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  1. Article ; Online: Porphyromonas gingivalis-dendritic cell interactions: consequences for coronary artery disease.

    Zeituni, Amir E / Carrion, Julio / Cutler, Christopher W

    Journal of oral microbiology

    2010  Volume 2

    Abstract: An estimated 80 million US adults have one or more types of cardiovascular diseases. Atherosclerosis is the single most important contributor to cardiovascular diseases; however, only 50% of atherosclerosis patients have currently identified risk factors. ...

    Abstract An estimated 80 million US adults have one or more types of cardiovascular diseases. Atherosclerosis is the single most important contributor to cardiovascular diseases; however, only 50% of atherosclerosis patients have currently identified risk factors. Chronic periodontitis, a common inflammatory disease, is linked to an increased cardiovascular risk. Dendritic cells (DCs) are potent antigen presenting cells that infiltrate arterial walls and may destabilize atherosclerotic plaques in cardiovascular disease. While the source of these DCs in atherosclerotic plaques is presently unclear, we propose that dermal DCs from peripheral inflamed sites such as CP tissues are a potential source. This review will examine the role of the opportunistic oral pathogen Porphyromonas gingivalis in invading DCs and stimulating their mobilization and misdirection through the bloodstream. Based on our published observations, combined with some new data, as well as a focused review of the literature we will propose a model for how P. gingivalis may exploit DCs to gain access to systemic circulation and contribute to coronary artery disease. Our published evidence supports a significant role for P. gingivalis in subverting normal DC function, promoting a semimature, highly migratory, and immunosuppressive DC phenotype that contributes to the inflammatory development of atherosclerosis and, eventually, plaque rupture.
    Language English
    Publishing date 2010-12-21
    Publishing country United States
    Document type Journal Article
    ISSN 2000-2297
    ISSN (online) 2000-2297
    DOI 10.3402/jom.v2i0.5782
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Porphyromonas gingivalis–dendritic cell interactions

    Amir E. Zeituni / Julio Carrion / Christopher W. Cutler

    Journal of Oral Microbiology, Vol 2, Iss 0, Pp 1-

    consequences for coronary artery disease

    2010  Volume 8

    Abstract: An estimated 80 million US adults have one or more types of cardiovascular diseases. Atherosclerosis is the single most important contributor to cardiovascular diseases; however, only 50% of atherosclerosis patients have currently identified risk factors. ...

    Abstract An estimated 80 million US adults have one or more types of cardiovascular diseases. Atherosclerosis is the single most important contributor to cardiovascular diseases; however, only 50% of atherosclerosis patients have currently identified risk factors. Chronic periodontitis, a common inflammatory disease, is linked to an increased cardiovascular risk. Dendritic cells (DCs) are potent antigen presenting cells that infiltrate arterial walls and may destabilize atherosclerotic plaques in cardiovascular disease. While the source of these DCs in atherosclerotic plaques is presently unclear, we propose that dermal DCs from peripheral inflamed sites such as CP tissues are a potential source. This review will examine the role of the opportunistic oral pathogen Porphyromonas gingivalis in invading DCs and stimulating their mobilization and misdirection through the bloodstream. Based on our published observations, combined with some new data, as well as a focused review of the literature we will propose a model for how P. gingivalis may exploit DCs to gain access to systemic circulation and contribute to coronary artery disease. Our published evidence supports a significant role for P. gingivalis in subverting normal DC function, promoting a semimature, highly migratory, and immunosuppressive DC phenotype that contributes to the inflammatory development of atherosclerosis and, eventually, plaque rupture.
    Keywords dendritic cells ; periodontitis ; atherosclerosis ; Porphyromonas gingivalis ; DC-SIGN ; Microbiology ; QR1-502 ; Science ; Q ; DOAJ:Microbiology ; DOAJ:Biology ; DOAJ:Biology and Life Sciences
    Subject code 610
    Language English
    Publishing date 2010-12-01T00:00:00Z
    Publisher Co-Action Publishing
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Targeting of DC-SIGN on human dendritic cells by minor fimbriated Porphyromonas gingivalis strains elicits a distinct effector T cell response.

    Zeituni, Amir E / Jotwani, Ravi / Carrion, Julio / Cutler, Christopher W

    Journal of immunology (Baltimore, Md. : 1950)

    2009  Volume 183, Issue 9, Page(s) 5694–5704

    Abstract: The oral mucosal pathogen Porphyromonas gingivalis expresses at least two adhesins: the 67-kDa mfa-1 (minor) fimbriae and the 41-kDa fimA (major) fimbriae. In periodontal disease, P. gingivalis associates in situ with dermal dendritic cells (DCs), many ... ...

    Abstract The oral mucosal pathogen Porphyromonas gingivalis expresses at least two adhesins: the 67-kDa mfa-1 (minor) fimbriae and the 41-kDa fimA (major) fimbriae. In periodontal disease, P. gingivalis associates in situ with dermal dendritic cells (DCs), many of which express DC-SIGN (DC-specific ICAM-3 grabbing nonintegrin; CD209). The cellular receptors present on DCs that are involved in the uptake of minor/major fimbriated P. gingivalis, along with the effector immune response induced, are presently unclear. In this study, stably transfected human DC-SIGN(+/-) Raji cell lines and monocyte-derived DCs (MoDCs) were pulsed with whole, live, wild-type Pg381 or isogenic major (DPG-3)-, minor (MFI)-, or double fimbriae (MFB)-deficient mutant P. gingivalis strains. The influence of blocking Abs, carbohydrates, full-length glycosylated HIV-1 gp120 envelope protein, and cytochalasin D on the uptake of strains and on the immune responses was determined in vitro. We show that the binding of minor fimbriated P. gingivalis strains to Raji cells and MoDCs is dependent on DC-SIGN, whereas the double fimbriae mutant strain does not bind. Binding to DC-SIGN on MoDCs is followed by the internalization of P. gingivalis into DC-SIGN-rich intracellular compartments, and MoDCs secrete low levels of inflammatory cytokines and remain relatively immature. Blocking DC-SIGN with HIV-1 gp120 prevents the uptake of minor fimbriated strains and deregulates the expression of inflammatory cytokines. Moreover, MoDCs promote a Th2 or Th1 effector response, depending on whether they are pulsed with minor or major fimbriated P. gingivalis strains, respectively, suggesting distinct immunomodulatory roles for the two adhesins of P. gingivalis.
    MeSH term(s) Bacterial Adhesion/genetics ; Bacterial Adhesion/immunology ; Cell Adhesion Molecules/genetics ; Cell Adhesion Molecules/metabolism ; Cell Adhesion Molecules/physiology ; Cell Compartmentation/genetics ; Cell Compartmentation/immunology ; Cell Line, Tumor ; Cells, Cultured ; Coculture Techniques ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Dendritic Cells/microbiology ; Endocytosis/immunology ; Fimbriae, Bacterial/genetics ; Fimbriae, Bacterial/immunology ; Fimbriae, Bacterial/metabolism ; Gene Targeting/methods ; Humans ; Lectins, C-Type/genetics ; Lectins, C-Type/metabolism ; Lectins, C-Type/physiology ; Monocytes/immunology ; Monocytes/metabolism ; Monocytes/microbiology ; Porphyromonas gingivalis/genetics ; Porphyromonas gingivalis/immunology ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/metabolism ; Receptors, Cell Surface/physiology ; Th1 Cells/immunology ; Th1 Cells/metabolism ; Th1 Cells/microbiology ; Th2 Cells/immunology ; Th2 Cells/metabolism ; Th2 Cells/microbiology
    Chemical Substances Cell Adhesion Molecules ; DC-specific ICAM-3 grabbing nonintegrin ; Lectins, C-Type ; Receptors, Cell Surface
    Language English
    Publishing date 2009-10-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.0901030
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The native 67-kilodalton minor fimbria of Porphyromonas gingivalis is a novel glycoprotein with DC-SIGN-targeting motifs.

    Zeituni, Amir E / McCaig, William / Scisci, Elizabeth / Thanassi, David G / Cutler, Christopher W

    Journal of bacteriology

    2010  Volume 192, Issue 16, Page(s) 4103–4110

    Abstract: We recently reported that the oral mucosal pathogen Porphyromonas gingivalis, through its 67-kDa Mfa1 (minor) fimbria, targets the C-type lectin receptor DC-SIGN for invasion and persistence within human monocyte-derived dendritic cells (DCs). The DCs ... ...

    Abstract We recently reported that the oral mucosal pathogen Porphyromonas gingivalis, through its 67-kDa Mfa1 (minor) fimbria, targets the C-type lectin receptor DC-SIGN for invasion and persistence within human monocyte-derived dendritic cells (DCs). The DCs respond by inducing an immunosuppressive and Th2-biased CD4(+) T-cell response. We have now purified the native minor fimbria by ion-exchange chromatography and sequenced the fimbria by tandem mass spectrometry (MS/MS), confirming its identity and revealing two putative N-glycosylation motifs as well as numerous putative O-glycosylation sites. We further show that the minor fimbria is glycosylated by ProQ staining and that glycosylation is partially removed by treatment with beta(1-4)-galactosidase, but not by classic N- and O-linked deglycosidases. Further monosaccharide analysis by gas chromatography-mass spectrometry (GC-MS) confirmed that the minor fimbria contains the DC-SIGN-targeting carbohydrates fucose (1.35 nmol/mg), mannose (2.68 nmol/mg), N-acetylglucosamine (2.27 nmol/mg), and N-acetylgalactosamine (0.652 nmol/mg). Analysis by transmission electron microscopy revealed that the minor fimbria forms fibers approximately 200 nm in length that could be involved in targeting or cross-linking DC-SIGN. These findings shed further light on molecular mechanisms of invasion and immunosuppression by this unique mucosal pathogen.
    MeSH term(s) Acetylgalactosamine/analysis ; Acetylglucosamine/analysis ; Amino Acid Sequence ; Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/isolation & purification ; Bacterial Proteins/metabolism ; Cell Adhesion Molecules/metabolism ; Fimbriae Proteins/chemistry ; Fimbriae Proteins/genetics ; Fimbriae Proteins/isolation & purification ; Fimbriae Proteins/metabolism ; Fimbriae, Bacterial/ultrastructure ; Fucose/analysis ; Gas Chromatography-Mass Spectrometry ; Glycoproteins/chemistry ; Glycoproteins/genetics ; Glycoproteins/isolation & purification ; Glycoproteins/metabolism ; Lectins, C-Type/metabolism ; Mannose/analysis ; Microscopy, Electron, Transmission ; Molecular Sequence Data ; Molecular Weight ; Porphyromonas gingivalis/chemistry ; Porphyromonas gingivalis/genetics ; Porphyromonas gingivalis/ultrastructure ; Protein Binding ; Receptors, Cell Surface/metabolism ; Sequence Analysis, Protein ; Tandem Mass Spectrometry ; Virulence Factors/chemistry ; Virulence Factors/genetics ; Virulence Factors/isolation & purification ; Virulence Factors/metabolism
    Chemical Substances Bacterial Proteins ; Cell Adhesion Molecules ; DC-specific ICAM-3 grabbing nonintegrin ; Glycoproteins ; Lectins, C-Type ; Mfa1 protein, Porphyromonas gingivalis ; Receptors, Cell Surface ; Virulence Factors ; Fimbriae Proteins (147680-16-8) ; Fucose (28RYY2IV3F) ; Acetylgalactosamine (KM15WK8O5T) ; Mannose (PHA4727WTP) ; Acetylglucosamine (V956696549)
    Language English
    Publishing date 2010-06-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2968-3
    ISSN 1098-5530 ; 0021-9193
    ISSN (online) 1098-5530
    ISSN 0021-9193
    DOI 10.1128/JB.00275-10
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Effects of age, hemoglobin type and parasite strain on IgG recognition of Plasmodium falciparum-infected erythrocytes in Malian children.

    Zeituni, Amir E / Miura, Kazutoyo / Diakite, Mahamadou / Doumbia, Saibou / Moretz, Samuel E / Diouf, Ababacar / Tullo, Gregory / Lopera-Mesa, Tatiana M / Bess, Cameron D / Mita-Mendoza, Neida K / Anderson, Jennifer M / Fairhurst, Rick M / Long, Carole A

    PloS one

    2013  Volume 8, Issue 10, Page(s) e76734

    Abstract: Background: Naturally-acquired antibody responses to antigens on the surface of Plasmodium falciparum-infected red blood cells (iRBCs) have been implicated in antimalarial immunity. To profile the development of this immunity, we have been studying a ... ...

    Abstract Background: Naturally-acquired antibody responses to antigens on the surface of Plasmodium falciparum-infected red blood cells (iRBCs) have been implicated in antimalarial immunity. To profile the development of this immunity, we have been studying a cohort of Malian children living in an area with intense seasonal malaria transmission.
    Methodology/principal findings: We collected plasma from a sub-cohort of 176 Malian children aged 3-11 years, before (May) and after (December) the 2009 transmission season. To measure the effect of hemoglobin (Hb) type on antibody responses, we enrolled age-matched HbAA, HbAS and HbAC children. To quantify antibody recognition of iRBCs, we designed a high-throughput flow cytometry assay to rapidly test numerous plasma samples against multiple parasite strains. We evaluated antibody reactivity of each plasma sample to 3 laboratory-adapted parasite lines (FCR3, D10, PC26) and 4 short-term-cultured parasite isolates (2 Malian and 2 Cambodian). 97% of children recognized ≥1 parasite strain and the proportion of IgG responders increased significantly during the transmission season for most parasite strains. Both strain-specific and strain-transcending IgG responses were detected, and varied by age, Hb type and parasite strain. In addition, the breadth of IgG responses to parasite strains increased with age in HbAA, but not in HbAS or HbAC, children.
    Conclusions/significance: Our assay detects both strain-specific and strain-transcending IgG responses to iRBCs. The magnitude and breadth of these responses varied not only by age, but also by Hb type and parasite strain used. These findings indicate that studies of acquired humoral immunity should account for Hb type and test large numbers of diverse parasite strains.
    MeSH term(s) Age Factors ; Antibodies, Protozoan/immunology ; Antigens, Protozoan/immunology ; Child ; Child, Preschool ; Cohort Studies ; Erythrocytes/metabolism ; Erythrocytes/parasitology ; Hemoglobins/classification ; Hemoglobins/genetics ; Humans ; Immunoglobulin G/immunology ; Incidence ; Malaria, Falciparum/epidemiology ; Malaria, Falciparum/genetics ; Malaria, Falciparum/immunology ; Malaria, Falciparum/parasitology ; Mali/epidemiology ; Plasmodium falciparum/immunology ; Seasons
    Chemical Substances Antibodies, Protozoan ; Antigens, Protozoan ; Hemoglobins ; Immunoglobulin G
    Language English
    Publishing date 2013-10-04
    Publishing country United States
    Document type Journal Article
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0076734
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Microbial carriage state of peripheral blood dendritic cells (DCs) in chronic periodontitis influences DC differentiation, atherogenic potential.

    Carrion, Julio / Scisci, Elizabeth / Miles, Brodie / Sabino, Gregory J / Zeituni, Amir E / Gu, Ying / Bear, Adam / Genco, Caroline A / Brown, David L / Cutler, Christopher W

    Journal of immunology (Baltimore, Md. : 1950)

    2012  Volume 189, Issue 6, Page(s) 3178–3187

    Abstract: The low-grade oral infection chronic periodontitis (CP) has been implicated in coronary artery disease risk, but the mechanisms are unclear. In this study, a pathophysiological role for blood dendritic cells (DCs) in systemic dissemination of oral ... ...

    Abstract The low-grade oral infection chronic periodontitis (CP) has been implicated in coronary artery disease risk, but the mechanisms are unclear. In this study, a pathophysiological role for blood dendritic cells (DCs) in systemic dissemination of oral mucosal pathogens to atherosclerotic plaques was investigated in humans. The frequency and microbiome of CD19(-)BDCA-1(+)DC-SIGN(+) blood myeloid DCs (mDCs) were analyzed in CP subjects with or without existing acute coronary syndrome and in healthy controls. FACS analysis revealed a significant increase in blood mDCs in the following order: healthy controls < CP < acute coronary syndrome/CP. Analysis of the blood mDC microbiome by 16S rDNA sequencing showed Porphyromonas gingivalis and other species, including (cultivable) Burkholderia cepacia. The mDC carriage rate with P. gingivalis correlated with oral carriage rate and with serologic exposure to P. gingivalis in CP subjects. Intervention (local debridement) to elicit a bacteremia increased the mDC carriage rate and frequency in vivo. In vitro studies established that P. gingivalis enhanced by 28% the differentiation of monocytes into immature mDCs; moreover, mDCs secreted high levels of matrix metalloproteinase-9 and upregulated C1q, heat shock protein 60, heat shock protein 70, CCR2, and CXCL16 transcripts in response to P. gingivalis in a fimbriae-dependent manner. Moreover, the survival of the anaerobe P. gingivalis under aerobic conditions was enhanced when within mDCs. Immunofluorescence analysis of oral mucosa and atherosclerotic plaques demonstrate infiltration with mDCs, colocalized with P. gingivalis. Our results suggest a role for blood mDCs in harboring and disseminating pathogens from oral mucosa to atherosclerosis plaques, which may provide key signals for mDC differentiation and atherogenic conversion.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Bacteroidaceae Infections/blood ; Bacteroidaceae Infections/immunology ; Bacteroidaceae Infections/microbiology ; Burkholderia Infections/blood ; Burkholderia Infections/immunology ; Burkholderia Infections/microbiology ; Carrier State/blood ; Carrier State/immunology ; Carrier State/microbiology ; Cell Differentiation/immunology ; Chronic Disease ; Dendritic Cells/immunology ; Dendritic Cells/microbiology ; Dendritic Cells/pathology ; Female ; Humans ; Immunophenotyping ; Male ; Middle Aged ; Monocytes/immunology ; Monocytes/microbiology ; Monocytes/pathology ; Mouth Mucosa/immunology ; Mouth Mucosa/microbiology ; Mouth Mucosa/pathology ; Myeloid Cells/immunology ; Myeloid Cells/microbiology ; Myeloid Cells/pathology ; Periodontitis ; Plaque, Atherosclerotic/blood ; Plaque, Atherosclerotic/immunology ; Plaque, Atherosclerotic/microbiology ; Porphyromonas gingivalis
    Language English
    Publishing date 2012-08-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1201053
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Immune characterization of Plasmodium falciparum parasites with a shared genetic signature in a region of decreasing transmission.

    Bei, Amy K / Diouf, Ababacar / Miura, Kazutoyo / Larremore, Daniel B / Ribacke, Ulf / Tullo, Gregory / Moss, Eli L / Neafsey, Daniel E / Daniels, Rachel F / Zeituni, Amir E / Nosamiefan, Iguosadolo / Volkman, Sarah K / Ahouidi, Ambroise D / Ndiaye, Daouda / Dieye, Tandakha / Mboup, Souleymane / Buckee, Caroline O / Long, Carole A / Wirth, Dyann F

    Infection and immunity

    2015  Volume 83, Issue 1, Page(s) 276–285

    Abstract: As the intensity of malaria transmission has declined, Plasmodium falciparum parasite populations have displayed decreased clonal diversity resulting from the emergence of many parasites with common genetic signatures (CGS). We have monitored such CGS ... ...

    Abstract As the intensity of malaria transmission has declined, Plasmodium falciparum parasite populations have displayed decreased clonal diversity resulting from the emergence of many parasites with common genetic signatures (CGS). We have monitored such CGS parasite clusters from 2006 to 2013 in Thiès, Senegal, using the molecular barcode. The first, and one of the largest observed clusters of CGS parasites, was present in 24% of clinical isolates in 2008, declined to 3.4% of clinical isolates in 2009, and then disappeared. To begin to explore the relationship between the immune responses of the population and the emergence and decline of specific parasite genotypes, we have determined whether antibodies to CGS parasites correlate with their prevalence. We measured (i) antibodies capable of inhibiting parasite growth in culture and (ii) antibodies recognizing the surfaces of infected erythrocytes (RBCs). IgG obtained from volunteers in 2009 showed increased reactivity to the surfaces of CGS-parasitized erythrocytes over IgG from 2008. Since P. falciparum EMP-1 (PfEMP-1) is a major variant surface antigen, we used var Ups quantitative reverse transcription-PCR (qRT-PCR) and sequencing with degenerate DBL1α domain primers to characterize the var genes expressed by CGS parasites after short-term in vitro culture. CGS parasites show upregulation of UpsA var genes and 2-cysteine-containing PfEMP-1 molecules and express the same dominant var transcript. Our work indicates that the CGS parasites in this cluster express similar var genes, more than would be expected by chance in the population, and that there is year-to-year variation in immune recognition of surface antigens on CGS parasite-infected erythrocytes. This study lays the groundwork for detailed investigations of the mechanisms driving the expansion or contraction of specific parasite clones in the population.
    MeSH term(s) Antibodies, Protozoan/blood ; Antigens, Protozoan/genetics ; Antigens, Protozoan/immunology ; Cluster Analysis ; DNA Barcoding, Taxonomic ; Humans ; Immunoglobulin G/blood ; Malaria, Falciparum/epidemiology ; Malaria, Falciparum/immunology ; Malaria, Falciparum/transmission ; Plasmodium falciparum/classification ; Plasmodium falciparum/genetics ; Plasmodium falciparum/immunology ; Protozoan Proteins/genetics ; Protozoan Proteins/immunology ; Senegal/epidemiology
    Chemical Substances Antibodies, Protozoan ; Antigens, Protozoan ; Immunoglobulin G ; Protozoan Proteins ; erythrocyte membrane protein 1, Plasmodium falciparum
    Language English
    Publishing date 2015-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218698-6
    ISSN 1098-5522 ; 0019-9567
    ISSN (online) 1098-5522
    ISSN 0019-9567
    DOI 10.1128/IAI.01979-14
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Plasmodium falciparum clearance rates in response to artesunate in Malian children with malaria: effect of acquired immunity.

    Lopera-Mesa, Tatiana M / Doumbia, Saibou / Chiang, Serena / Zeituni, Amir E / Konate, Drissa S / Doumbouya, Mory / Keita, Abdoul S / Stepniewska, Kasia / Traore, Karim / Diakite, Seidina A S / Ndiaye, Daouda / Sa, Juliana M / Anderson, Jennifer M / Fay, Michael P / Long, Carole A / Diakite, Mahamadou / Fairhurst, Rick M

    The Journal of infectious diseases

    2013  Volume 207, Issue 11, Page(s) 1655–1663

    Abstract: Background: Artemisinin resistance, a long parasite clearance half-life in response to artemisinin, has been described in patients with Plasmodium falciparum malaria in southeast Asia. Few baseline half-lives have been reported from Africa, where ... ...

    Abstract Background: Artemisinin resistance, a long parasite clearance half-life in response to artemisinin, has been described in patients with Plasmodium falciparum malaria in southeast Asia. Few baseline half-lives have been reported from Africa, where artemisinins were recently introduced.
    Methods: We treated P. falciparum malaria in 215 Malian children aged 0.5-15 years with artesunate (0, 24, 48 hours) and amodiaquine (72, 96, 120 hours). We estimated half-life by measuring parasite density every 6 hours until undetectable and evaluated the effects of age, sex, ethnicity, and red blood cell (RBC) polymorphisms on half-life. We quantified the proportion of parasitized RBCs recognized by autologous immunoglobulin G (IgG).
    Results: The geometric mean half-life was 1.9 hours (95% confidence interval, 1.8-2.0) and did not correlate with parasite ex vivo susceptibility to artemisinins. In a linear model accounting for host factors, half-life decreased by 4.1 minutes for every 1-year increase in age. The proportion of parasitized RBCs recognized by IgG correlated inversely with half-life (r = -0.475; P = .0006).
    Conclusions: Parasite clearance in response to artesunate is faster in Mali than in southeast Asia. IgG responses to parasitized RBCs shorten half-life and may influence this parameter in areas where age is not an adequate surrogate of immunity and correlates of parasite-clearing immunity have not been identified.
    Clinical trials registration: NCT00669084.
    MeSH term(s) Adaptive Immunity ; Adolescent ; Amodiaquine/administration & dosage ; Antibodies, Protozoan/blood ; Antimalarials/administration & dosage ; Artemisinins/administration & dosage ; Artesunate ; Child ; Child, Preschool ; Cohort Studies ; Erythrocytes/parasitology ; Female ; Humans ; Immunoglobulin G/blood ; Infant ; Malaria, Falciparum/drug therapy ; Malaria, Falciparum/immunology ; Male ; Mali ; Parasite Load ; Parasitemia/drug therapy ; Parasitemia/immunology ; Plasmodium falciparum/immunology ; Plasmodium falciparum/isolation & purification
    Chemical Substances Antibodies, Protozoan ; Antimalarials ; Artemisinins ; Immunoglobulin G ; Amodiaquine (220236ED28) ; Artesunate (60W3249T9M)
    Language English
    Publishing date 2013-02-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 3019-3
    ISSN 1537-6613 ; 0022-1899
    ISSN (online) 1537-6613
    ISSN 0022-1899
    DOI 10.1093/infdis/jit082
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality.

    Wu, Jian / Tian, Linjie / Yu, Xiao / Pattaradilokrat, Sittiporn / Li, Jian / Wang, Mingjun / Yu, Weishi / Qi, Yanwei / Zeituni, Amir E / Nair, Sethu C / Crampton, Steve P / Orandle, Marlene S / Bolland, Silvia M / Qi, Chen-Feng / Long, Carole A / Myers, Timothy G / Coligan, John E / Wang, Rongfu / Su, Xin-zhuan

    Proceedings of the National Academy of Sciences of the United States of America

    2014  Volume 111, Issue 4, Page(s) E511–20

    Abstract: Malaria infection triggers vigorous host immune responses; however, the parasite ligands, host receptors, and the signaling pathways responsible for these reactions remain unknown or controversial. Malaria parasites primarily reside within RBCs, thereby ... ...

    Abstract Malaria infection triggers vigorous host immune responses; however, the parasite ligands, host receptors, and the signaling pathways responsible for these reactions remain unknown or controversial. Malaria parasites primarily reside within RBCs, thereby hiding themselves from direct contact and recognition by host immune cells. Host responses to malaria infection are very different from those elicited by bacterial and viral infections and the host receptors recognizing parasite ligands have been elusive. Here we investigated mouse genome-wide transcriptional responses to infections with two strains of Plasmodium yoelii (N67 and N67C) and discovered differences in innate response pathways corresponding to strain-specific disease phenotypes. Using in vitro RNAi-based gene knockdown and KO mice, we demonstrated that a strong type I IFN (IFN-I) response triggered by RNA polymerase III and melanoma differentiation-associated protein 5, not Toll-like receptors (TLRs), binding of parasite DNA/RNA contributed to a decline of parasitemia in N67-infected mice. We showed that conventional dendritic cells were the major sources of early IFN-I, and that surface expression of phosphatidylserine on infected RBCs might promote their phagocytic uptake, leading to the release of parasite ligands and the IFN-I response in N67 infection. In contrast, an elevated inflammatory response mediated by CD14/TLR and p38 signaling played a role in disease severity and early host death in N67C-infected mice. In addition to identifying cytosolic DNA/RNA sensors and signaling pathways previously unrecognized in malaria infection, our study demonstrates the importance of parasite genetic backgrounds in malaria pathology and provides important information for studying human malaria pathogenesis.
    MeSH term(s) Aged ; Animals ; Host-Parasite Interactions ; Humans ; Immunity, Innate ; Inflammation/immunology ; Inflammation/metabolism ; Interferon Type I/metabolism ; Malaria/immunology ; Malaria/mortality ; Malaria/parasitology ; Mice ; Mice, Knockout ; Parasitemia/immunology ; Parasitemia/parasitology ; Phagocytosis ; Plasmodium yoelii/immunology ; Plasmodium yoelii/physiology ; Signal Transduction
    Chemical Substances Interferon Type I
    Language English
    Publishing date 2014-01-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1316467111
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Effects of age, hemoglobin type and parasite strain on IgG recognition of Plasmodium falciparum-infected erythrocytes in Malian children.

    Amir E Zeituni / Kazutoyo Miura / Mahamadou Diakite / Saibou Doumbia / Samuel E Moretz / Ababacar Diouf / Gregory Tullo / Tatiana M Lopera-Mesa / Cameron D Bess / Neida K Mita-Mendoza / Jennifer M Anderson / Rick M Fairhurst / Carole A Long

    PLoS ONE, Vol 8, Iss 10, p e

    2013  Volume 76734

    Abstract: BACKGROUND:Naturally-acquired antibody responses to antigens on the surface of Plasmodium falciparum-infected red blood cells (iRBCs) have been implicated in antimalarial immunity. To profile the development of this immunity, we have been studying a ... ...

    Abstract BACKGROUND:Naturally-acquired antibody responses to antigens on the surface of Plasmodium falciparum-infected red blood cells (iRBCs) have been implicated in antimalarial immunity. To profile the development of this immunity, we have been studying a cohort of Malian children living in an area with intense seasonal malaria transmission. METHODOLOGY/PRINCIPAL FINDINGS:We collected plasma from a sub-cohort of 176 Malian children aged 3-11 years, before (May) and after (December) the 2009 transmission season. To measure the effect of hemoglobin (Hb) type on antibody responses, we enrolled age-matched HbAA, HbAS and HbAC children. To quantify antibody recognition of iRBCs, we designed a high-throughput flow cytometry assay to rapidly test numerous plasma samples against multiple parasite strains. We evaluated antibody reactivity of each plasma sample to 3 laboratory-adapted parasite lines (FCR3, D10, PC26) and 4 short-term-cultured parasite isolates (2 Malian and 2 Cambodian). 97% of children recognized ≥1 parasite strain and the proportion of IgG responders increased significantly during the transmission season for most parasite strains. Both strain-specific and strain-transcending IgG responses were detected, and varied by age, Hb type and parasite strain. In addition, the breadth of IgG responses to parasite strains increased with age in HbAA, but not in HbAS or HbAC, children. CONCLUSIONS/SIGNIFICANCE:Our assay detects both strain-specific and strain-transcending IgG responses to iRBCs. The magnitude and breadth of these responses varied not only by age, but also by Hb type and parasite strain used. These findings indicate that studies of acquired humoral immunity should account for Hb type and test large numbers of diverse parasite strains.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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