| 1. |
- Arama, Charles, 1975-, et al.
(författare)
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Interethnic Differences in Antigen-Presenting Cell Activation and TLR Responses in Malian Children during Plasmodium falciparum Malaria
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:3, s. e18319-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Boström, Stéphanie, 1985-, et al.
(författare)
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Biomarkers of Plasmodium falciparum infection during pregnancy in women living in Northeastern Tanzania
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:11, s. e48763-
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Tidskriftsartikel (refereegranskat)abstract
- In pregnant women, Plasmodium falciparum infections are an important cause of maternal morbidity as well as fetal and neonatal mortality. Erythrocytes infected by these malaria-causing parasites accumulate through adhesive interactions in placental intervillous spaces, thus evading detection in peripheral blood smears. Sequestered infected erythrocytes induce inflammation, offering the possibility of detecting inflammatory mediators in peripheral blood that could act as biomarkers of placental infection. In a longitudinal, prospective study in Tanzania, we quantified a range of different cytokines, chemokines and angiogenic factors in peripheral plasma samples, taken on multiple sequential occasions during pregnancy up to and including delivery, from P. falciparum-infected women and matched uninfected controls. The results show that during healthy, uninfected pregnancies the levels of most of the panel of molecules we measured were largely unchanged except at delivery. In women with P. falciparum, however, both comparative and longitudinal assessments consistently showed that the levels of IL-10 and IP-10 increased significantly whilst that of RANTES decreased significantly, regardless of gestational age at the time the infection was detected. ROC curve analysis indicated that a combination of increased IL-10 and IP-10 levels and decreased RANTES levels might be predictive of P. falciparum infections. In conclusion, our data suggest that host biomarkers in peripheral blood may represent useful diagnostic markers of P. falciparum infection during pregnancy, but placental histology results would need to be included to verify these findings.
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| 3. |
- Boström, Stephanie, 1985-, et al.
(författare)
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Changes in the levels of cytokines, chemokines and malaria specific antibodies in response to Plasmodium falciparum infection in children living in sympatry in Mali
- 2012
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875 .- 1475-2875. ; 11, s. 109-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Fulani are known to be less susceptible to Plasmodium falciparum malaria as reflected by lower parasitaemia and fewer clinical symptoms than other sympatric ethnic groups. So far most studies in these groups have been performed on adults, which is why little is known about these responses in children. This study was designed to provide more information on this gap. Methods: Circulating inflammatory factors and antibody levels in children from the Fulani and Dogon ethnic groups were measured. The inflammatory cytokines; interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12p70, tumor necrosis factor (TNF) and the chemokines; regulated on activation normal T cell expressed and secreted (RANTES), monokine-induced by IFN-gamma (MIG), monocyte chemotactic protein (MCP)-1 and IFN-gamma-inducible protein (IP)-10 were measured by cytometric bead arrays. The levels of interferon (IFN)-alpha, IFN-gamma and malaria-specific antibodies; immunoglobulin (Ig) G, IgM and IgG subclasses (IgG1-IgG4) were measured by ELISA. Results: The results revealed that the Fulani children had higher levels of all tested cytokines compared to the Dogon, in particular IFN-gamma, a cytokine known to be involved in parasite clearance. Out of all the tested chemokines, only MCP-1 was increased in the Fulani compared to the Dogon. When dividing the children into infected and uninfected individuals, infected Dogon had significantly lower levels of RANTES compared to their uninfected peers, and significantly higher levels of MIG and IP-10 as well as MCP-1, although the latter did not reach statistical significance. In contrast, such patterns were not seen in the infected Fulani children and their chemokine levels remained unchanged upon infection compared to uninfected counterparts. Furthermore, the Fulani also had higher titres of malaria-specific IgG and IgM as well as IgG1-3 subclasses compared to the Dogon. Conclusions: Taken together, this study demonstrates, in accordance with previous work, that Fulani children mount a stronger inflammatory and antibody response against P. falciparum parasites compared to the Dogon and that these differences are evident already at an early age. The inflammatory responses in the Fulani were not influenced by an active infection which could explain why less clinical symptoms are seen in this group.
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| 4. |
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| 5. |
- Boström, Stéphanie, 1985-
(författare)
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Malaria during pregnancy and childhood : A focus on soluble mediators and neutrophils
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In areas where malaria is endemic, pregnant women and children bear the main burden of severe and life-threatening malarial disease. The aim of this work was to study the impact of Plasmodium falciparum infection on inflammatory responses in pregnant women and children residing in African countries. In paper I we investigated peripheral blood samples from pregnant women, living in Tanzania, for potential biomarkers of P. falciparum infection during pregnancy. We found that IL-10 and IP-10 were potential candidates, which increased upon infection, irrespective of gestational age. In addition, increased IL-10 and IP-10 and decreased RANTES levels were predictive of an infection. In paper II we investigated frequencies of peripheral blood-cell types and biomarkers upon infection, in pregnant women living in Benin, and assessed the predictive values of variables measured at inclusion for pregnancy outcomes at delivery. Higher IL-10 levels distinguished quantitative PCR-detectable, sub-microscopic infections, at inclusion, but not at delivery. Maternal anaemia at delivery was associated with increased numbers of circulating monocytes, Treg cells and IL-10 levels measured at inclusion. In paper III we investigated neutrophil functions in the context of pregnancy malaria in vivo and in vitro. Numbers of circulating neutrophils and IL-8 levels were reduced in the infected women, whilst increased levels of IL-8 were found in placental blood of those infected. In vitro assays suggested migration of neutrophils to infected placentas, which also was supported by histological examinations showing the presence of neutrophils containing hemozoin (Hz), in the infected placenta. Stimulation of neutrophils with various Hz preparations revealed distinct patterns of neutrophil activation. In paper IV we investigated cytokines and malaria-specific antibody titres in children belonging to two African ethnic groups, living in Mali, with known different susceptibility to malaria. The Fulani showed increased cytokines (IL-6, IL-8, IL-12, IFN-α, IFN-γ) and higher titres of malaria-specific antibody subclasses (IgG, IgM and IgG1-IgG3), compared to the Dogon. Taken together, this thesis shows that host biomarkers in peripheral blood may represent useful diagnostic markers for malaria during pregnancy. The neutrophil population was shown to be highly affected by the presence of P. falciparum parasites, suggesting a role for neutrophils during malaria infections. The Fulani, showed increased pro-inflammatory and antibody responses against P. falciparum parasites, as compared to Dogon, and these differences are established already at an early age.
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| 6. |
- Boström, Stephanie, et al.
(författare)
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Neutrophil alterations in pregnancy-associated malaria and induction of neutrophil chemotaxis by Plasmodium falciparum
- 2017
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Ingår i: Parasite immunology (Print). - : Wiley. - 0141-9838 .- 1365-3024. ; 39:6
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Tidskriftsartikel (refereegranskat)abstract
- Pregnancy-associated malaria (PAM) is a severe form of the disease caused by sequestration of Plasmodium falciparum-infected red blood cells (iRBCs) in the developing placenta. Pathogenesis of PAM is partially based on immunopathology, with frequent monocyte infiltration into the placenta. Neutrophils are abundant blood cells that are essential for immune defence but may also cause inflammatory pathology. Their role in PAM remains unclear. We analysed neutrophil alterations in the context of PAM to better understand their contribution to disease development. Pregnant women exposed to Plasmodium falciparum had decreased numbers of circulating neutrophils. Placental-like BeWo cells stimulated with malaria parasites produced the neutrophil chemoattractant IL-8 and recruited neutrophils in a trans-well assay. Finally, immunostaining of a PAM placenta confirmed neutrophil accumulation in the intervillous space. Our data indicate neutrophils may play a role in placental malaria and should be more closely examined as an etiological agent in the pathophysiology of disease.
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| 7. |
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| 8. |
- Ibitokou, Samad A., et al.
(författare)
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Submicroscopic Infections with Plasmodium falciparum during Pregnancy and Their Association with Circulating Cytokine, Chemokine, and Cellular Profiles
- 2014
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Ingår i: Clinical and Vaccine Immunology. - 1556-6811 .- 1556-679X. ; 21:6, s. 859-866
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Tidskriftsartikel (refereegranskat)abstract
- The immunological consequences of pregnancy-associated malaria (PAM) due to Plasmodium falciparum have been extensively investigated in cross-sectional studies conducted at delivery, but there have been very few longitudinal studies of changes due to PAM during pregnancy. We conducted a prospective study in Benin to investigate the changes associated with PAM in groups of 131 and 111 women at inclusion in the second trimester and at delivery, respectively. Infected women were identified by standard microscopic examinations of blood smears and by quantitative PCR (qPCR) assays and were matched to uninfected control women by age, gestational age, and gravidity. We quantified plasma levels of a panel of soluble immunological mediators and other mediators, as well as the frequencies of peripheral blood mononuclear cell types. Comparisons of these variables in infected and uninfected women used multivariate analyses, and we also assessed the predictive value of variables measured at inclusion for pregnancy outcomes at delivery. In multivariate analyses, peripheral plasma interleukin 10 (IL-10) and gamma interferon-inducible protein 10 (IP-10) levels were associated with PAM at inclusion and at delivery, while higher IL-10 levels distinguished qPCR-detectable submicroscopic infections at inclusion but not at delivery. Maternal anemia at delivery was associated with markers of proinflammatory (increased frequency of monocytes) and anti-inflammatory (increased IL-10 levels and increased activation of regulatory T cells) activity measured at inclusion. Elevated concentrations of IL-10 are associated with the majority of P. falciparum infections during pregnancy, but this marker alone does not identify all submicroscopic infections. Reliably identifying such occult infections will require more sensitive and specific methods.
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| 9. |
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| 10. |
- Perdijk, Olaf, et al.
(författare)
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Haptoglobin phenotype prevalence and cytokine profiles during Plasmodium falciparum infection in Dogon and Fulani ethnic groups living in Mali
- 2013
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875 .- 1475-2875. ; 12, s. 432-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Fulani are known to have a lower parasitaemia and less clinical episodes of malaria as compared to the Dogon sympatric ethnic group, living in Mali. Higher circulating malaria-specific antibody titers and increased pro-inflammatory cytokine levels have been shown in Fulani individuals. Several studies have tried to link haptoglobin (Hp) phenotypes with susceptibility to malaria, but without consensus. This study investigated the role of Hp phenotypes and cytokine levels in Dogon and Fulani during asymptomatic Plasmodium falciparum infection. Methods: Two different cohorts were combined in this study: a 2008 cohort with 77 children aged between two and ten years and a 2001 cohort, with 82 children and adults, aged between 11 and 68 years. Hp phenotypes in plasma were measured by Western Blot. Circulating levels of sCD163, IL-6, IL-10, IFN-gamma and TNF were measured by ELISA. Multiple regression analysis was performed to associate Hp phenotypes with cytokine profiles. In addition, in vitro stimulation of peripheral blood mononuclear cells (PBMCs) with Hp:Hb complexes was performed and cytokine release in corresponding supernatants were measured using cytometric bead array. Results: The results revealed a higher Hp2-2 phenotype prevalence in the Fulani. The Hp2-2 phenotype was associated with a higher susceptibility to P. falciparum infection in Dogon, but not in Fulani. In concordance with previous studies, Fulani showed increased inflammatory mediators (IL-6, IFN-gamma) and additionally also increased sCD163 levels compared to Dogon, irrespective of infection. Furthermore, infected individuals showed elevated sCD163 levels compared to uninfected individuals, in both Fulani and Dogon. Multiple regression analysis revealed that the Hp1-1 phenotype was associated with higher levels of TNF and IFN-gamma, as compared to the Hp2-2 phenotype. In vitro stimulation of PBMCs with Hb:Hp1-1 complexes resulted in a pro-inflammatory cytokine profile, whilst stimulation with Hb: Hp2-2 complexes showed a more balanced profile. Conclusions: Ethnicity might be an important confounder on the Hp phenotype-dependent susceptibility to malaria and future studies could consider taking this into account when designing new immunological studies. Although, the relatively small sample size used in this study warrens for precautions in the interpretation of the data and these findings should ideally be validated in a bigger cohort.
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