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Interethnic Differences in Antigen-Presenting Cell Activation and TLR Responses in Malian Children during Plasmodium falciparum Malaria
Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 3, e18319- p.Article in journal (Refereed) Published
Abstract [en]

The Fulani ethnic group from West Africa is relatively better protected against Plasmodium falciparum malaria as compared to other sympatric ethnic groups, such as the Dogon. However, the mechanisms behind this lower susceptibility to malaria are largely unknown, particularly those concerning innate immunity. Antigen-presenting cells (APCs), and in particular dendritic cells (DCs) are important components of the innate and adaptive immune systems. Therefore, in this study we investigated whether APCs obtained from Fulani and Dogon children exhibited differences in terms of activation status and toll-like receptor (TLR) responses during malaria infection. Lower frequency and increased activation was observed in circulating plasmacytoid DCs and BDCA-3+ myeloid DCs of infected Fulani as compared to their uninfected counterparts. Conversely, a higher frequency and reduced activation was observed in the same DC subsets obtained from peripheral blood of P. falciparum-infected Dogon children as compared to their uninfected peers. Moreover, infected individuals of both ethnic groups exhibited higher percentages of both classical and inflammatory monocytes that were less activated as compared to their non-infected counterparts. In line with APC impairment during malaria infection, TLR4, TLR7 and TLR9 responses were strongly inhibited by P. falciparum infection in Dogon children, while no such TLR inhibition was observed in the Fulani children. Strikingly, the TLR-induced IFN-γ release was completely abolished in the Dogon undergoing infection while no difference was seen within infected and non-infected Fulani. Thus, P. falciparum infection is associated with altered activation status of important APC subsets and strongly inhibited TLR responses in peripheral blood of Dogon children. In contrast, P. falciparum induces DC activation and does not affect the innate response to specific TLR ligands in Fulani children. These findings suggest that DCs and TLR signalling may be of importance for the protective immunity against malaria observed in the Fulani.

Place, publisher, year, edition, pages
2011. Vol. 6, no 3, e18319- p.
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-60418DOI: 10.1371/journal.pone.0018319ISI: 000289057200056OAI: oai:DiVA.org:su-60418DiVA: diva2:434881
Note
Publikationen har totalt 9 författare, Charles Arama et al.Available from: 2011-08-16 Created: 2011-08-16 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Characterization of antigen-presenting cell function in vitro and ex vivo
Open this publication in new window or tab >>Characterization of antigen-presenting cell function in vitro and ex vivo
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Long-term protective immunity depends on proper initiation of professional antigen-presenting cells (APCs). Autoimmune disorders and certain infections can cause disease through modulation of APCs and thereby affecting the outcome of these diseases. This work aimed to investigate the behaviour of different APC subsets during conditions known to cause improper immune responses.

In Paper I, the effects of an anti-inflammatory compound called Rabeximod, intended for treatment of rheumatoid arthritis were investigated on different subsets of APCs. The results showed that Rabeximod affected the differentiation and behaviour of inflammatory subsets of dendritic cells (DCs) and macrophages while no effects were observed on anti-inflammatory subsets. Our findings suggest that Rabeximod acts by inhibiting the functionality of inflammatory subsets of APCs.

In Paper II, the effects of different malaria derived stimuli such as hemozoin (Hz) and infected red-blood cells (iRBCs) on monocyte-derived dendritic cells (MoDCs) were investigated. Both stimuli triggered activation and migration of MoDCs. MoDCs exposed to iRBCs induced allogeneic T-cell proliferation while those exposed to Hz did not. These results indicate that different malaria derived stimuli may differently affect DCs and that this could lead to improper and inefficient T-cell activation.

In Paper III, innate aspects of malarial immunity were compared in children from two sympatric ethnic groups. We observed decreased activation of APCs and severely supressed TLR responses in Dogon children as compared to Fulani. This may indicate an important role for TLR and APC activation in the Fulani, known to be better protected against malaria than the Dogon.

In summary, detailed knowledge of APC activation will be helpful in the understanding of specific effector immune responses. This could in turn, improve treatment of inflammatory disorders as well as the generation of efficient vaccines against infectious diseases.

Place, publisher, year, edition, pages
Stockholm: The Wenner-Gren Institute, Stockholm University, 2011. 100 p.
Keyword
Immunology, Antigen presentation, Dendritic Cells, Macrophages, Toll-like receptors, Malaria
National Category
Microbiology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-60433 (URN)978-91-7447-344-5 (ISBN)
Public defence
2011-09-24, DeGeersalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2011-09-01 Created: 2011-08-16 Last updated: 2011-08-18Bibliographically approved
2. Novel immunization strategies and interethnic differences in response to malaria infection
Open this publication in new window or tab >>Novel immunization strategies and interethnic differences in response to malaria infection
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A better understanding of the role of antigen-presenting cells (APCs) in host resistance to malaria is essential to unravel the complex interactions between the host and the parasite. This would improve the design of malaria vaccines.

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) has been utilized as a vector to deliver vaccine candidate antigens. We assessed the immunogenicity of a recombinant BCG-expressing (BCG-CS) circumsporozoite protein (CSp) as a malaria vaccine candidate. Immunization of BALB/c mice with BCG-CS augmented the numbers of dendritic cells (DCs) in draining lymph nodes and in the spleen. The activation markers MHC-class-II, CD40, CD80, and CD86 on DCs were significantly upregulated by BCG-CS as compared to wild-type BCG (wt-BCG). In vitro stimulation of bone marrow-derived DCs and macrophages with BCG-CS induced IL-12 and TNF-α production. BCG-CS induced higher phagocytic activity in macrophages as compared to wt-BCG. Finally, BCG-CS induced CSp-specific antibodies and IFN-γ-producing memory cells. Taken together, we found that BCG-CS is highly efficient in activating innate immune responses and could effectively prime the adaptive immune system.

Heterologous prime–boost approaches using vectors are optimal strategies to improve a broad and prolonged immunogenicity of malaria vaccines. We have demonstrated in BALB/c mice that priming with a replication-defective human adenovirus serotype 35 (Ad35) vector encoding CSp (Ad35-CS), followed by boosting with BCG-CS, maintained antibody responses and significantly increased levels of long-lived plasma cells (LLPC) and IFN-g-producing cells in response to CSp peptides. The increased number of IFN-g-producing cells induced by the combination of Ad35-CS/BCG-CS and the sustained type 1 antibody profile, together with high levels of LLPCs, may be essential for the development of long-term protective immunity against liver-stage parasites.

Fulani and Dogon, two sympatric ethnic groups living in northeastern Mali, are characterized by a marked difference in the susceptibility to P. falciparum malaria. We investigated whether APCs obtained from Fulani and Dogon children exhibited differences in terms of activation status and toll-like receptor (TLR) responses during malaria infection. We observed decreased activation of APCs and markedly suppressed TLR responses in Dogon children as compared to Fulani. These findings suggest that APCs and TLR signaling may be of importance for the protective immunity against malaria observed in the Fulani.

In conclusion, this thesis provides new insights that could facilitate a rational design of novel vaccines against malaria. Furthermore, the results elicit some immunological bases of the APC activation underlying the differences in host susceptibility to malaria infections.

Place, publisher, year, edition, pages
Stockholm: The Wenner-Gren Institute, Stockholm University, 2012. 93 p.
Keyword
Malaria, Immunization, Ethnic groups, vaccines
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-72288 (URN)978-91-7447-450-3 (ISBN)
Public defence
2012-03-15, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: In Press. Paper 2: Manuscript.Available from: 2012-02-22 Created: 2012-02-06 Last updated: 2012-02-08Bibliographically approved

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