3 to HRP-II, and IgG3 to 6NANP) predicted eBL better than models with just one of the markers. These data suggest children with eBL in Ghana had decreased SE36 IgG1 and increased HRPII IgG3 antibodies compared to children without eBL from the same Pf endemic areas. These results fit with the hypothesis that eBL risk increases with greater exposure to Pf malaria parasites. They also provide the first confirmation of the hypothesis that antibodies elicited by antigens targeted by protective immunity might be protective for eBL. However, they also highlight that the relationship between eBL and Pf antibodies is complex as it appears to depend on whether the antibodies reflect exposure, protection, or both. A better understanding of the specific contribution of immune response to malaria in eBL risk should be the priority of efforts to discover a biomarker profile for eBL. Disclosures: No relevant conflicts of interest to declare.

Characterization of a Plasmodium falciparum PHISTc protein, PF3D7_0801000, in blood- stage malaria parasites

2021 ◽  
Vol 80 ◽  
pp. 102240
Author(s):  
Hikaru Nagaoka ◽  
Bernard N. Kanoi ◽  
Masayuki Morita ◽  
Takahiro Nakata ◽  
Nirianne M.Q. Palacpac ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Blood Stage ◽  
Malaria Parasites ◽  
Blood Stage Malaria

Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum

Nature ◽  
2007 ◽  
Vol 446 (7131) ◽  
pp. 88-91 ◽  
Author(s):  
Heather J. Painter ◽  
Joanne M. Morrisey ◽  
Michael W. Mather ◽  
Akhil B. Vaidya
Keyword(s):  
Plasmodium Falciparum ◽  
Electron Transport ◽  
Blood Stage ◽  
Specific Role

The Role of Hematopoietic Cell Transplantation (HCT) for Burkitt Lymphoma: a Report From the Center for International Blood and Marrow Transplant Research (CIBMTR)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2390-2390
Author(s):  
James L. Gajewski ◽  
Jeanette Carreras ◽  
Hillard M. Lazarus ◽  
Ginna G. Laport ◽  
Silvia Montoto ◽  
...  
Keyword(s):  
Burkitt Lymphoma ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
B Cell Lymphoma ◽  
Unrelated Donor ◽  
Free Survival ◽  
Disease Free

Abstract Abstract 2390 Burkitt lymphoma (BL) is an aggressive B cell lymphoma primarily affecting children and young adults and is characterized by the highest doubling time of any tumor. Cyclical intensive chemotherapy and rituximab confer high complete remission (CR) rates and 80% long term disease free survival in chemotherapy sensitive disease. The role of autologous (autoHCT) or allogeneic (alloHCT) transplant is not well described in BL. We report the outcomes of 241 recipients of HCT for BL between 1985 and 2007 reported to the CIBMTR. Five patients (pts) received syngeneic twin grafts in addition to autoHCT in 113 pts, HLA identical sibling alloHCT (SIB) in 80 pts and mismatched related or unrelated donor (UNR/MM) alloHCT in 48 pts. Baseline patient and disease related risk factors varied significantly between cohorts (table1). The autoHCT cohort had a higher proportion of pts with chemotherapy sensitive disease (86%), peripheral blood grafts (73%) and HCT in first CR (42%). In the UNR/MM cohort, 25% pts were chemotherapy resistant and only 6% were in CR1. The use of autoHCT has declined in recent years with the majority (81%) performed before 2001. Conditioning regimen for alloHCT was myeloablative in 88% (86% and 92% in SIB and UNR/MM respectively). Treatment related mortality (TRM) was higher in alloHCT recipients (table1). Cumulative incidence of relapse/progression at 5 yrs (95% CI) was 44 (35-53)% for autoHCT, 42(31-53)% for SIB and 48 (34-62)% for UNR/MM. For autoHCT, 5-yr progression free survival (PFS) was 48(39-58)%, 78% for those in first CR versus 27% for disease beyond CR1 (p<0.001). For alloHCT, 5-yr PFS was 50% for those in first CR versus 19% for disease beyond CR1 (p=0.001) (figure 1). 5-yr PFS was 30 (20-41)% for SIB and 22 (12-35)% for UNR/MM. Progressive BL was the commonest cause of death. Conclusion: While autoHCT and alloHCT are both feasible in patients with BL, the use of autoHCT appears to be declining in recent years concomitant with the advent of modern chemotherapy. AlloHCT was performed in those with considerably higher risk disease. Approximately one fifth of advanced BL pts receiving alloHCT beyond CR1 had long term disease free survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Age-Dependent IgG Subclass Responses to Plasmodium falciparum EBA-175 Are Differentially Associated with Incidence of Malaria in Mozambican Children

2011 ◽  
Vol 19 (2) ◽  
pp. 157-166 ◽  
Author(s):  
Carlota Dobaño ◽  
Diana Quelhas ◽  
Llorenç Quintó ◽  
Laura Puyol ◽  
Elisa Serra-Casas ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Incidence ◽  
Controlled Trial ◽  
Intermittent Preventive Treatment ◽  
Antibody Test ◽  
Merozoite Surface Protein ◽  
Blood Stage ◽  
Enzyme Linked Immunosorbent Assay ◽  
Igg Subclass ◽  
Content Type

ABSTRACTPlasmodium falciparumblood-stage antigens such as merozoite surface protein 1 (MSP-1), apical membrane antigen 1 (AMA-1), and the 175-kDa erythrocyte binding antigen (EBA-175) are considered important targets of naturally acquired immunity to malaria. However, it is not clear whether antibodies to these antigens are effectors in protection against clinical disease or mere markers of exposure. In the context of a randomized, placebo-controlled trial of intermittent preventive treatment in infants conducted between 2002 and 2004, antibody responses toPlasmodium falciparumblood-stage antigens in a cohort of 302 Mozambican children were evaluated by immunofluorescence antibody test and enzyme-linked immunosorbent assay at 5, 9, 12, and 24 months of age. We found that IgG subclass responses to EBA-175 were differentially associated with the incidence of malaria in the follow-up period. A double amount of cytophilic IgG1 or IgG3 was associated with a significant decrease in the incidence of malaria (incidence rate ratio [IRR] = 0.49, 95% confidence interval [CI] = 0.25 to 0.97, andP= 0.026 and IRR = 0.44, CI = 0.19 to 0.98, andP= 0.037, respectively), while a double amount of noncytophilic IgG4 was significantly correlated with an increased incidence of malaria (IRR = 3.07, CI = 1.08 to 8.78,P= 0.020). No significant associations between antibodies to the 19-kDa fragment of MSP-1 (MSP-119) or AMA-1 and incidence of malaria were found. Age, previous episodes of malaria, present infection, and neighborhood of residence were the main factors influencing levels of antibodies to all merozoite antigens. Deeper understanding of the acquisition of antibodies against vaccine target antigens in early infancy is crucial for the rational development and deployment of malaria control tools in this vulnerable population.

scholarly journals Pre-erythrocytic antibody profiles induced by controlled human malaria infections in healthy volunteers under chloroquine prophylaxis

2013 ◽  
Vol 3 (1) ◽  
Author(s):  
Philip L. Felgner ◽  
Meta Roestenberg ◽  
Li Liang ◽  
Christopher Hung ◽  
Aarti Jain ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Healthy Volunteers ◽  
Protective Immunity ◽  
Circumsporozoite Protein ◽  
Blood Stage ◽  
Asexual Blood Stage ◽  
Liver Stage ◽  
Human Malaria ◽  
Life Cycle Stages

Abstract Complete sterile protection to Plasmodium falciparum (Pf) infection mediated by pre-erythrocytic immunity can be experimentally induced under chloroquine prophylaxis, through immunization with sporozoites from infected mosquitoes' bites (CPS protocol). To characterize the profile of CPS induced antibody (Ab) responses, we developed a proteome microarray containing 809 Pf antigens showing a distinct Ab profile with recognition of antigens expressed in pre-erythrocytic life-cycle stages. In contrast, plasma from naturally exposed semi-immune individuals from Kenya was skewed toward antibody reactivity against asexual blood stage antigens. CPS-immunized and semi-immune individuals generated antibodies against 192 and 202 Pf antigens, respectively, but only 60 antigens overlapped between the two groups. Although the number of reactive antigens varied between the CPS-immunized individuals, all volunteers reacted strongly against the pre-erythrocytic antigens circumsporozoite protein (CSP) and liver stage antigen 1 (LSA1). Well classified merozoite and erythrocytic antigens were strongly reactive in semi-immune individuals but lacking in the CPS immunized group. These data show that the antibody profile of CPS-immunized and semi-immune groups have quite distinct profiles reflecting their protective immunity; antibodies from CPS immunized individuals react strongly against pre-erythrocytic while semi-immune individuals mainly react against erythrocytic antigens.

scholarly journals Orthosteric-allosteric dual inhibitors of PfHT1 as selective anti-malarial agents

2020 ◽  
Author(s):  
Jian Huang ◽  
Yafei Yuan ◽  
Na Zhao ◽  
Debing Pu ◽  
Qingxuan Tang ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Rational Design ◽  
Glucose Transporter ◽  
Blood Stage ◽  
Host Cells ◽  
Sugar Uptake ◽  
Hexose Transporter ◽  
Next Generation ◽  
Malaria Parasites ◽  
Glucose Transporter 1

AbstractArtemisinin-resistant malaria parasites have emerged and been spreading, posing a significant public health challenge. Anti-malarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a “selective starvation” strategy by selectively inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in Plasmodium falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. Comparison of the crystal structures of human GLUT3 and PfHT1 bound to C3361, a PfHT1-specific moderate inhibitor, revealed an inhibitor binding-induced pocket that presented a promising druggable site. We thereby designed small-molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure-activity relationship (SAR) studies, the TH-PF series was identified to selectively inhibit PfHT1 over GLUT1 and potent against multiple strains of the blood-stage P. falciparum. Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously targeting the orthosteric and allosteric sites of a transporter.Significance statementBlocking sugar uptake in P. falciparum by selectively inhibiting the hexose transporter PfHT1 kills the blood-stage parasites without affecting the host cells, indicating PfHT1 as a promising therapeutic target. Here, we report the development of novel small-molecule inhibitors that are selectively potent to the malaria parasites over human cell lines by simultaneously targeting the orthosteric and the allosteric binding sites of PfHT1. Our findings established the basis for the rational design of next-generation anti-malarial drugs.

scholarly journals Analysis of the Role of TpUB05 Antigen from Theileria parva in Immune Responses to Malaria in Humans Compared to Its Homologue in Plasmodium falciparum the UB05 Antigen

Pathogens ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 271
Author(s):  
Jerome Nyhalah Dinga ◽  
Stephanie Numenyi Perimbie ◽  
Stanley Dobgima Gamua ◽  
Francis N. G. Chuma ◽  
Dieudonné Lemuh Njimoh ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Immune Responses ◽  
Protective Immunity ◽  
Vaccine Development ◽  
Theileria Parva ◽  
Peripheral Blood Mononuclear ◽  
Significant Difference ◽  
First Time

Despite the amount of resources deployed and the technological advancements in molecular biology, vaccinology, immunology, genetics, and biotechnology, there are still no effective vaccines against malaria. Immunity to malaria is usually seen to be species- and/or strain-specific. However, there is a growing body of evidence suggesting the possibility of the existence of cross-strain, cross-species, and cross-genus immune responses in apicomplexans. The principle of gene conservation indicates that homologues play a similar role in closely related organisms. The homologue of UB05 in Theileria parva is TpUB05 (XP_763711.1), which has been tested and shown to be associated with protective immunity in East Coast fever. In a bid to identify potent markers of protective immunity to aid malaria vaccine development, TpUB05 was tested in malaria caused by Plasmodium falciparum. It was observed that TpUB05 was better at detecting antigen-specific antibodies in plasma compared to UB05 when tested by ELISA. The total IgG raised against TpUB05 was able to block parasitic growth in vitro more effectively than that raised against UB05. However, there was no significant difference between the two study antigens in recalling peripheral blood mononuclear cell (PBMC) memory through IFN-γ production. This study suggests, for the first time, that TpUB05 from T. parva cross-reacts with UB05 from P. falciparum and is a marker of protective immunity in malaria. Hence, TpUB05 should be considered for possible development as a potential subunit vaccine candidate against malaria.

Risk for Endemic Burkitt Lymphoma Is Elevated in Children Who Are Resistant to Blood-Stage Plasmodium Falciparum Malaria Infection: Preliminary Results from the Emblem Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1676-1676
Author(s):  
Samuel Kirimunda ◽  
Tobias Kinyera ◽  
Martin Ogwang ◽  
Steven J Reynolds ◽  
Moses Joloba ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Burkitt Lymphoma ◽  
Malaria Infection ◽  
Malaria Parasite ◽  
Blood Stage ◽  
Bed Net ◽  
Previous Night ◽  
History Of ◽  
Population Controls ◽  
Blood Stage Malaria

Abstract Introduction: Infection with Plasmodium falciparum (Pf) malaria is widely accepted as a risk factor for endemic Burkitt lymphoma (eBL), but whether children with eBL are more likely to have detectable blood-stage Pfmalaria parasites and/or report a history of malaria morbidity compared to location-matched control children without eBL is unknown. We investigated this hypothesis in children with eBL (cases) compared to location-matched children without eBL (controls) from the National Cancer Institute (NCI)-sponsored EMBLEM Study. Methods: Cases were children with eBL aged 0-15 years presenting to two hospitals in northern Uganda from 11/2010 to 07/2014 with histologically proven, untreated eBL. Controls were children with similar malaria exposure in the region, including children attending village health centers for minor complaints (pilot health-center controls [PHCs]), at home in 12 randomly selected villages (pilot population controls [PPCs]),and at home in 88 randomly selected villages with matching for the age- and sex-distribution of eBL cases (matched population controls [MPCs]). Cases and controls provided a venous blood sample and questionnaire information on exposure to Pf malaria parasites (mosquito bed net use, insecticide sprays, proximity to a river/swamp, history of treatment for malaria). Blood-stage malaria was evaluated microscopically with giemsa-stained thin and thick blood films and with a commercially available histidine-rich protein (HRPII) antigen-based rapid diagnostic test. The log of thick-film malaria parasite count in cases and controls was compared using the Students t-test. Associations were evaluated by calculating odds ratios (ORs) and 95% confidence intervals (95% CIs) using unconditional logistic regression adjusting for sex, age, ownership/ use of mosquito bed net, and in- or out-patient treatment for malaria. Results:We studied 280 eBL cases (61% male, mean + SD age 7.9 + 3.4 years) and 1619 controls including 171 PHCs (37% male, mean + SD age 7.3 + 4.0 years), 1005 PPCs (48% male, mean + SD age 7.0 + 4.1 years) and 443 MPCs (56% male, mean + SD age 7.5 + 3.3 years). Overall, eBL cases were less likely to own a mosquito bed net than controls (46% versus 67% - 79% in controls, p<0.0001), but among those who owned a mosquito bed net, eBL cases were more likely to have used it the previous night (42% versus 21% - 31% in controls, p<0.0001). Blood-stage malaria infection was detected less frequently in cases compared to controls (Figure 1). In adjusted results, eBL cases were less likely to have current blood-stage malaria infection based on the thin film (OR 0.42 [95% CI 0.26-0.67], p<0.0001) or thick film (OR 0.55 [95% CI 0.38-0.80], p=0.001) and less likely to have had recent infection based on the HRPII rapid diagnostic test (OR 0.31 [95% CI 0.22-0.44], p<0.0001) using all controls combined, with similar results using separate control groups (OR 0.28 – 0.60). Blood-stage malaria parasite count was 0.88 log lower in parasitemic eBL cases than controls (2.24 log versus 3.12 log, p=0.0003). With all controls combined and adjusting for HRPII antigen, the risk of eBL was inversely associated with female sex (OR 0.65 [95% CI 0.46-0.90], p=0.011), ownership of mosquito bed net (OR 0.03 [95% CI 0.01-0.07], p<0.0001), and any inpatient admission for severe malaria (OR 0.56 [95% CI 0.39-0.80], p=0.001) or outpatient treatment for moderate malaria (OR 0.47 [95% CI 0.32-0.69], p<0.0001). The risk of eBL was directly associated with older age (OR 3.1 [95% CI 1.9-5.00] and OR 2.6 [95% CI 1.60-4.40], for 5-9 and 10-15 years versus 0-4 years) and not sleeping under a mosquito net the previous night (OR 10.9 [95% CI 4.34-27.3], p<0.0001). Socioeconomics, spraying insecticides, and proximity to river/swamp did not influence the results. Conclusions: Cases of eBL were unlikely to have Pf malaria parasitemia despite high exposure to mosquitoes and low ownership of bed nets. These results reject the hypothesis that eBL is associated with current or recent blood-stage Pf malaria. They support an alternative hypothesis that children with eBL have superior immunological control of blood-stage infection (Pf elite controller phenotype) and that eBL might be an accident of robust immunological control of blood-stage malaria infection. Further studies are needed to characterize the molecular spectrum of Pf parasites and other mechanisms that drive eBL genesis. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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