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Plasmodium falciparum-mediated modulation of innate immune cells: responses and regulation
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Plasmodium falciparum (P. falciparum) infection modulates the response of innate immune cells. The aim of this work was to study the impact of P. falciparum infection and P. falciparum-derived molecules on the response of dendritic cells (DC) and monocytes.

In paper I we investigated the effects of natural hemozoin (nHZ), a P. falciparum-derived molecule, on the phenotype and functionality of DC. We found that exposure to nHZ impaired the capacity of DC to mature. Paper II is a follow-up on paper I, where the underlying transcriptional events preceding the nHZ-induced impairment of DC maturation were investigated. More specifically, we examined the involvement of certain transcription factors, subunits of chromatin remodeling complexes and histone modifications in the regulation of DC maturation. Our findings suggest that nHZ-exposure of DC does not lead to recruitment or enrichment of molecules needed for transcriptional activation. In paper III we investigated P. falciparum effects in vivo in sympatric ethnic groups with differential susceptibility towards P. falciparum infection living in Burkina Faso. The aim of this study was to establish the transcriptional networks underlying the relatively better protection against P. falciparum infection observed in the Fulani ethnic group compared to other sympatric ethnic groups. Our findings reveal differential gene expression in monocytes of infected Fulani compared to uninfected Fulani and the difference concerned multiple classes of genes including signal transduction, immunological responses and chromatin remodelers. The results provide new aspects on molecules and regulatory mechanisms that are involved in the relatively more protective response against P. falciparum infection.

Taken together, the work presented in this thesis leads to a deeper understanding of the P. falciparum-induced modulation of responses of innate immune cells and the underlying mechanisms possibly regulating those responses.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2016. , 56 p.
Keyword [en]
Plasmodium falciparum, hemozoin, innate immune cells, sympatric ethnic groups
National Category
Biological Sciences
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-126138ISBN: 978-91-7649-296-3 (print)OAI: oai:DiVA.org:su-126138DiVA: diva2:897432
Public defence
2016-03-17, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrheniusväg 20 A, Stockholm, 09:30 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Manuscript.

Available from: 2016-02-23 Created: 2016-01-25 Last updated: 2017-02-17Bibliographically approved
List of papers
1. Malaria-derived hemozoin exerts early modulatory effects on the phenotype and maturation of human dendritic cells
Open this publication in new window or tab >>Malaria-derived hemozoin exerts early modulatory effects on the phenotype and maturation of human dendritic cells
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2016 (English)In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 18, no 3, 413-423 p.Article in journal (Refereed) Published
Abstract [en]

Plasmodium falciparum (P. falciparum)-induced effects on the phenotype of human dendritic cells (DC) could contribute to poor induction of long-lasting protective immunity against malaria. DC ability to present antigens to naïve T cells, thus initiating adaptive immune responses depends on complex switches in chemokine receptors, production of soluble mediators and expression of molecules enabling antigen-presentation and maturation. To examine the cellular basis of these processes in the context of malaria, we performed detailed analysis of early events following exposure of human monocyte-derived DC to natural hemozoin (nHZ) and the synthetic analog of its heme core, β-hematin. DC exposed to either molecule produced high levels of the inflammatory chemokine MCP-1, showed continuous high expression of the inflammatory chemokine receptor CCR5, no upregulation of the lymphoid homing receptor CCR7 and no cytoskeletal actin redistribution with loss of podosomes. DC partially matured as indicated by increased expression of major histocompatibility complex (MHC) class II and CD86 following nHZ and β-hematin exposure, however there was a lack in expression of the maturation marker CD83 following nHZ but not β-hematin exposure. Overall our data demonstrate that exposure to nHZ partially impairs the capacity of DC to mature, an effect in part differential to β-hematin.

National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-125622 (URN)10.1111/cmi.12521 (DOI)000370643500009 ()26348250 (PubMedID)
Available from: 2016-01-15 Created: 2016-01-15 Last updated: 2017-11-30Bibliographically approved
2. Exposure to Plasmodium falciparum-derived hemozoin leads to impairment of transcriptional activation upon dendritic cell maturation
Open this publication in new window or tab >>Exposure to Plasmodium falciparum-derived hemozoin leads to impairment of transcriptional activation upon dendritic cell maturation
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(English)Manuscript (preprint) (Other academic)
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-125623 (URN)
Available from: 2016-01-15 Created: 2016-01-15 Last updated: 2016-01-25Bibliographically approved
3. Transcriptome and DNA methylome analysis of two sympatric ethic groups with differential susceptibility to Plasmodium falciparum infection living in Burkina Faso
Open this publication in new window or tab >>Transcriptome and DNA methylome analysis of two sympatric ethic groups with differential susceptibility to Plasmodium falciparum infection living in Burkina Faso
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(English)Manuscript (preprint) (Other academic)
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-125850 (URN)
Available from: 2016-01-19 Created: 2016-01-19 Last updated: 2016-01-25Bibliographically approved

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