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James W Kazura - One of the best experts on this subject based on the ideXlab platform.

  • stability of interferon gamma and interleukin 10 responses to plasmodium falciparum Liver Stage Antigen 1 and thrombospondin related adhesive protein immunodominant epitopes in a highland population from western kenya
    American Journal of Tropical Medicine and Hygiene, 2009
    Co-Authors: Ann M Moormann, Peter Odada Sumba, James W Kazura, Daniel J Tisch, Paula Embury, Charles H King, Chandy C. John
    Abstract:

    Long-term planning to prevent malaria epidemics requires in-depth understanding of immunity to Plasmodium falciparum in areas of unstable transmission. Cytokine responses to immunodominant epitope peptides from Liver Stage Antigen 1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) were evaluated over a nine-month interval in adults and children in Kenya from a malaria epidemic–prone highland area after several years of low transmission. The proportion and magnitude of interferon-gamma ELISPOT responses and the proportion of interleukin-10 responders to LSA-1 and TRAP peptides tended to be higher in adults than children. Frequencies of interferon-gamma responders to these peptides were similar at the two time points, but responses were not consistently generated by the same persons. These results suggest that T cell memory to pre-erythrocytic Stage malaria Antigens is maintained but may be unavailable for consistent detection in peripheral blood, and that these Antigens induce both pro-inflammatory and anti-inflammatory cytokine responses in this population.

  • stability of interferon γ and interleukin 10 responses to plasmodium falciparum Liver Stage Antigen 1 and thrombospondin related adhesive protein in residents of a malaria holoendemic area
    American Journal of Tropical Medicine and Hygiene, 2006
    Co-Authors: Ann M Moormann, Chandy C. John, Peter Odada Sumba, Daniel J Tisch, Paula Embury, James W Kazura
    Abstract:

    The stability of anti-malarial immunity will influence the interpretation of immunologic endpoints during malaria vaccine trials conducted in endemic areas. Therefore, we evaluated cytokine responses to Plasmodium falci- parum Liver Stage Antigen-1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) by Kenyans from a ho- loendemic area at a 9-month interval. The proportion of adults with interferon- (IFN-) responses to 9-mer LSA-1 peptides was similar at both time-points, whereas responses from children decreased (P < 0.05). Response to the longer, 23-mer LSA-1 peptide was variable, decreasing in adults and children over time (P < 0.02 and P < 0.001, respectively). The proportion of children with IFN- responses to either Antigen at the second time-point was significantly lower than that of adults, yet more adults responded to 9-mer TRAP peptides (P < 0.02). In contrast, the proportion of interleukin- 10 responses to LSA-1 and TRAP was similar at both time-points for both age groups. Most noteworthy was that even when the repeat cross-sectional frequency of cytokine responses was the same, these responses were not generated by the same individuals. This suggests that cytokine responses to LSA-1 and TRAP are transient under natural exposure conditions.

  • antibodies to plasmodium falciparum Antigens vary by age and Antigen in children in a malaria holoendemic area of kenya
    Pediatric Infectious Disease Journal, 2005
    Co-Authors: Kiprotich Chelimo, Ayub V Ofulla, David L Narum, David E. Lanar, James W Kazura, Chandy C. John
    Abstract:

    Background: Antibodies are important in protection against infection and disease caused by Plasmodium falciparum, but the frequencies of antibodies to multiple P. falciparum Antigens in children are not well-characterized. Methods: IgG and IgM antibodies to the vaccine candidate Antigens circumsporozoite protein, thrombospondin-related adhesive protein, Liver Stage Antigen-1, apical membrane Antigen-1, erythrocyte-binding Antigen-175 and merozoite surface protein-1 were measured by enzyme-linked immunosorbent assay in 110 children 0–50 months of age in a malaria holoendemic area of Kenya. Results: A similar pattern was seen for IgG antibodies to circumsporozoite protein, thrombospondin-related adhesive protein, apical membrane Antigen-1 and erythrocyte-binding Antigen-175: high frequencies (70–90%) in children 0–4 months of age; a decrease in children 5–20 months of age (35–71%); and progressive increases in children 21–36 and 37–50 months of age (53–80% and 60–100%, respectively). In contrast, IgG antibodies to Liver Stage Antigen-1 were infrequent in children 0–4 months of age (5%) and increased with age to 64%, and IgG antibody frequencies to merozoite surface protein-1 were similar across age groups (26–52%). IgG antibodies to all Antigens were predominantly of the IgG1 and IgG3 subclasses. Frequencies of IgM antibodies to all Antigens were low in children 0–4 months of age (0–15%) and increased with age (24–56% in the oldest children). Conclusion: In children in a malaria-holoendemic area, IgM antibody to all P. falciparum Antigens is infrequent in the first 4 months of life but increases with age and increased exposure. The pattern of age-related IgG response frequencies to P. falciparum Antigens varies significantly by Antigen.

  • gamma interferon responses to plasmodium falciparum Liver Stage Antigen 1 and thrombospondin related adhesive protein and their relationship to age transmission intensity and protection against malaria
    Infection and Immunity, 2004
    Co-Authors: Chandy C. John, Peter Odada Sumba, Ayub V Ofulla, Ann M Moormann, Daniel C Pregibon, James W Kazura
    Abstract:

    Gamma interferon (IFN-γ) responses to the Plasmodium falciparum Antigens Liver-Stage Antigen 1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) are thought to be important in protection against malaria. Optimal methods of testing and the effects of age and transmission intensity on these responses are unknown. IFN-γ responses to LSA-1 and TRAP peptides were assessed by the enzyme-linked immunospot assay (ELISPOT) and enzyme-linked immunosorbent assay (ELISA) in children and adults from areas of stable and unstable malaria transmission in Kenya. Adults in the areas of stable and unstable transmission had similar frequencies and levels of IFN-γ responses to LSA-1 and TRAP as determined by ELISPOT and ELISA. In contrast, IFN-γ responses to the LSA-1 T3 peptide (assessed by ELISPOT) and to any LSA-1 peptide (assessed by ELISA) were less frequent in children in the area of unstable transmission than in children in the area of stable transmission. IFN-γ responses to LSA-1 were more frequently detected by ELISA than by ELISPOT in the stable-transmission area. IFN-γ responses detected by ELISA and ELISPOT did not correlate with each other. In children in the stable-transmission area, IFN-γ responses to LSA-1 peptides assessed by ELISA, but not by ELISPOT, were associated with protection against clinical malaria and anemia. IFN-γ responses to LSA-1 appear to require repeated P. falciparum exposure and/or increased age and, as measured by ELISA, are associated with protection against clinical malaria and anemia.

  • interferon gamma responses to plasmodium falciparum Liver Stage Antigen 1 and merozoite surface protein 1 increase with age in children in a malaria holoendemic area of western kenya
    Malaria Journal, 2003
    Co-Authors: Ayub V Ofula, Peter Odada Sumba, Kiprotich Chelimo, James W Kazura, Chandy C. John
    Abstract:

    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.

Chandy C. John - One of the best experts on this subject based on the ideXlab platform.

  • Distributed under Creative Commons CC-BY 4.0 Interferon-γ responses to Plasmodium falciparum vaccine candidate Antigens decrease in the absence of malaria transmission
    2020
    Co-Authors: Cyrus Ayieko, Bilha S Ogola, Lyticia Ochola, Gideon A M Ngwena, George Ayodo, James S Hodges, Gregory S Noland, Chandy C. John
    Abstract:

    ABSTRACT Background. Malaria elimination campaigns are planned or active in many countries. The effects of malaria elimination on immune responses such as Antigen-specific IFN-γ responses are not well characterized. Methods. IFN-γ responses to the P. falciparum Antigens circumsporozoite protein, Liver Stage Antigen-1, thrombospondin-related adhesive protein, apical membrane Antigen-1, MB2, and merozoite surface protein-1 were tested by ELISA in 243 individuals in highland Keny

  • stability of interferon gamma and interleukin 10 responses to plasmodium falciparum Liver Stage Antigen 1 and thrombospondin related adhesive protein immunodominant epitopes in a highland population from western kenya
    American Journal of Tropical Medicine and Hygiene, 2009
    Co-Authors: Ann M Moormann, Peter Odada Sumba, James W Kazura, Daniel J Tisch, Paula Embury, Charles H King, Chandy C. John
    Abstract:

    Long-term planning to prevent malaria epidemics requires in-depth understanding of immunity to Plasmodium falciparum in areas of unstable transmission. Cytokine responses to immunodominant epitope peptides from Liver Stage Antigen 1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) were evaluated over a nine-month interval in adults and children in Kenya from a malaria epidemic–prone highland area after several years of low transmission. The proportion and magnitude of interferon-gamma ELISPOT responses and the proportion of interleukin-10 responders to LSA-1 and TRAP peptides tended to be higher in adults than children. Frequencies of interferon-gamma responders to these peptides were similar at the two time points, but responses were not consistently generated by the same persons. These results suggest that T cell memory to pre-erythrocytic Stage malaria Antigens is maintained but may be unavailable for consistent detection in peripheral blood, and that these Antigens induce both pro-inflammatory and anti-inflammatory cytokine responses in this population.

  • stability of interferon γ and interleukin 10 responses to plasmodium falciparum Liver Stage Antigen 1 and thrombospondin related adhesive protein in residents of a malaria holoendemic area
    American Journal of Tropical Medicine and Hygiene, 2006
    Co-Authors: Ann M Moormann, Chandy C. John, Peter Odada Sumba, Daniel J Tisch, Paula Embury, James W Kazura
    Abstract:

    The stability of anti-malarial immunity will influence the interpretation of immunologic endpoints during malaria vaccine trials conducted in endemic areas. Therefore, we evaluated cytokine responses to Plasmodium falci- parum Liver Stage Antigen-1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) by Kenyans from a ho- loendemic area at a 9-month interval. The proportion of adults with interferon- (IFN-) responses to 9-mer LSA-1 peptides was similar at both time-points, whereas responses from children decreased (P < 0.05). Response to the longer, 23-mer LSA-1 peptide was variable, decreasing in adults and children over time (P < 0.02 and P < 0.001, respectively). The proportion of children with IFN- responses to either Antigen at the second time-point was significantly lower than that of adults, yet more adults responded to 9-mer TRAP peptides (P < 0.02). In contrast, the proportion of interleukin- 10 responses to LSA-1 and TRAP was similar at both time-points for both age groups. Most noteworthy was that even when the repeat cross-sectional frequency of cytokine responses was the same, these responses were not generated by the same individuals. This suggests that cytokine responses to LSA-1 and TRAP are transient under natural exposure conditions.

  • antibodies to plasmodium falciparum Antigens vary by age and Antigen in children in a malaria holoendemic area of kenya
    Pediatric Infectious Disease Journal, 2005
    Co-Authors: Kiprotich Chelimo, Ayub V Ofulla, David L Narum, David E. Lanar, James W Kazura, Chandy C. John
    Abstract:

    Background: Antibodies are important in protection against infection and disease caused by Plasmodium falciparum, but the frequencies of antibodies to multiple P. falciparum Antigens in children are not well-characterized. Methods: IgG and IgM antibodies to the vaccine candidate Antigens circumsporozoite protein, thrombospondin-related adhesive protein, Liver Stage Antigen-1, apical membrane Antigen-1, erythrocyte-binding Antigen-175 and merozoite surface protein-1 were measured by enzyme-linked immunosorbent assay in 110 children 0–50 months of age in a malaria holoendemic area of Kenya. Results: A similar pattern was seen for IgG antibodies to circumsporozoite protein, thrombospondin-related adhesive protein, apical membrane Antigen-1 and erythrocyte-binding Antigen-175: high frequencies (70–90%) in children 0–4 months of age; a decrease in children 5–20 months of age (35–71%); and progressive increases in children 21–36 and 37–50 months of age (53–80% and 60–100%, respectively). In contrast, IgG antibodies to Liver Stage Antigen-1 were infrequent in children 0–4 months of age (5%) and increased with age to 64%, and IgG antibody frequencies to merozoite surface protein-1 were similar across age groups (26–52%). IgG antibodies to all Antigens were predominantly of the IgG1 and IgG3 subclasses. Frequencies of IgM antibodies to all Antigens were low in children 0–4 months of age (0–15%) and increased with age (24–56% in the oldest children). Conclusion: In children in a malaria-holoendemic area, IgM antibody to all P. falciparum Antigens is infrequent in the first 4 months of life but increases with age and increased exposure. The pattern of age-related IgG response frequencies to P. falciparum Antigens varies significantly by Antigen.

  • gamma interferon responses to plasmodium falciparum Liver Stage Antigen 1 and thrombospondin related adhesive protein and their relationship to age transmission intensity and protection against malaria
    Infection and Immunity, 2004
    Co-Authors: Chandy C. John, Peter Odada Sumba, Ayub V Ofulla, Ann M Moormann, Daniel C Pregibon, James W Kazura
    Abstract:

    Gamma interferon (IFN-γ) responses to the Plasmodium falciparum Antigens Liver-Stage Antigen 1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) are thought to be important in protection against malaria. Optimal methods of testing and the effects of age and transmission intensity on these responses are unknown. IFN-γ responses to LSA-1 and TRAP peptides were assessed by the enzyme-linked immunospot assay (ELISPOT) and enzyme-linked immunosorbent assay (ELISA) in children and adults from areas of stable and unstable malaria transmission in Kenya. Adults in the areas of stable and unstable transmission had similar frequencies and levels of IFN-γ responses to LSA-1 and TRAP as determined by ELISPOT and ELISA. In contrast, IFN-γ responses to the LSA-1 T3 peptide (assessed by ELISPOT) and to any LSA-1 peptide (assessed by ELISA) were less frequent in children in the area of unstable transmission than in children in the area of stable transmission. IFN-γ responses to LSA-1 were more frequently detected by ELISA than by ELISPOT in the stable-transmission area. IFN-γ responses detected by ELISA and ELISPOT did not correlate with each other. In children in the stable-transmission area, IFN-γ responses to LSA-1 peptides assessed by ELISA, but not by ELISPOT, were associated with protection against clinical malaria and anemia. IFN-γ responses to LSA-1 appear to require repeated P. falciparum exposure and/or increased age and, as measured by ELISA, are associated with protection against clinical malaria and anemia.

Peter Odada Sumba - One of the best experts on this subject based on the ideXlab platform.

  • plasmodium falciparum protein microarray antibody profiles correlate with protection from symptomatic malaria in kenya
    The Journal of Infectious Diseases, 2015
    Co-Authors: Peter Odada Sumba, Ann M Moormann, Arlene E Dent, Rie Nakajima, Li Liang, Elisabeth Baum, John M Vulule, Denise C Babineau, Arlo Randall
    Abstract:

    BACKGROUND: Immunoglobulin G antibodies (Abs) to Plasmodium falciparum Antigens have been associated with naturally acquired immunity to symptomatic malaria. METHODS: We probed protein microarrays covering 824 unique P. falciparum protein features with plasma from residents of a community in Kenya monitored for 12 weeks for (re)infection and symptomatic malaria after administration of antimalarial drugs. P. falciparum proteins recognized by Abs from 88 children (aged 1-14 years) and 86 adults (aged ≥ 18 years), measured at the beginning of the observation period, were ranked by Ab signal intensity. RESULTS: Abs from immune adults reacted with a total 163 of 824 P. falciparum proteins. Children gradually acquired Abs to the full repertoire of Antigens recognized by adults. Abs to some Antigens showed high seroconversion rates, reaching maximal levels early in childhood, whereas others did not reach adult levels until adolescence. No correlation between Ab signal intensity and time to (re)infection was observed. In contrast, Ab levels to 106 Antigens were significantly higher in children who were protected from symptomatic malaria compared with those who were not. Abs to Antigens predictive of protection included P. falciparum erythrocyte membrane protein 1, merozoite surface protein (MSP) 10, MSP2, Liver-Stage Antigen 3, PF70, MSP7, and Plasmodium helical interspersed subtelomeric domain protein. CONCLUSIONS: Protein microarrays may be useful in the search for malaria Antigens associated with protective immunity.

  • plasmodium falciparum protein microarray antibody profiles correlate with protection from symptomatic malaria in kenya
    The Journal of Infectious Diseases, 2015
    Co-Authors: Peter Odada Sumba, Ann M Moormann, Arlene E Dent, Rie Nakajima, Li Liang, Elisabeth Baum, John M Vulule, Denise C Babineau, Arlo Randall
    Abstract:

    BACKGROUND Immunoglobulin G antibodies (Abs) to Plasmodium falciparum Antigens have been associated with naturally acquired immunity to symptomatic malaria. METHODS We probed protein microarrays covering 824 unique P. falciparum protein features with plasma from residents of a community in Kenya monitored for 12 weeks for (re)infection and symptomatic malaria after administration of antimalarial drugs. P. falciparum proteins recognized by Abs from 88 children (aged 1-14 years) and 86 adults (aged ≥ 18 years), measured at the beginning of the observation period, were ranked by Ab signal intensity. RESULTS Abs from immune adults reacted with a total 163 of 824 P. falciparum proteins. Children gradually acquired Abs to the full repertoire of Antigens recognized by adults. Abs to some Antigens showed high seroconversion rates, reaching maximal levels early in childhood, whereas others did not reach adult levels until adolescence. No correlation between Ab signal intensity and time to (re)infection was observed. In contrast, Ab levels to 106 Antigens were significantly higher in children who were protected from symptomatic malaria compared with those who were not. Abs to Antigens predictive of protection included P. falciparum erythrocyte membrane protein 1, merozoite surface protein (MSP) 10, MSP2, Liver-Stage Antigen 3, PF70, MSP7, and Plasmodium helical interspersed subtelomeric domain protein. CONCLUSIONS Protein microarrays may be useful in the search for malaria Antigens associated with protective immunity.

  • stability of interferon gamma and interleukin 10 responses to plasmodium falciparum Liver Stage Antigen 1 and thrombospondin related adhesive protein immunodominant epitopes in a highland population from western kenya
    American Journal of Tropical Medicine and Hygiene, 2009
    Co-Authors: Ann M Moormann, Peter Odada Sumba, James W Kazura, Daniel J Tisch, Paula Embury, Charles H King, Chandy C. John
    Abstract:

    Long-term planning to prevent malaria epidemics requires in-depth understanding of immunity to Plasmodium falciparum in areas of unstable transmission. Cytokine responses to immunodominant epitope peptides from Liver Stage Antigen 1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) were evaluated over a nine-month interval in adults and children in Kenya from a malaria epidemic–prone highland area after several years of low transmission. The proportion and magnitude of interferon-gamma ELISPOT responses and the proportion of interleukin-10 responders to LSA-1 and TRAP peptides tended to be higher in adults than children. Frequencies of interferon-gamma responders to these peptides were similar at the two time points, but responses were not consistently generated by the same persons. These results suggest that T cell memory to pre-erythrocytic Stage malaria Antigens is maintained but may be unavailable for consistent detection in peripheral blood, and that these Antigens induce both pro-inflammatory and anti-inflammatory cytokine responses in this population.

  • stability of interferon γ and interleukin 10 responses to plasmodium falciparum Liver Stage Antigen 1 and thrombospondin related adhesive protein in residents of a malaria holoendemic area
    American Journal of Tropical Medicine and Hygiene, 2006
    Co-Authors: Ann M Moormann, Chandy C. John, Peter Odada Sumba, Daniel J Tisch, Paula Embury, James W Kazura
    Abstract:

    The stability of anti-malarial immunity will influence the interpretation of immunologic endpoints during malaria vaccine trials conducted in endemic areas. Therefore, we evaluated cytokine responses to Plasmodium falci- parum Liver Stage Antigen-1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) by Kenyans from a ho- loendemic area at a 9-month interval. The proportion of adults with interferon- (IFN-) responses to 9-mer LSA-1 peptides was similar at both time-points, whereas responses from children decreased (P < 0.05). Response to the longer, 23-mer LSA-1 peptide was variable, decreasing in adults and children over time (P < 0.02 and P < 0.001, respectively). The proportion of children with IFN- responses to either Antigen at the second time-point was significantly lower than that of adults, yet more adults responded to 9-mer TRAP peptides (P < 0.02). In contrast, the proportion of interleukin- 10 responses to LSA-1 and TRAP was similar at both time-points for both age groups. Most noteworthy was that even when the repeat cross-sectional frequency of cytokine responses was the same, these responses were not generated by the same individuals. This suggests that cytokine responses to LSA-1 and TRAP are transient under natural exposure conditions.

  • gamma interferon responses to plasmodium falciparum Liver Stage Antigen 1 and thrombospondin related adhesive protein and their relationship to age transmission intensity and protection against malaria
    Infection and Immunity, 2004
    Co-Authors: Chandy C. John, Peter Odada Sumba, Ayub V Ofulla, Ann M Moormann, Daniel C Pregibon, James W Kazura
    Abstract:

    Gamma interferon (IFN-γ) responses to the Plasmodium falciparum Antigens Liver-Stage Antigen 1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) are thought to be important in protection against malaria. Optimal methods of testing and the effects of age and transmission intensity on these responses are unknown. IFN-γ responses to LSA-1 and TRAP peptides were assessed by the enzyme-linked immunospot assay (ELISPOT) and enzyme-linked immunosorbent assay (ELISA) in children and adults from areas of stable and unstable malaria transmission in Kenya. Adults in the areas of stable and unstable transmission had similar frequencies and levels of IFN-γ responses to LSA-1 and TRAP as determined by ELISPOT and ELISA. In contrast, IFN-γ responses to the LSA-1 T3 peptide (assessed by ELISPOT) and to any LSA-1 peptide (assessed by ELISA) were less frequent in children in the area of unstable transmission than in children in the area of stable transmission. IFN-γ responses to LSA-1 were more frequently detected by ELISA than by ELISPOT in the stable-transmission area. IFN-γ responses detected by ELISA and ELISPOT did not correlate with each other. In children in the stable-transmission area, IFN-γ responses to LSA-1 peptides assessed by ELISA, but not by ELISPOT, were associated with protection against clinical malaria and anemia. IFN-γ responses to LSA-1 appear to require repeated P. falciparum exposure and/or increased age and, as measured by ELISA, are associated with protection against clinical malaria and anemia.

David E. Lanar - One of the best experts on this subject based on the ideXlab platform.

  • plasmodium falciparum Liver Stage Antigen 1 is cross linked by tissue transglutaminase
    Malaria Journal, 2011
    Co-Authors: William S Nicoll, John B Sacci, Michael R Hollingdale, Carlo Rodolfo, Giuseppina Di Giacomo, Mauro Piacentini, Zoe Holland, Christian Doerig, David E. Lanar
    Abstract:

    Background: Plasmodium falciparum sporozoites injected by mosquitoes into the blood rapidly enter Liver hepatocytes and undergo pre-erythrocytic developmental schizogony forming tens of thousands of merozoites per hepatocyte. Shortly after hepatocyte invasion, the parasite starts to produce Liver Stage Antigen-1 (LSA-1), which accumulates within the parasitophorous vacuole surrounding the mass of developing merozoites. The LSA-1 protein has been described as a flocculent mass, but its role in parasite development has not been determined. Methods: Recombinant N-terminal, C-terminal or a construct containing both the N- and C- terminal regions flanking two 17 amino acid residue central repeat sequences (LSA-NRC) were subjected to in vitro modification by tissue transglutaminase-2 (TG2) to determine if cross-linking occurred. In addition, tissue sections of P. falciparuminfected human hepatocytes were probed with monoclonal antibodies to the isopeptide e-(g-glutamyl)lysine crossbridge formed by TG2 enzymatic activity to determine if these antibodies co-localized with antibodies to LSA-1 in the growing Liver schizonts. Results: This study identified a substrate motif for (TG2) and a putative casein kinase 2 phosphorylation site within the central repeat region of LSA-1. The function of TG2 is the post-translational modification of proteins by the formation of a unique isopeptide e-(g-glutamyl)lysine cross-bridge between glutamine and lysine residues. When recombinant LSA-1 protein was crosslinked in vitro by purified TG2 in a calcium dependent reaction, a flocculent mass of protein was formed that was highly resistant to degradation. The cross-linking was not detectably affected by phosphorylation with plasmodial CK2 in vitro. Monoclonal antibodies specific to the very unique TG2 catalyzed e- lysine cross-bridge co-localized with antibodies to LSA-1 in infected human hepatocytes providing visual evidence that LSA-1 was cross-linked in vivo. Conclusions: While the role of LSA-1 is still unknown these results suggest that it becomes highly cross-linked which may aid in the protection of the parasite as it develops.

  • a reductionist cell free major histocompatibility complex class ii Antigen processing system identifies immunodominant epitopes
    Nature Medicine, 2010
    Co-Authors: Isamu Z. Hartman, Tatiana Boronina, David E. Lanar, Robert Schwenk, Aeryon Kim, Robert J Cotter, Kimberly Walter, Sarat K Dalai, Wendell P Griffith, Urszula Krzych
    Abstract:

    Immunodominance is defined as restricted responsiveness of T cells to a few selected epitopes from complex Antigens. Strategies currently used for elucidating CD4(+) T cell epitopes are inadequate. To understand the mechanism of epitope selection for helper T cells, we established a cell-free Antigen processing system composed of defined proteins: human leukocyte Antigen-DR1 (HLA-DR1), HLA-DM and cathepsins. Our reductionist system successfully identified the physiologically selected immunodominant epitopes of two model Antigens: hemagglutinin-1 (HA1) from influenza virus (A/Texas/1/77) and type II collagen (CII). When applied for identification of new epitopes from a recombinant Liver-Stage Antigen of malaria falciparum (LSA-NRC) or HA1 from H5N1 influenza virus ('avian flu'), the system selected single epitopes from each protein that were confirmed to be immunodominant by their capacity to activate CD4(+) T cells from H5N1-immunized HLA-DR1-transgenic mice and LSA-NRC-vaccinated HLA-DR1-positive human volunteers. Thus, we provide a new tool for the identification of physiologically relevant helper T cell epitopes from Antigens.

  • impact of recombinant adenovirus serotype 35 priming versus boosting of a plasmodium falciparum protein characterization of t and b cell responses to Liver Stage Antigen 1
    Infection and Immunity, 2008
    Co-Authors: Ariane Rodriguez, Jaap Goudsmit, Arjen Companjen, Ratna Mintardjo, Gert Gillissen, Dennis Tax, Jeroen Sijtsma, Gerrit Jan Weverling, Lennart Holterman, David E. Lanar
    Abstract:

    Prime-boost vaccination regimens with heterologous Antigen deLivery systems have indicated that redirection of the immune response is feasible. We showed earlier that T-cell responses to circumsporozoite (CS) protein improved significantly when the protein is primed with recombinant adenovirus serotype 35 coding for CS (rAd35.CS). The current study was designed to answer the question whether such an effect can be extended to Liver-Stage Antigens (LSA) of Plasmodium falciparum such as LSA-1. Studies with mice have demonstrated that the LSA-1 protein induces strong antibody response but a weak T-cell immunity. We first identified T-cell epitopes in LSA-1 by use of intracellular gamma interferon (IFN-γ) staining and confirmed these epitopes by means of enzyme-linked immunospot assay and pentamer staining. We show that a single immunization with rAd35.LSA-1 induced a strong Antigen-specific IFN-γ CD8+ T-cell response but no measurable antibody response. In contrast, vaccinations with the adjuvanted recombinant LSA-1 protein induced remarkably low cellular responses but strong antibody responses. Finally, both priming and boosting of the adjuvanted protein by rAd35 resulted in enhanced T-cell responses without impairing the level of antibody responses induced by the protein immunizations alone. Furthermore, the incorporation of rAd35 in the vaccination schedule led to a skewing of LSA-1-specific antibody responses toward a Th1-type immune response. Our results show the ability of rAd35 to induce potent T-cell immunity in combination with protein in a prime-boost schedule without impairing the B-cell response.

  • preclinical evaluation of the safety and immunogenicity of a vaccine consisting of plasmodium falciparum Liver Stage Antigen 1 with adjuvant as01b administered alone or concurrently with the rts s as01b vaccine in rhesus primates
    Infection and Immunity, 2008
    Co-Authors: Sathit Pichyangkul, David E. Lanar, Lisa A Ware, U Kumarb, Kosol Yongvanitchit, Amporn Limsalakpetch, M Gettayacamin, V A Stewart, D G Heppner, Pascal Mettens
    Abstract:

    Several lines of evidence suggest that targeting pre-erythrocytic-Stage parasites for malaria vaccine development can provide sterile immunity. The objectives of this study were (i) to evaluate preclinically the safety and immunogenicity of a new recombinant pre-erythrocytic-Stage Antigen, Liver-Stage Antigen 1 (LSA1), in nonhuman primates; and (ii) to investigate the potential for immune interference between LSA1 and the leading malaria vaccine candidate, RTS,S, by comparing the immune responses after single-Antigen vaccination to responses after simultaneous administration of both Antigens at separate sites. Using a rhesus monkey model, we found that LSA1 formulated with the GlaxoSmithKline proprietary adjuvant system AS01B (LSA1/AS01B) was safe and immunogenic, inducing high titers of Antigen-specific antibody and CD4+ T-cell responses, as monitored by the production of interleukin-2 and gamma interferon, using intracellular cytokine staining. RTS,S/AS01B vaccination was well tolerated and demonstrated robust antibody and moderate CD4+ T-cell responses to circumsporozoite protein (CSP) and HBsAg. Positive CD8+ T-cell responses to HBsAg were detected, whereas the responses to CSP and LSA1 were negligible. For both LSA1/AS01B and RTS,S/AS01B, no statistically significant differences were observed between individual and concurrent administration in the magnitude or duration of antibody and T-cell responses. Our results revealed that both pre-erythrocytic-Stage Antigens were safe and immunogenic, administered either separately or simultaneously to rhesus monkeys, and that no significant immune cross interference occurred with concurrent separate-site administration. The comparison of the profiles of immune responses induced by separate-site and single-site vaccinations with LSA1 and RTS,S warrants further investigation.

  • murine immune responses to Liver Stage Antigen 1 protein fmp011 a malaria vaccine candidate deLivered with adjuvant as01b or as02a
    Infection and Immunity, 2007
    Co-Authors: Clara Brando, Lisa A Ware, Arnoldo Barbosa, Gray D Heppner, Helen R Freyberger, April K Kathcart, Sylvie Cayphas, Marieange Demoitie, Pascal Mettens, David E. Lanar
    Abstract:

    Liver-Stage Antigen 1 (LSA1) is expressed by Plasmodium falciparum only during the intrahepatic cell Stage of the parasite's development. Immunoepidemiological studies in regions where malaria is endemic suggested an association between the level of LSA1-specific humoral and cell-mediated immune responses and susceptibility to clinical malaria. A recombinant LSA1 protein, FMP011, has been manufactured as a preerythrocytic vaccine to induce an immune response that would have the effect of controlling parasitemia and disease in humans. To evaluate the immunogenicity of FMP011, we analyzed the immune response of three inbred strains of mice to Antigen immunization using two different adjuvant formulations, AS01B and AS02A. We report here the ability of BALB/c and A/J mice, but not C57BL/6J mice, to mount FMP011-specific humoral (antibody titer) and cellular (gamma interferon [IFN-γ] production) responses following immunization with FMP011 formulated in AS01B or AS02A. Immunization of BALB/c and A/J mice with FMP011/AS01B induced more Antigen-specific IFN-γ-producing splenocytes than immunization with FMP011/AS02A. A slightly higher titer of antibody was induced using AS02A than AS01B in both strains. C57BL/6J mice did not respond with any detectable FMP011-specific IFN-γ splenocytes or antibody when immunized with FMP011 in AS01B or AS02A. Intracellular staining of cells isolated from FMP011/AS01B-immunized BALB/c mice indicated that CD4+ cells, but not CD8+ cells, were the main IFN-γ-producing splenocyte. However, inclusion of blocking anti-CD4+ antibody during the in vitro restimulation ELISpot analysis failed to completely abolish IFN-γ production, indicating that while CD4+ T cells were the major source of IFN-γ, other cell types also were involved.

Ann M Moormann - One of the best experts on this subject based on the ideXlab platform.

  • plasmodium falciparum protein microarray antibody profiles correlate with protection from symptomatic malaria in kenya
    The Journal of Infectious Diseases, 2015
    Co-Authors: Peter Odada Sumba, Ann M Moormann, Arlene E Dent, Rie Nakajima, Li Liang, Elisabeth Baum, John M Vulule, Denise C Babineau, Arlo Randall
    Abstract:

    BACKGROUND: Immunoglobulin G antibodies (Abs) to Plasmodium falciparum Antigens have been associated with naturally acquired immunity to symptomatic malaria. METHODS: We probed protein microarrays covering 824 unique P. falciparum protein features with plasma from residents of a community in Kenya monitored for 12 weeks for (re)infection and symptomatic malaria after administration of antimalarial drugs. P. falciparum proteins recognized by Abs from 88 children (aged 1-14 years) and 86 adults (aged ≥ 18 years), measured at the beginning of the observation period, were ranked by Ab signal intensity. RESULTS: Abs from immune adults reacted with a total 163 of 824 P. falciparum proteins. Children gradually acquired Abs to the full repertoire of Antigens recognized by adults. Abs to some Antigens showed high seroconversion rates, reaching maximal levels early in childhood, whereas others did not reach adult levels until adolescence. No correlation between Ab signal intensity and time to (re)infection was observed. In contrast, Ab levels to 106 Antigens were significantly higher in children who were protected from symptomatic malaria compared with those who were not. Abs to Antigens predictive of protection included P. falciparum erythrocyte membrane protein 1, merozoite surface protein (MSP) 10, MSP2, Liver-Stage Antigen 3, PF70, MSP7, and Plasmodium helical interspersed subtelomeric domain protein. CONCLUSIONS: Protein microarrays may be useful in the search for malaria Antigens associated with protective immunity.

  • plasmodium falciparum protein microarray antibody profiles correlate with protection from symptomatic malaria in kenya
    The Journal of Infectious Diseases, 2015
    Co-Authors: Peter Odada Sumba, Ann M Moormann, Arlene E Dent, Rie Nakajima, Li Liang, Elisabeth Baum, John M Vulule, Denise C Babineau, Arlo Randall
    Abstract:

    BACKGROUND Immunoglobulin G antibodies (Abs) to Plasmodium falciparum Antigens have been associated with naturally acquired immunity to symptomatic malaria. METHODS We probed protein microarrays covering 824 unique P. falciparum protein features with plasma from residents of a community in Kenya monitored for 12 weeks for (re)infection and symptomatic malaria after administration of antimalarial drugs. P. falciparum proteins recognized by Abs from 88 children (aged 1-14 years) and 86 adults (aged ≥ 18 years), measured at the beginning of the observation period, were ranked by Ab signal intensity. RESULTS Abs from immune adults reacted with a total 163 of 824 P. falciparum proteins. Children gradually acquired Abs to the full repertoire of Antigens recognized by adults. Abs to some Antigens showed high seroconversion rates, reaching maximal levels early in childhood, whereas others did not reach adult levels until adolescence. No correlation between Ab signal intensity and time to (re)infection was observed. In contrast, Ab levels to 106 Antigens were significantly higher in children who were protected from symptomatic malaria compared with those who were not. Abs to Antigens predictive of protection included P. falciparum erythrocyte membrane protein 1, merozoite surface protein (MSP) 10, MSP2, Liver-Stage Antigen 3, PF70, MSP7, and Plasmodium helical interspersed subtelomeric domain protein. CONCLUSIONS Protein microarrays may be useful in the search for malaria Antigens associated with protective immunity.

  • stability of interferon gamma and interleukin 10 responses to plasmodium falciparum Liver Stage Antigen 1 and thrombospondin related adhesive protein immunodominant epitopes in a highland population from western kenya
    American Journal of Tropical Medicine and Hygiene, 2009
    Co-Authors: Ann M Moormann, Peter Odada Sumba, James W Kazura, Daniel J Tisch, Paula Embury, Charles H King, Chandy C. John
    Abstract:

    Long-term planning to prevent malaria epidemics requires in-depth understanding of immunity to Plasmodium falciparum in areas of unstable transmission. Cytokine responses to immunodominant epitope peptides from Liver Stage Antigen 1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) were evaluated over a nine-month interval in adults and children in Kenya from a malaria epidemic–prone highland area after several years of low transmission. The proportion and magnitude of interferon-gamma ELISPOT responses and the proportion of interleukin-10 responders to LSA-1 and TRAP peptides tended to be higher in adults than children. Frequencies of interferon-gamma responders to these peptides were similar at the two time points, but responses were not consistently generated by the same persons. These results suggest that T cell memory to pre-erythrocytic Stage malaria Antigens is maintained but may be unavailable for consistent detection in peripheral blood, and that these Antigens induce both pro-inflammatory and anti-inflammatory cytokine responses in this population.

  • stability of interferon γ and interleukin 10 responses to plasmodium falciparum Liver Stage Antigen 1 and thrombospondin related adhesive protein in residents of a malaria holoendemic area
    American Journal of Tropical Medicine and Hygiene, 2006
    Co-Authors: Ann M Moormann, Chandy C. John, Peter Odada Sumba, Daniel J Tisch, Paula Embury, James W Kazura
    Abstract:

    The stability of anti-malarial immunity will influence the interpretation of immunologic endpoints during malaria vaccine trials conducted in endemic areas. Therefore, we evaluated cytokine responses to Plasmodium falci- parum Liver Stage Antigen-1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) by Kenyans from a ho- loendemic area at a 9-month interval. The proportion of adults with interferon- (IFN-) responses to 9-mer LSA-1 peptides was similar at both time-points, whereas responses from children decreased (P < 0.05). Response to the longer, 23-mer LSA-1 peptide was variable, decreasing in adults and children over time (P < 0.02 and P < 0.001, respectively). The proportion of children with IFN- responses to either Antigen at the second time-point was significantly lower than that of adults, yet more adults responded to 9-mer TRAP peptides (P < 0.02). In contrast, the proportion of interleukin- 10 responses to LSA-1 and TRAP was similar at both time-points for both age groups. Most noteworthy was that even when the repeat cross-sectional frequency of cytokine responses was the same, these responses were not generated by the same individuals. This suggests that cytokine responses to LSA-1 and TRAP are transient under natural exposure conditions.

  • gamma interferon responses to plasmodium falciparum Liver Stage Antigen 1 and thrombospondin related adhesive protein and their relationship to age transmission intensity and protection against malaria
    Infection and Immunity, 2004
    Co-Authors: Chandy C. John, Peter Odada Sumba, Ayub V Ofulla, Ann M Moormann, Daniel C Pregibon, James W Kazura
    Abstract:

    Gamma interferon (IFN-γ) responses to the Plasmodium falciparum Antigens Liver-Stage Antigen 1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) are thought to be important in protection against malaria. Optimal methods of testing and the effects of age and transmission intensity on these responses are unknown. IFN-γ responses to LSA-1 and TRAP peptides were assessed by the enzyme-linked immunospot assay (ELISPOT) and enzyme-linked immunosorbent assay (ELISA) in children and adults from areas of stable and unstable malaria transmission in Kenya. Adults in the areas of stable and unstable transmission had similar frequencies and levels of IFN-γ responses to LSA-1 and TRAP as determined by ELISPOT and ELISA. In contrast, IFN-γ responses to the LSA-1 T3 peptide (assessed by ELISPOT) and to any LSA-1 peptide (assessed by ELISA) were less frequent in children in the area of unstable transmission than in children in the area of stable transmission. IFN-γ responses to LSA-1 were more frequently detected by ELISA than by ELISPOT in the stable-transmission area. IFN-γ responses detected by ELISA and ELISPOT did not correlate with each other. In children in the stable-transmission area, IFN-γ responses to LSA-1 peptides assessed by ELISA, but not by ELISPOT, were associated with protection against clinical malaria and anemia. IFN-γ responses to LSA-1 appear to require repeated P. falciparum exposure and/or increased age and, as measured by ELISA, are associated with protection against clinical malaria and anemia.