Hyperreactive Onchocerciasis is Characterized by a Combination of Th17-Th2 Immune Responses and Reduced Regulatory T Cells
Identifieur interne : 006F10 ( Ncbi/Merge ); précédent : 006F09; suivant : 006F11Hyperreactive Onchocerciasis is Characterized by a Combination of Th17-Th2 Immune Responses and Reduced Regulatory T Cells
Auteurs : Gnatoulma Katawa [Allemagne, Togo] ; Laura E. Layland [Allemagne] ; Alex Y. Debrah [Ghana] ; Charlotte Von Horn [Allemagne] ; Linda Batsa [Ghana] ; Alexander Kwarteng [Allemagne] ; Sandra Arriens [Allemagne] ; David W. Taylor [Royaume-Uni] ; Sabine Specht [Allemagne] ; Achim Hoerauf [Allemagne] ; Tomabu Adjobimey [Allemagne]Source :
- PLoS Neglected Tropical Diseases [ 1935-2727 ] ; 2015.
Abstract
Clinical manifestations in onchocerciasis range from generalized onchocerciasis (GEO) to the rare but severe hyperreactive (HO)/sowda form. Since disease pathogenesis is associated with host inflammatory reactions, we investigated whether Th17 responses could be related to aggravated pathology in HO. Using flow cytometry, filarial-specific cytokine responses and PCR arrays, we compared the immune cell profiles, including Th subsets, in individuals presenting the two polar forms of infection and endemic normals (EN). In addition to elevated frequencies of memory CD4+ T cells, individuals with HO showed accentuated Th17 and Th2 profiles but decreased CD4+CD25hiFoxp3+ regulatory T cells. These profiles included increased IL-17A+, IL-4+, RORC2+ and GATA3+CD4+ T cell populations. Flow cytometry data was further confirmed using a PCR array since Th17-related genes (IL-17 family members, IL-6, IL-1β and IL-22) and Th2-related (IL-4, IL-13, STAT6) genes were all significantly up-regulated in HO individuals. In addition, stronger
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DOI: 10.1371/journal.pntd.0003414
PubMed: 25569210
PubMed Central: 4288720
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Layland</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Debrah, Alex Y" sort="Debrah, Alex Y" uniqKey="Debrah A" first="Alex Y." last="Debrah">Alex Y. Debrah</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Kumasi</wicri:regionArea><wicri:noRegion>Kumasi</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Faculty of Allied Health Sciences and School of Medical Sciences of Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>Faculty of Allied Health Sciences and School of Medical Sciences of Kwame Nkrumah University of Science and Technology, Kumasi</wicri:regionArea><wicri:noRegion>Kumasi</wicri:noRegion></affiliation></author><author><name sortKey="Von Horn, Charlotte" sort="Von Horn, Charlotte" uniqKey="Von Horn C" first="Charlotte" last="Von Horn">Charlotte Von Horn</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Batsa, Linda" sort="Batsa, Linda" uniqKey="Batsa L" first="Linda" last="Batsa">Linda Batsa</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Kumasi</wicri:regionArea><wicri:noRegion>Kumasi</wicri:noRegion></affiliation></author><author><name sortKey="Kwarteng, Alexander" sort="Kwarteng, Alexander" uniqKey="Kwarteng A" first="Alexander" last="Kwarteng">Alexander Kwarteng</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Arriens, Sandra" sort="Arriens, Sandra" uniqKey="Arriens S" first="Sandra" last="Arriens">Sandra Arriens</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="W Taylor, David" sort="W Taylor, David" uniqKey="W Taylor D" first="David" last="W. Taylor">David W. Taylor</name><affiliation wicri:level="2"><nlm:aff id="aff5"><addr-line>Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, Scotland</addr-line></nlm:aff><country>Royaume-Uni</country><placeName><region type="country">Écosse</region></placeName><wicri:cityArea>Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh</wicri:cityArea></affiliation></author><author><name sortKey="Specht, Sabine" sort="Specht, Sabine" uniqKey="Specht S" first="Sabine" last="Specht">Sabine Specht</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Hoerauf, Achim" sort="Hoerauf, Achim" uniqKey="Hoerauf A" first="Achim" last="Hoerauf">Achim Hoerauf</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Adjobimey, Tomabu" sort="Adjobimey, Tomabu" uniqKey="Adjobimey T" first="Tomabu" last="Adjobimey">Tomabu Adjobimey</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author></analytic><series><title level="j">PLoS Neglected Tropical Diseases</title><idno type="ISSN">1935-2727</idno><idno type="eISSN">1935-2735</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Clinical manifestations in onchocerciasis range from generalized onchocerciasis (GEO) to the rare but severe hyperreactive (HO)/sowda form. Since disease pathogenesis is associated with host inflammatory reactions, we investigated whether Th17 responses could be related to aggravated pathology in HO. Using flow cytometry, filarial-specific cytokine responses and PCR arrays, we compared the immune cell profiles, including Th subsets, in individuals presenting the two polar forms of infection and endemic normals (EN). In addition to elevated frequencies of memory CD4<sup>+</sup> T cells, individuals with HO showed accentuated Th17 and Th2 profiles but decreased CD4<sup>+</sup>CD25<sup>hi</sup>Foxp3<sup>+</sup> regulatory T cells. These profiles included increased IL-17A<sup>+</sup>, IL-4<sup>+</sup>, RORC2<sup>+</sup> and GATA3<sup>+</sup>CD4<sup>+</sup> T cell populations. Flow cytometry data was further confirmed using a PCR array since Th17-related genes (IL-17 family members, IL-6, IL-1β and IL-22) and Th2-related (IL-4, IL-13, STAT6) genes were all significantly up-regulated in HO individuals. In addition, stronger <italic>Onchocerca volvulus</italic>-specific Th2 responses, especially IL-13, were observed <italic>in vitro</italic> in hyperreactive individuals when compared to GEO or EN groups. This study provides initial evidence that elevated frequencies of Th17 and Th2 cells form part of the immune network instigating the development of severe onchocerciasis.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Crump, A" uniqKey="Crump A">A Crump</name></author><author><name sortKey="Morel, Cm" uniqKey="Morel C">CM Morel</name></author><author><name sortKey="Omura, S" uniqKey="Omura S">S Omura</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Taylor, Mj" uniqKey="Taylor M">MJ Taylor</name></author><author><name sortKey="Hoerauf, A" uniqKey="Hoerauf A">A Hoerauf</name></author><author><name sortKey="Bockarie, M" uniqKey="Bockarie M">M Bockarie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tamarozzi, F" uniqKey="Tamarozzi F">F Tamarozzi</name></author><author><name sortKey="Halliday, A" uniqKey="Halliday A">A 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Negl Trop Dis</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Negl Trop Dis</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosntds</journal-id><journal-title-group><journal-title>PLoS Neglected Tropical Diseases</journal-title></journal-title-group><issn pub-type="ppub">1935-2727</issn><issn pub-type="epub">1935-2735</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25569210</article-id><article-id pub-id-type="pmc">4288720</article-id><article-id pub-id-type="publisher-id">PNTD-D-14-01562</article-id><article-id pub-id-type="doi">10.1371/journal.pntd.0003414</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Medicine and Health Sciences</subject><subj-group><subject>Infectious Diseases</subject></subj-group><subj-group><subject>Parasitic Diseases</subject></subj-group><subj-group><subject>Tropical Diseases</subject></subj-group></subj-group></article-categories><title-group><article-title>Hyperreactive Onchocerciasis is Characterized by a Combination of Th17-Th2 Immune Responses and Reduced Regulatory T Cells</article-title><alt-title alt-title-type="running-head">Th17/Th2 and Pathological Onchocerciasis</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Katawa</surname><given-names>Gnatoulma</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Layland</surname><given-names>Laura E.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Debrah</surname><given-names>Alex Y.</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>von Horn</surname><given-names>Charlotte</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Batsa</surname><given-names>Linda</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kwarteng</surname><given-names>Alexander</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Arriens</surname><given-names>Sandra</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>W. Taylor</surname><given-names>David</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Specht</surname><given-names>Sabine</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hoerauf</surname><given-names>Achim</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Adjobimey</surname><given-names>Tomabu</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>‡</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Advanced School of Medical Biology and Food Technology (ESTBA), University of Lomé, Lomé, Togo</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Kumasi, Ghana</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Faculty of Allied Health Sciences and School of Medical Sciences of Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></aff><aff id="aff5"><label>5</label><addr-line>Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, Scotland</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Makepeace</surname><given-names>Benjamin L.</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>University of Liverpool, United Kingdom</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>hoerauf@microbiology-bonn.de</email></corresp><fn fn-type="conflict"><p>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con"><p>Conceived and designed the experiments: TA GK AH LEL. Performed the experiments: GK TA CvH SA. Analyzed the data: TA GK LEL SS AH. Contributed reagents/materials/analysis tools: AYD LB AK DWT SS AH. Wrote the paper: GK AT LEL AH.</p></fn><fn id="fn1" fn-type="other"><p>‡ GK and LEL contributed equally to this work. AH and TA also contributed equally to this work.</p></fn></author-notes><pub-date pub-type="collection"><month>1</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>8</day><month>1</month><year>2015</year></pub-date><volume>9</volume><issue>1</issue><elocation-id>e3414</elocation-id><history><date date-type="received"><day>10</day><month>9</month><year>2014</year></date><date date-type="accepted"><day>12</day><month>11</month><year>2014</year></date></history><permissions><copyright-year>2015</copyright-year><copyright-holder>Katawa et al</copyright-holder><license><license-p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><abstract><p>Clinical manifestations in onchocerciasis range from generalized onchocerciasis (GEO) to the rare but severe hyperreactive (HO)/sowda form. Since disease pathogenesis is associated with host inflammatory reactions, we investigated whether Th17 responses could be related to aggravated pathology in HO. Using flow cytometry, filarial-specific cytokine responses and PCR arrays, we compared the immune cell profiles, including Th subsets, in individuals presenting the two polar forms of infection and endemic normals (EN). In addition to elevated frequencies of memory CD4<sup>+</sup> T cells, individuals with HO showed accentuated Th17 and Th2 profiles but decreased CD4<sup>+</sup>CD25<sup>hi</sup>Foxp3<sup>+</sup> regulatory T cells. These profiles included increased IL-17A<sup>+</sup>, IL-4<sup>+</sup>, RORC2<sup>+</sup> and GATA3<sup>+</sup>CD4<sup>+</sup> T cell populations. Flow cytometry data was further confirmed using a PCR array since Th17-related genes (IL-17 family members, IL-6, IL-1β and IL-22) and Th2-related (IL-4, IL-13, STAT6) genes were all significantly up-regulated in HO individuals. In addition, stronger <italic>Onchocerca volvulus</italic>-specific Th2 responses, especially IL-13, were observed <italic>in vitro</italic> in hyperreactive individuals when compared to GEO or EN groups. This study provides initial evidence that elevated frequencies of Th17 and Th2 cells form part of the immune network instigating the development of severe onchocerciasis.</p></abstract><abstract abstract-type="summary"><title>Author Summary</title><p>Onchocerciasis, also known as river blindness is a tropical disease causing health and socioeconomic problems in endemic communities especially sub-Saharan Africa. The disease is transmitted by a filarial nematode called <italic>Onchocerca volvulus</italic>, which is spread by the bite of infected <italic>Simulium</italic> black flies. Characteristic disease symptoms include dermatological disorders and eye lesions that can lead to blindness. Two polar forms of clinical manifestations can occur: generalized onchocerciasis (GEO) presenting mild skin disease or the hyperreactive form (HO) exhibiting severe skin disorders and inflammation. The immunological determinants behind such disease polarization are still not fully clarified. Here, we compared the immune profiles of individuals presenting these two polar forms with those of endemic normals (EN): individuals who have no clinical or parasitological evidence of infection despite ongoing exposure to the infectious agent. We could show that HO individuals, in contrast to GEO and EN, simultaneously presented elevated Th17 and Th2 profiles which were accompanied by reduced numbers of Foxp3<sup>+</sup> regulatory T cells. This study provides initial evidence that elevated frequencies of Th17 and Th2 cells form part of the immune network associated with severe onchocerciasis.</p></abstract><funding-group><funding-statement>This work was primarily supported through a grant from the German Research Council (DFG Ho2009/8-2). The study was further supported by the European Commission (grant No. 242121, EPIAF), the BONFOR intramural funding program of the Medical Faculty of Bonn University, and a European Foundation Initiative into African Research in Neglected Tropical diseases (EFINTD) awarded to AYD (grant 1/81995 and 86 52). GK and AK were supported by a fellowship awarded by the German Academic Exchange Committee (DAAD). LEL, AYD and AH are recipients of further DFG funding within the "African-German Cooperation Projects in Infectiology" (HO 2009/10-1). AH is a member of the Excellence Cluster Immunosensation (DFG, EXC 1023) and of the German Centre of Infectious Disease (DZIF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><page-count count="11"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.</p></notes></front></pmc><affiliations><list><country><li>Allemagne</li><li>Ghana</li><li>Royaume-Uni</li><li>Togo</li></country><region><li>District de Cologne</li><li>Rhénanie-du-Nord-Westphalie</li><li>Écosse</li></region><settlement><li>Bonn</li></settlement></list><tree><country name="Allemagne"><region name="Rhénanie-du-Nord-Westphalie"><name sortKey="Katawa, Gnatoulma" sort="Katawa, Gnatoulma" uniqKey="Katawa G" first="Gnatoulma" last="Katawa">Gnatoulma Katawa</name></region><name sortKey="Adjobimey, Tomabu" sort="Adjobimey, Tomabu" uniqKey="Adjobimey T" first="Tomabu" last="Adjobimey">Tomabu Adjobimey</name><name sortKey="Arriens, Sandra" sort="Arriens, Sandra" uniqKey="Arriens S" first="Sandra" last="Arriens">Sandra Arriens</name><name sortKey="Hoerauf, Achim" sort="Hoerauf, Achim" uniqKey="Hoerauf A" first="Achim" last="Hoerauf">Achim Hoerauf</name><name sortKey="Kwarteng, Alexander" sort="Kwarteng, Alexander" uniqKey="Kwarteng A" first="Alexander" last="Kwarteng">Alexander Kwarteng</name><name sortKey="Layland, Laura E" sort="Layland, Laura E" uniqKey="Layland L" first="Laura E." last="Layland">Laura E. Layland</name><name sortKey="Specht, Sabine" sort="Specht, Sabine" uniqKey="Specht S" first="Sabine" last="Specht">Sabine Specht</name><name sortKey="Von Horn, Charlotte" sort="Von Horn, Charlotte" uniqKey="Von Horn C" first="Charlotte" last="Von Horn">Charlotte Von Horn</name></country><country name="Togo"><noRegion><name sortKey="Katawa, Gnatoulma" sort="Katawa, Gnatoulma" uniqKey="Katawa G" first="Gnatoulma" last="Katawa">Gnatoulma Katawa</name></noRegion></country><country name="Ghana"><noRegion><name sortKey="Debrah, Alex Y" sort="Debrah, Alex Y" uniqKey="Debrah A" first="Alex Y." last="Debrah">Alex Y. Debrah</name></noRegion><name sortKey="Batsa, Linda" sort="Batsa, Linda" uniqKey="Batsa L" first="Linda" last="Batsa">Linda Batsa</name><name sortKey="Debrah, Alex Y" sort="Debrah, Alex Y" uniqKey="Debrah A" first="Alex Y." last="Debrah">Alex Y. Debrah</name></country><country name="Royaume-Uni"><region name="Écosse"><name sortKey="W Taylor, David" sort="W Taylor, David" uniqKey="W Taylor D" first="David" last="W. Taylor">David W. Taylor</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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