52 research outputs found
A novel approach to identifying patterns of human invasion-inhibitory antibodies guides the design of malaria vaccines incorporating polymorphic antigens
No full textBackground: The polymorphic nature of many malaria vaccine candidates presents major challenges to achieving highly efficacious vaccines. Presently, there is very little knowledge on the prevalence and patterns of functional immune responses to polymorphic vaccine candidates in populations to guide vaccine design. A leading polymorphic vaccine candidate against blood-stage Plasmodium falciparum is apical membrane antigen 1 (AMA1), which is essential for erythrocyte invasion. The importance of AMA1 as a target of acquired human inhibitory antibodies, their allele specificity and prevalence in populations is unknown, but crucial for vaccine design. Methods: P. falciparum lines expressing different AMA1 alleles were genetically engineered and used to quantify functional antibodies from two malaria-exposed populations of adults and children. The acquisition of AMA1 antibodies was also detected using enzyme-linked immunosorbent assay (ELISA) and competition ELISA (using different AMA1 alleles) from the same populations. Results: We found that AMA1 was a major target of naturally acquired invasion-inhibitory antibodies that were highly prevalent in malaria-endemic populations and showed a high degree of allele specificity. Significantly, the prevalence of inhibitory antibodies to different alleles varied substantially within populations and between geographic locations. Inhibitory antibodies to three specific alleles were highly prevalent (FVO and W2mef in Papua New Guinea; FVO and XIE in Kenya), identifying them for potential vaccine inclusion. Measurement of antibodies by standard or competition ELISA was not strongly predictive of allele-specific inhibitory antibodies. The patterns of allele-specific functional antibody responses detected with our novel assays may indicate that acquired immunity is elicited towards serotypes that are prevalent in each geographic location. Conclusions These findings provide new insights into the nature and acquisition of functional immunity to a polymorphic vaccine candidate and strategies to quantify functional immunity in populations to guide rational vaccine design.Damien R. Drew, Danny W. Wilson, Salenna R. Elliott, Nadia Cross, Ulrich Terheggen, Anthony N. Hodder, Peter M. Siba, Kiprotich Chelimo, Arlene E. Dent, James W. Kazura, Ivo Mueller and James G. Beeso
The company malaria keeps: how co-infection with Epstein–Barr virus leads to endemic Burkitt lymphoma
No full textCo-infection with Plasmodium falciparum (Pf-) malaria and Epstein-Barr virus (EBV) are implicated in the etiology of endemic Burkitt lymphoma (eBL), the most prevalent pediatric cancer in equatorial Africa. Although the causal association between EBV and eBL has been established, Pf-malaria’s role is not as clearly defined. This review focuses on how malaria may disrupt EBV persistence and immunity
Assessment of Anti-Proliferative Activities of Selected Medicinal Plant Extracts Used for Management of Diseases around Lake Victoria Basin
No full text
Interferon-gamma responses to <it>Plasmodium falciparum </it>liver-stage antigen-1 and merozoite-surface protein-1 increase with age in children in a malaria holoendemic area of western Kenya
No full textAbstract Background In areas of high-level, year-round malaria transmission, morbidity and mortality due to malaria decrease after the first two to three years of life. This reduction may be related to the development of cellular immunity to specific antigens expressed in the different life-cycle stages of Plasmodium falciparum. Methods A cross sectional study was conducted to evaluate T cell cytokine responses to the P. falciparum pre-erythrocytic antigen liver-stage antigen-1 (LSA-1) and the blood-stage antigen merozoite-surface protein-1 (MSP-1) in children under five years of age residing in a malaria holoendemic region of western Kenya. Interferon-γ (IFN-γ) and interleukin-10 (IL-10) responses to the LSA-1 T3 peptide (aa 1813–1835) and the MSP-1 aa20–39 peptide were tested in 48 children. Results The proportion of children producing IFN-γ to LSA-1 and to MSP-1 increased with age: in the 0–12, 13–24, 25–36 and 37–48 month age groups, zero, 11.1, 36.4 and 40% of children had IFN-γ responses to LSA-1 (p = 0.019), and 10, 10, 27.7 and 40% of children had IFN-γ responses to MSP-1 (p = 0.07), respectively. In contrast, the proportion of children producing IL-10 to LSA-1 and MSP-1 was similar in all age groups. Conclusion The data suggest that development of IFN-γ responses to LSA-1 and MSP-1 requires increased age and/or repeated exposure, whereas IL-10 responses to these antigens may occur at any age and with limited exposure. The data also demonstrate that by the age of 4 years, children in a malaria holoendemic area develop frequencies of IFN-γ responses to LSA-1 and MSP-1 similar to those seen in adults in the area.</p
Time-to-infection by Plasmodium falciparum is largely determined by random factors
No full textBACKGROUND: The identification of protective immune responses to P. falciparum infection is an important goal for the development of a vaccine for malaria. This requires the identification of susceptible and resistant individuals, so that their immune responses may be studied. Time-to-infection studies are one method for identifying putative susceptible individuals (infected early) versus resistant individuals (infected late). However, the timing of infection is dependent on random factors, such as whether the subject was bitten by an infected mosquito, as well as individual factors, such as their level of immunity. It is important to understand how much of the observed variation in infection is simply due to chance. METHODS: We analyse previously published data from a treatment-time-to-infection study of 201 individuals aged 0.5 to 78 years living in Western Kenya. We use a mathematical modelling approach to investigate the role of immunity versus random factors in determining time-to-infection in this cohort. We extend this analysis using a modelling approach to understand what factors might increase or decrease the utility of these studies for identifying susceptible and resistant individuals. RESULTS: We find that, under most circumstances, the observed distribution of time-to-infection is consistent with this simply being a random process. We find that age, method for detection of infection (PCR versus microscopy), and underlying force of infection are all factors in determining whether time-to-infection is a useful correlate of immunity. CONCLUSIONS: Many epidemiological studies of P. falciparum infection assume that the observed variation in infection outcomes, such as time-to-infection or presence or absence of infection, is determined by host resistance or susceptibility. However, under most circumstances, this distribution appears largely due to the random timing of infection, particularly in children. More direct measurements, such as parasite growth rate, may be more useful than time-to-infection in segregating patients based on their level of immunity
The Systematic Phonological Realization in Keiyo Language as Spoken by the Keiyo Community in Kenya
No full textAbstract This paper gives a brief phonological system of Keiyo Language. It not only discusses the vowel and consonant inventories and their realizations, but also the diphthongs, syllable structure and the phonotactic possibilities. It analyzes the phonological and prosodic processes that Keiyo nouns (both definite and indefinite) undergo when inflected for number. The author is a native speaker of the language and generated the data, and later subjected it to four adult native speakers drawn from Tambach Division of Keiyo District in Rift Valley Province. Like the other Kalenjin languages, the vowel system of Keiyo is based on the five basic vowel qualities a, e, i, o, u. Beyond this basic level, these vowels are also distinguishable within the phonological supra segmental level of tongue root position -the retracted (RTR) versus (ATR) and length. The Keiyo phonemic inventory has a total of ten diphthongs . The language has a limited inventory of its consonants and this could be attributed to the fact that, voicing is not actually a distinctive feature
Alterations on peripheral B cell subsets following an acute uncomplicated clinical malaria infection in children
No full textAbstract Background The effects of Plasmodium falciparum on B-cell homeostasis have not been well characterized. This study investigated whether an episode of acute malaria in young children results in changes in the peripheral B cell phenotype. Methods Using flow-cytofluorimetric analysis, the B cell phenotypes found in the peripheral blood of children aged 2–5 years were characterized during an episode of acute uncomplicated clinical malaria and four weeks post-recovery and in healthy age-matched controls. Results There was a significant decrease in CD19+ B lymphocytes during acute malaria. Characterization of the CD19+ B cell subsets in the peripheral blood based on expression of IgD and CD38 revealed a significant decrease in the numbers of naive 1 CD38-IgD+ B cells while there was an increase in CD38+IgD- memory 3 B cells during acute malaria. Further analysis of the peripheral B cell phenotype also identified an expansion of transitional CD10+CD19+ B cells in children following an episode of acute malaria with up to 25% of total CD19+ B cell pool residing in this subset. Conclusion Children experiencing an episode of acute uncomplicated clinical malaria experienced profound disturbances in B cell homeostasis.</p
Human and Epstein-Barr Virus miRNA Profiling as Predictive Biomarkers for Endemic Burkitt Lymphoma
No full textIntegrative microRNA and mRNA deep-sequencing expression profiling in endemic Burkitt lymphoma
No full textBACKGROUND: Burkitt lymphoma (BL) is characterized by overexpression of the c-myc oncogene, which in the vast majority of cases is a consequence of an IGH/MYC translocation. While myc is the seminal event, BL is a complex amalgam of genetic and epigenetic changes causing dysregulation of both coding and non-coding transcripts. Emerging evidence suggest that abnormal modulation of mRNA transcription via miRNAs might be a significant factor in lymphomagenesis. However, the alterations in these miRNAs and their correlations to their putative mRNA targets have not been extensively studied relative to normal germinal center (GC) B cells. METHODS: Using more sensitive and specific transcriptome deep sequencing, we compared previously published small miRNA and long mRNA of a set of GC B cells and eBL tumors. MiRWalk2.0 was used to identify the validated target genes for the deregulated miRNAs, which would be important for understanding the regulatory networks associated with eBL development. RESULTS: We found 211 differentially expressed (DE) genes (79 upregulated and 132 downregulated) and 49 DE miRNAs (22 up-regulated and 27 down-regulated). Gene Set enrichment analysis identified the enrichment of a set of MYC regulated genes. Network propagation-based method and correlated miRNA-mRNA expression analysis identified dysregulated miRNAs, including miR-17~95 cluster members and their target genes, which have diverse oncogenic properties to be critical to eBL lymphomagenesis. Central to all these findings, we observed the downregulation of ATM and NLK genes, which represent important regulators in response to DNA damage in eBL tumor cells. These tumor suppressors were targeted by multiple upregulated miRNAs (miR-19b-3p, miR-26a-5p, miR-30b-5p, miR-92a-5p and miR-27b-3p) which could account for their aberrant expression in eBL. CONCLUSION: Combined loss of p53 induction and function due to miRNA-mediated regulation of ATM and NLK, together with the upregulation of TFAP4, may be a central role for human miRNAs in eBL oncogenesis. This facilitates survival of eBL tumor cells with the IGH/MYC chromosomal translocation and promotes MYC-induced cell cycle progression, initiating eBL lymphomagenesis. This characterization of miRNA-mRNA interactions in eBL relative to GC B cells provides new insights on miRNA-mediated transcript regulation in eBL, which are potentially useful for new improved therapeutic strategies
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