scholarly journals Impact of a rapid decline in malaria transmission on antimalarial IgG subclasses and avidity

2020 ◽  
Author(s):  
Isaac Ssewanyana ◽  
John Rek ◽  
Isabel Rodriguez ◽  
Lindsey Wu ◽  
Emmanuel Arinaitwe ◽  
...  
Keyword(s):  
Malaria Transmission ◽  
Affinity Maturation ◽  
Igg Subclasses ◽  
Rapid Decline ◽  
Avidity Index ◽  
Time Points ◽  
Rate Of Decay ◽  
Differential Expansion ◽  
Strength Of Association ◽  
Multiplex Bead

AbstractUnderstanding how immunity to malaria is affected by declining transmission is important to aid vaccine design and understand disease resurgence. Both IgG subclasses and avidity of antigen-specific responses are important components of an effective immune response.Using a multiplex bead array assay, we measured the total IgG, IgG subclasses, and avidity profiles of responses to 18 P. falciparum blood stage antigens in samples from 160 Ugandans collected at 2 time points during high malaria transmission and 2 time points following a dramatic reduction in transmission.Results demonstrated that, for the antigens tested, (i) the rate of decay of total IgG following infection declined with age and was driven consistently by the decrease in IgG3 and occasionally the decrease in IgG1; (ii) the proportion of IgG3 relative to IgG1 in the absence of infection increased with age; (iii) the increase in avidity index (the strength of association between the antibody and antigen) following infection was largely due to a rapid loss of non-avid compared to avid total IgG; and (iv) both avid and non-avid total IgG in the absence of infection increased with age.Further studies are required to understand the functional differences between IgG1 and IgG3 in order to determine their contribution to the longevity of protective immunity to malaria. Measuring changes in antibody avidity may be a better approach of detecting affinity maturation compared to avidity index due to the differential expansion and contraction of high and low avidity total IgG.

scholarly journals Impact of a Rapid Decline in Malaria Transmission on Antimalarial IgG Subclasses and Avidity

2021 ◽  
Vol 11 ◽  
Author(s):  
Isaac Ssewanyana ◽  
John Rek ◽  
Isabel Rodriguez ◽  
Lindsey Wu ◽  
Emmanuel Arinaitwe ◽  
...  
Keyword(s):  
Malaria Transmission ◽  
Affinity Maturation ◽  
Igg Subclasses ◽  
Rapid Decline ◽  
Avidity Index ◽  
Time Points ◽  
Rate Of Decay ◽  
Differential Expansion ◽  
Strength Of Association ◽  
Multiplex Bead

Understanding how immunity to malaria is affected by declining transmission is important to aid vaccine design and understand disease resurgence. Both IgG subclasses and avidity of antigen-specific responses are important components of an effective immune response. Using a multiplex bead array assay, we measured the total IgG, IgG subclasses, and avidity profiles of responses to 18 P. falciparum blood stage antigens in samples from 160 Ugandans collected at two time points during high malaria transmission and two time points following a dramatic reduction in transmission. Results demonstrated that, for the antigens tested, (i) the rate of decay of total IgG following infection declined with age and was driven consistently by the decrease in IgG3 and occasionally the decrease in IgG1; (ii) the proportion of IgG3 relative to IgG1 in the absence of infection increased with age; (iii) the increase in avidity index (the strength of association between the antibody and antigen) following infection was largely due to a rapid loss of non-avid compared to avid total IgG; and (iv) both avid and non-avid total IgG in the absence of infection increased with age. Further studies are required to understand the functional differences between IgG1 and IgG3 in order to determine their contribution to the longevity of protective immunity to malaria. Measuring changes in antibody avidity may be a better approach of detecting affinity maturation compared to avidity index due to the differential expansion and contraction of high and low avidity total IgG.

scholarly journals Does Antibody Avidity to Plasmodium falciparum Merozoite Antigens increase with Age in Individuals living in Malaria-Endemic Areas?

2021 ◽  
Author(s):  
Samuel Tassi Yunga ◽  
Naveen Bobbili ◽  
Yukie M. Lloyd ◽  
Jovikka Antallan ◽  
Masako Matsunaga ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Affinity Maturation ◽  
High Avidity ◽  
Plasma Samples ◽  
Avidity Index ◽  
Hyperendemic Area ◽  
Age Related ◽  
Falciparum Merozoite ◽  
Merozoite Antigens ◽  
Strength Of Association

Introduction: High avidity antibodies (Abs) are acquired after a few Plasmodium falciparum infections in low transmission areas, but it remains unclear if Ab avidity to different merozoite antigens increases with age in individuals with persistent antigenemia and if so, when a fully mature Ab response occurs. Methods: The study used plasma samples collected between 1996 and 1998 from 566 individuals aged 4-84 years in Simbok, Cameroon where residents received an estimated 1.6 infectious mosquito bites/person/night. Plasma samples were examined for Ab levels (median fluorescence intensity, MFI) and Ab avidity index (AI = [MFI after treatment with 2M NH4SCN/MFI without salt] x 100) using a bead-based multiplex immunoassay for recombinant AMA1, EBA-175, MSP1-42 (3D7, FVO), MSP2 (3D7, Fc27), and MSP3. Results: Blood-smear positivity for P. falciparum declined with age from 54.3% at 4-5 years to 18% at 16-40 years and <11% at >40 years of age, although most individuals had submicroscopic parasitemia. Ab affinity maturation, based on age-related patterns of median AI, percent of individuals with AI ≥50 and strength of association between MFI and AI, occurred at different rates among the antigens: developing rapidly before age 4 years for AMA1, increasing gradually with age for EBA-175 and MSP1 until ∼16-25 years, but occurring negligibly for MSP2 and MSP3. Conclusion: In a hyperendemic area with perennial transmission, affinity maturation resulting in an increase in the proportion of high avidity Abs occurred for some merozoite antigens, in parallel with a decline in malaria slide passivity, but not for others.

scholarly journals Malaria is associated with Kaposi sarcoma-associated herpesvirus (KSHV) seroconversion in a cohort of western Kenyan children

2020 ◽  
Author(s):  
Katherine R Sabourin ◽  
Ibrahim Daud ◽  
Sidney Ogolla ◽  
Nazzarena Labo ◽  
Wendell Miley ◽  
...  
Keyword(s):  
Malaria Transmission ◽  
Proportional Hazards ◽  
Kaposi Sarcoma ◽  
Cox Proportional Hazards ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cox Proportional Hazards Models ◽  
Malaria Exposure ◽  
Significant Difference ◽  
Transmission Region ◽  
Multiplex Bead

Abstract Background We aimed to determine whether Plasmodium falciparum (Pf) infection affects age of Kaposi sarcoma-associated herpesvirus (KSHV) seroconversion in Kenyan children. Methods Kenyan children (n=144) enrolled at age one month, from two sites with different levels of malaria transmission (stable/high malaria vs. unstable/low malaria transmission) were followed through 24 months. Plasma was tested for KSHV antibodies using enzyme-linked immunosorbent assay (ELISA) (K8.1 and LANA) and a multiplex bead-based assay (K8.1, K10.5, ORF38, ORF50, and LANA) and whole blood tested for Pf DNA using quantitative-PCR. Cox proportional hazards models were used to assess associations between Pf DNA detection, malaria annualized rate (Pf detections/person-years), and enrollment site (malaria-high vs malaria-low) with time to KSHV seroconversion. Results KSHV seroprevalence was 63% by 2 years of age when assessed by multiplex assay. Children with Pf were at increased hazards of earlier KSHV seroconversion and among children with malaria, the hazard of becoming KSHV seropositive increased significantly with increasing malaria annualized rate. Children from the malaria-high transmission region had no significant difference in hazards of KSHV seroconversion at 12 months but were more likely to become KSHV seropositive by 24 months of age. Discussion Malaria exposure increases the risk for KSHV seroconversion early in life.

scholarly journals Urinary Metabolome Analyses of Patients with Acute Kidney Injury Using Capillary Electrophoresis-Mass Spectrometry

Metabolites ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 671
Author(s):  
Rintaro Saito ◽  
Akiyoshi Hirayama ◽  
Arisa Akiba ◽  
Yushi Kamei ◽  
Yuyu Kato ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Acute Kidney Injury ◽  
Capillary Electrophoresis ◽  
Kidney Injury ◽  
Urine Samples ◽  
Rapid Decline ◽  
Time Points ◽  
Flight Mass Spectrometry ◽  
Best Value ◽  
Time Point

Acute kidney injury (AKI) is defined as a rapid decline in kidney function. The associated syndromes may lead to increased morbidity and mortality, but its early detection remains difficult. Using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS), we analyzed the urinary metabolomic profile of patients admitted to the intensive care unit (ICU) after invasive surgery. Urine samples were collected at six time points: before surgery, at ICU admission and 6, 12, 24 and 48 h after. First, urine samples from 61 initial patients (non-AKI: 23, mild AKI: 24, severe AKI: 14) were measured, followed by the measurement of urine samples from 60 additional patients (non-AKI: 40, mild AKI: 20). Glycine and ethanolamine were decreased in patients with AKI compared with non-AKI patients at 6–24 h in the two groups. The linear statistical model constructed at each time point by machine learning achieved the best performance at 24 h (median AUC: 89%, cross-validated) for the 1st group. When cross-validated between the two groups, the AUC showed the best value of 70% at 12 h. These results identified metabolites and time points that show patterns specific to subjects who develop AKI, paving the way for the development of better biomarkers.

Autogenous regulation of tubulin synthesis via RNA stability during sea urchin embryogenesis

Development ◽  
1988 ◽  
Vol 102 (1) ◽  
pp. 31-43
Author(s):  
Z.Y. Gong ◽  
B. Brandhorst
Keyword(s):  
Rna Stability ◽  
Rapid Decline ◽  
Lytechinus Pictus ◽  
Tubulin Genes ◽  
Low Concentrations ◽  
Rate Of Decay ◽  
Tubulin Mrna ◽  
High Concentrations ◽  
Autogenous Regulation ◽  
Microtubule Stabilizing Agent

When pluteus embryos of Lytechinus pictus were treated with colcemid, the incorporation of [35S]methionine into tubulin declined by 5- to 15-fold within 4 h. This was mostly accounted for by a rapid decline in the concentration of alpha- and beta-tubulin mRNA in the cytoplasm. Treatment with other microtubule depolymerizing agents (colchicine, nocodazole, low concentrations of vinblastine) had similar effects. Treatment of embryos with the microtubule-stabilizing agent, taxol, or high concentrations of vinblastine resulted in increased synthesis of tubulin. The concentration of tubulin mRNA increases during development and becomes increasingly sensitive to colcemid and decreasingly sensitive to taxol. The transcriptional activity of tubulin genes, estimated by an RNA run-on assay in isolated nuclei, was not altered after colcemid treatment. On the other hand, the rate of decay of tubulin mRNA in prism embryos treated with actinomycin D was increased several fold by colcemid treatment, while taxol treatment led to an increased half-life of tubulin mRNA. These observations suggest that tubulin synthesis is autogenously regulated at the level of mRNA stability by the level of unpolymerized tubulin. The increasing polymerization of microtubules and declining level of unpolymerized tubulin during embryogenesis would result in a stabilization of tubulin mRNA accounting for the increasing concentration of tubulin mRNA and rate of tubulin synthesis, as well as the increasing sensitivity of tubulin synthesis to microtubule-depolymerizing agents. Evidence is also presented for a rapid influence of the level of unpolymerized tubulin on the efficiency of translation of tubulin mRNA.

scholarly journals Proviral sequencing suggests the majority of the HIV reservoir is expressed over time but significant decay is obscured by clonal expansion

2018 ◽  
Author(s):  
Marilia Rita Pinzone ◽  
D. Jake VanBelzen ◽  
Sam Weissman ◽  
Maria Paola Bertuccio ◽  
LaMont Cannon ◽  
...  
Keyword(s):  
Protein Expression ◽  
Clonal Expansion ◽  
Rapid Decline ◽  
Plasma Viremia ◽  
Significant Extent ◽  
Splice Donor ◽  
Time Points ◽  
Selective Pressures ◽  
Over Time ◽  
Viral Outgrowth Assay

AbstractAfter initiating antiretroviral therapy (ART), a rapid decline in plasma viremia is followed by reservoir stabilization. Viral outgrowth assay suggests the reservoir continues to decline slowly, but variation over time and among individuals complicates our understanding of selective pressures during ART. We used full-length sequencing to study more than 800 HIV proviruses of two subjects on ART at four time points over nine years to investigate the selection pressures influencing the dynamics of the reservoir. We found that intact as well as defective proviruses capable of significant protein expression decrease over time. Moreover, proviruses lacking genetic elements to promote viral protein expression, yet containing strong splice donor sequences increase relative to other defectives over time, especially among clones. Our work suggests that HIV expression occurs to a significant extent during ART and results in HIV clearance, but this is obscured by clones generated by donor splice site-enhanced clonal expansion.

scholarly journals Growth Modeling of the Maternal Cytokine Milieu throughout Normal Pregnancy: Macrophage-Derived Chemokine Decreases as Inflammation/Counterregulation Increases

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Shernan G. Holtan ◽  
Yiyi Chen ◽  
Rajani Kaimal ◽  
Douglas J. Creedon ◽  
Elizabeth Ann L. Enninga ◽  
...  
Keyword(s):  
Growth Modeling ◽  
First Trimester ◽  
Normal Pregnancy ◽  
Cd40 Ligand ◽  
Soluble Cd40 Ligand ◽  
Cross Sectional ◽  
Time Points ◽  
Cytokine Milieu ◽  
Multiplex Bead

Several recent studies have shown differences in the maternal immune milieu at different phases of pregnancy, but most studies have been cross-sectional or of relatively few time points. Levels of 42 cytokines were determined using a multiplex bead-based assay on archived serum from a cohort of pregnant womenN=16at median of 18 time points tested, from the first trimester through to parturition, per woman. Unconditional growth modeling was then used to determine time-dependent changes in levels of these cytokines. Macrophage-derived chemokine (MDC, aka CCL22) decreases as pregnancy progresses. IL-1β, IL-6, IL-8, IL-12p70, IL-13, IL-15, IP-10, and FLT3-ligand increase as a function of gestational weeks, and IFNα2, IL-1ra, IL-3, IL-9, IL-12p40, and soluble CD40 ligand increase as a function of trimester. As pregnancy normally progresses, a maternal shift away from a type 2-biased immune response and toward an inflammatory/counterregulatory response is observed.

scholarly journals Potent antibody lineage against malaria transmission elicited by human vaccination with Pfs25

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Brandon McLeod ◽  
Kazutoyo Miura ◽  
Stephen W. Scally ◽  
Alexandre Bosch ◽  
Ngan Nguyen ◽  
...  
Keyword(s):  
Malaria Transmission ◽  
Affinity Maturation ◽  
Human Antibody ◽  
Blocking Antibody ◽  
Transmission Blocking ◽  
Clinical Models ◽  
Humoral Responses ◽  
Transmission Blocking Vaccines ◽  
Transmission Blocking Vaccine

Abstract Transmission-blocking vaccines have the potential to be key contributors to malaria elimination. Such vaccines elicit antibodies that inhibit parasites during their development in Anopheles mosquitoes, thus breaking the cycle of transmission. To date, characterization of humoral responses to Plasmodium falciparum transmission-blocking vaccine candidate Pfs25 has largely been conducted in pre-clinical models. Here, we present molecular analyses of human antibody responses generated in a clinical trial evaluating Pfs25 vaccination. From a collection of monoclonal antibodies with transmission-blocking activity, we identify the most potent transmission-blocking antibody yet described against Pfs25; 2544. The interactions of 2544 and three other antibodies with Pfs25 are analyzed by crystallography to understand structural requirements for elicitation of human transmission-blocking responses. Our analyses provide insights into Pfs25 immunogenicity and epitope potency, and detail an affinity maturation pathway for a potent transmission-blocking antibody in humans. Our findings can be employed to guide the design of improved malaria transmission-blocking vaccines.

scholarly journals Development of a novel assay to assess the avidity of dengue virus-specific antibodies elicited in response to a tetravalent dengue vaccine

2021 ◽  
Author(s):  
Isamu Tsuji ◽  
David Dominguez ◽  
Michael A Egan ◽  
Hansi J Dean
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Serum Antibody ◽  
Neutralizing Antibody ◽  
Affinity Maturation ◽  
Antibody Responses ◽  
Antibody Affinity ◽  
Dengue Vaccine ◽  
Avidity Index ◽  
Two Phase

Abstract Antibody affinity maturation is a critical step in development of functional antiviral immunity, however, accurate measurement of affinity maturation of polyclonal serum antibody responses to particulate antigens such as virions is challenging. We describe a novel avidity assay employing bio-layer interferometry and dengue virus-like particles. After validation using anti-dengue monoclonal antibodies, the assay was used to assess avidity of antibody responses to a tetravalent dengue vaccine candidate (TAK-003) in children, adolescents and adults during two Phase 2 clinical trials conducted in dengue endemic regions. Vaccination increased avidity index and avidity remained high through one-year post vaccination. Neutralizing antibody titers and avidity index did not correlate overall, however, a correlation was observed between neutralizing antibody titer and avidity index in those subjects with the highest degree of antibody affinity maturation. Therefore, vaccination with TAK-003 stimulates polyclonal affinity maturation and functional antibody responses including neutralizing antibodies.

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