Elevated IL-17 levels in semi-immune anaemic mice infected with Plasmodium berghei ANKA
© The Author(s) 2018
Received: 26 November 2017
Accepted: 3 March 2018
Published: 17 April 2018
Alterations in inflammatory cytokines and genetic background of the host contribute to the outcome of malaria infection. Despite the promising protective role of IL-17 in infections, little attention is given to further understand its importance in the pathogenesis of severe malaria anaemia in chronic/endemic situations. The objective of this study, therefore, was to evaluate IL-17 levels in anaemic condition and its association with host genetic factors.
Two mice strains (Balb/c and CBA) were crossed to get the F1 progeny, and were (F1, Balb/c, CBA) taken through 6 cycles of Plasmodium berghei (ANKA strain) infection and chloroquine/pyrimethamine treatment to generate semi-immune status. Cytokine levels and kinetics of antibody production, CD4+CD25+T regulatory cells were evaluated by bead-based multiplex assay kit, ELISA and FACs, respectively.
High survival with high Hb loss at significantly low parasitaemia was observed in Balb/c and F1. Furthermore, IgG levels were two times higher in Balb/c, F1 than CBA. While CD4+CD25+ Treg cells were lower in CBA; IL-4, IFN-γ, IL-12α and IL-17 were significantly higher (p < 0.05) in Balb/c, F1.
In conclusion, elevated IL-17 levels together with high IL-4, IL-12α and IFN-γ levels may be a marker of protection, and the mechanism may be controlled by host factor (s). Further studies of F2 between the F1 and Balb/c will be informative in evaluating if these genes are segregated or further apart.
Malaria, a protozoan disease caused by parasites of the genus Plasmodium, continues to be a major public health threat worldwide. There are currently six known species (Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium knowlesi, Plasmodium ovale wallikeri and P. o. curtisi) , that cause malaria in human. Of these Plasmodium species, P. falciparum is the leading cause of death in the tropics. According to the latest World Health Organization estimates, there were 212 million cases of malaria in 2015 and 429,000 deaths due to P. falciparum . Acquiring immunity to malaria is dependent on age and repeated infections an individual has had. Therefore, in endemic areas, adults usually show a symptomatic form of the disease and in some instances, are chronically infected with low parasitaemias . In areas with high transmission of malaria, children under 5 are particularly susceptible to infection, illness and death; more than two-thirds (70%) of all malaria deaths occur in this age group. Most of the deaths are due to complications from the severe forms of malaria, i.e. severe malaria anaemia (SMA), cerebral malaria and intra-vascular haemolysis (IVH) . Between 2010 and 2015, the under-5 malaria death rate fell by 29% globally. However, malaria remains a major killer of children under 5 years old, taking the life of a child every 2 min.
Several studies have reported on the role played by anti- and pro-inflammatory cytokines in the pathogenesis of malaria [5–11]. Furthermore, high levels of some pro-inflammatory cytokines (e.g., IFN-γ and TNF) have been observed to be protective [10, 12]. Though little attention has been given to IL-17 in malaria infection few studies have shown that IL-17 is needed for IL-23 to offer protection against Plasmodium berghei (NK65 strain) infection ; significant expansion of IL-17 producing cells correlated to a pro-inflammatory cytokine profile in Plasmodium vivax infection ; high IL-17 is associated with high mortality in P. berghei (ANKA strain) infections . In addition to its role in host defence against extracellular bacterial infection, IL-17 has been shown to be important in protection against fungal and parasitic infection. IL-17R-deficient mice were reported to have increased kidney fungal burden and decreased survival upon Candida albicans challenge . The paradox about IL-17 is that it is both protective and pathological. The balance between protection and pathologic consequences was seen in the association between Helicobacter pylori, IL-17 and damage to gastric mucosa that leads to ulceration . IL-17 has been shown to be involved in central nervous system (CNS) diseases . In that study, the evidence supplied indicates that inhibiting the function of the IL-17 cytokine family could have a beneficial effect on pathogenic conditions in the CNS.
Anaemia in malaria has been extensively studied and documented. Mechanisms proposed to be involved in the anaemia in malaria have ranged from rupture of infected red blood cell (iRBC) due to parasite proliferation , immune mediated dependent destruction of RBC (antibody, complement, cytokines, cellular) [20–24] to suppression of the bone marrow . A study has shown variation of IL-17 levels in different semi-immune mice strains implicating a role of IL-17 in RBC loss due to Plasmodium infection . Recent reports have also shown IL-17 relationship with SMA [26, 27]. Apart from these studies linking IL-17 with haemoglobin (Hb) loss, other studies have shown IL-17 to be involved in multiple organ dysfunction , and also found to be associated with higher risk in developing cerebral malaria (CM) . Since previous studies have reported the recovery of a group of semi-immune mice at low parasitaemia [23, 24], and also for the fact that IL-17 was implicated in one study , it is hypothesized that IL-17 is involved in the recovery/protection of the semi-immune mice at low Hb levels. The aim of this study, therefore, was to assess levels of IL-17 in anaemic condition as well as evaluate its association with host genetic factors. A significance for this current study is that change in levels of IL-17 and its association with other immunological parameters can be exploited as candidates for disease biomarkers and possible therapy in malaria anaemia.
Mice, infection and generation of semi-immune status
Measurement of antibody titer using ELISA
Immunoglobulin G and its subtype antibody responses were assessed by ELISA from the sera collected after the fifth cycle. Briefly, 96-well plates were coated with 100 μL of 0.5 μg/mL of P. berghei crude antigen in coating buffer and kept overnight at 4 °C. Plates were washed three times with 400 μL/well of 0.05% Tween-PBS (phosphate-buffered saline) and then blocked for nonspecific binding using 340 μL/well of 0.1% blocking reagent (Roche Diagnostics, Mannheim, Germany) for 1 h at 37 °C. Plates were washed three times with 400 μL/well of 0.05% Tween-PBS and 100 μL of serially diluted pooled sera (1:80) was added and incubated at 37 °C for 3 h. Plates were then washed five times with 400 μL/well of 0.05% Tween-PBS, and 100 μL of horseradish peroxidase (HRP)-conjugated goat anti-mouse IgG and subclasses IgG1, IgG2a and IgG3 (Southern Biotechnology, Birmingham, AL) diluted with blocking buffer (1:2500) was added and incubated for 1 h at room temperature. Plates were washed 5 times with 400 μL/well of 0.05% Tween-PBS and antigen–antibody reaction was visualized by the addition of 50 μL/well of 3, 3′, 5, 5′-tetramethylbenzidine (TMB) (Vector Laboratories, CA, USA). The colour development reaction was stopped after 30 min by adding 50 μL of 1 N of H2SO4, and the absorbance was measured in an automated plate reader (Bio-Rad, Hercules, CA) at 450 nm.
Analysis of splenocytes populations by flow cytometry (FACs analysis)
Spleens were excised from individual mouse during the sixth cycle of infection without treatment (days zero for the mice strains used in the experiment; days 12 for CBA; days 16 and 28 for F1 and Balb/c). The frequency of CD4(+) CD25(+) Treg cell was measured by FACS. Analysis of cell surface markers (CD3, CD4, and CD25) from BD Pharmingen (BD Biosciences San Jose, California, USA), intracellular cytokine (Foxp3) expression recognition were done. Fluorescent-conjugated monoclonal antibodies, and isotype control were purchased from Biolegend (San Diego, California, USA). Purified Rat Anti Mouse CD16/CD32 antibody was purchased from BD Biosciences Pharmingen (San Jose, California, USA) to block non-antigen-specific binding of immunoglobulins to the FcγIII and FcγII. Cells were stained with CD3, CD4, CD25 surface markers. Cells were then fixed for 20 min at 4 °C in 4% paraformaldehyde, washed and permeabilized in the presence of 0.1% saponin. Finally, re-suspended cells were incubated for 30 min at 4 °C in the presence of optimal concentrations of Foxp3 and conjugated rat IgG2a isotype controls were used for the intracellular staining. The Tregs frequency was evaluated by flow cytometry using Becton Coulter Gallios, Flow Cytometer (Beckman Coulter, Inc.), and data were analysed using Kaluza software.
Inflammatory cytokines measurement
This method as described previously  was done according to the manufacturer’s instructions. Cytokines measurement was done using Procarta Mouse Cytokine Assay Kit plex according to manufacturer’s instructions (Luminex, Affymetrix). Briefly, after the reading buffer was used to wet the plate, it (the plate with the reading buffer) was incubated at room temperature for 5 min, and later filtered. To each well was added antibody beads (50 μL), then filtered and washed once with washing buffer (150 μL). This procedure was followed by the addition of 25 μL of serum standard buffer to all the sample wells, followed with the addition of equal volume (25 μL) of serum to each well, and then incubated for 60 min at room temperature. Washing was done three times, later followed with the addition of 25 μL premixed detection, and then incubated for 30 min on the shaker at room temperature. Washing and filtration was done three times afterwards. One hundred and fifty (150) μL of washing buffer was used during each wash. Washing and filtration was done three times after incubation was done for 30 min with Streptavidin-PE (50 μL).The plate was prepared for analysis after the third wash, with the addition of 120 μL reading buffer.
GraphPad Prism Version5.00 for Windows, GraphPad Software, San Diego California, USA, [Graph pad prism version 5.0 for Windows; http://www.graphpad.com] was used for the data analysis. Data are expressed as the mean with standard deviation (SD) unless otherwise stated. To ensure normal distribution, data were log transformed before one-way analysis of variance (ANOVA, with Tukey’s post-test, two tailed), were performed. The differences of means were considered statistically significant if p < 0.05.
The Fundamental Guidelines for Proper Conduct of Animal Experiment and Related Activities in Academic Research Institutions under the jurisdiction of the Ministry of Education, Culture, Sports, Science and Technology, Japan (Notice no. 71) was strictly followed during the study. All efforts were made to humanely minimize animal suffering. The Nagasaki University, Board of Animal Research approved all animal experiments, according to Japanese Guideline for use of Experimental animals (Permit Number 0811130716).
Mortality, parasitaemia-time course, profile of haemoglobin loss and erythropoietic response in the semi-immune ice strains
Hb reduction, peak reticulocyte count, and peak parasitaemia levels in the semi-immune mice strain on day minimum Hb was observed
Mean Hb reduction (SD)
Mean parasitaemia, % (SD)
Mean reticulocyte level, % (SD)
Mean of reticulocyte level/Hb reduction (SD)
Mean period, day (SD) at which Hbm was observed
Antibody levels, T cell responses and cytokines levels in the semi-immune mice strains
Cytokine levels in the semi-immune mice of Balb/c, F1 and CBA
Mouse strains (number)
F1 (n = 5)
Balb/c (n = 5)
CBA (n = 5)
Uninfected control (3)
TNF-α: IL-10 (SD)
Studies have shown that malaria anaemia at low parasitaemia occurs in malaria endemic areas as individuals have become immune or semi-immune [23, 33]. Mice studies have modeled recovery/survival from malaria infection, and factors associated with that include destruction of uninfected RBC (uRBC) [23, 32] and elevated levels of anti- erythropoietin antibodies  among others; and in humans elevated levels of some pro-inflammatory cytokines (e.g., IFN-γ and TNF) have been observed to be protective [10, 12]. High levels of IL-17 cytokines have been observed in SMA cases [26, 27], but no studies of IL-17 association with recovery from plasmodium infection at low Hb in the semi-immune has been explored even though IL-17 has been noted to be protective in some infections . Results from this study indicates that elevated levels of IL-17 together with IL-4, IL-12 and IFN-γ are observed in semi-immune mice that recovered from malaria infections via Hb loss, and certain genes may be involved.
Crossing of Balb/c and CBA to get the F1 generation was to assess the role of a possible candidate gene that might be responsible in eliciting destruction of high amount of uRBC via some immune mediated mechanism resulting in malaria anaemia. The survival (Fig. 2), extent of Hb loss (Table 1) and effect of parasitaemia on Hb loss (Fig. 5) were similar in the Balb/c and F1 semi-immune mice. These observations mirror a previous report  by the authors, and further implicating an immune mediated mechanism (elevated levels of anti-erythropoietin antibodies) resulting in chronic low Hb , suggesting two ways in lowering the Hb, which are RBC destruction (both infected and uninfected) and suppression of erythropoiesis. These findings strengthen the consistency and reproducibility in earlier studies by the authors and the hypothesis generated that low Hb observed in malaria infections is partly due to high destruction of uRBC, which is likely controlled by a gene(s), and was passed on from Balb/c to the F1 progeny. The chronic low Hb creates an environment of limited iron bio-availability for the Plasmodium parasite to proliferate, hence the recovery at low Hb (Hm).
High parasitaemia in CBA resulting in their death might be explained by the lack of efficient control of plasmodium parasites growth. This is stemmed from the observation of relatively low IgG subtypes in CBA semi-immune mice. IgG subtypes were, however, higher in the Balb/c and F1 semi-immune mice strains. These IgG subtypes are important in enhancing the efficient control of Plasmodium parasitaemia either through the immune mechanism of RBC destruction and/or direct destruction of the infected RBCs in addition to the suppression of erythropoiesis. Furthermore, studies have shown that Th1 cytokine response made up TNF, IFN-γ, IL-1 and IL-6 are required for the activation of immune cells against malaria infection [34, 35]. It is postulated that CBA attempts to fight the high parasitaemia via CD3 T cells in association with CD4 T cells, a helper T cell. The higher CD3 T cells recorded for CBA at low Hb (Hm) suggests an auto-immune involvement. Anti-CD3 antibodies have been shown to ameliorate the symptoms of auto-immune disorders . This suggests that CD3 levels are important in auto-immune activities. Thus, much higher levels of CD3 was expected in Balb/c and F1. However, the converse is the case. The extent of auto-immune involvement in CBA to lower the parasitaemia needs to be explored. It is postulated that the parasite growth in the CBA initiates a sustained high level of CD4 T cells from Day 0 till minimum Hb is observed (Hm, Figs. 7, 8). This is not surprising as T helper cells (identified by CD4 marker), will obviously be involved in such immune activity. Balb/c and F1 on the other hand use a concerted effort of higher and sustained level of IgG levels together with regulatory cells at D0. The T regulatory cells (CD4+CD25+), then get lowered at Hm, where IgG subtypes gets higher to keep the parasite at bay (low or zero parasitaemia by microscopy). After the Hm (i.e. at recovery, Rec), T regulatory cells increases again, which is necessary to limit and control the hyper immune activity. With the high IL-17 levels in Balb/c and F1 at the minimum Hb point, it is possible that IL-17 is involved in mobilizing IgG subtypes to limit rapid Plasmodium proliferation in the Balb/c and F1. Furthermore, IL-17 may act to generate cellular foci to contain chronic infection as modelled in the semi-immune mice used in this and other studies [23, 24, 32] and also observed in the malaria endemic areas. Interestingly, two recent studies reported a significantly lower IL-17 in SMA cases compared with mild malaria anaemia (MMA) [26, 27]. This is in contrast with the studies of higher IL-17 levels in the anaemic semi-immune mice. The current study mirrors a chronic situation at recovery, and this might contribute to the differences observed in this current study and the other two [26, 27]. Nevertheless, the results presented here can be relevant for malaria infection in general, which has been explored in other studies [13–15].
Meanwhile some studies report of high plasma levels of IL-17 with increase in mortality , and low levels of IL-10 and TGF-β due to Plasmodium infection . However, this current study reports of significantly higher IL-17 as well as high IL-12, IL-4 and IFN-γ in the Balb/c and F1 semi-immune mice with zero/low parasitaemia (by microscopy) during Rec. The high IL-17 level and high survival reported in this current study is at variance with what is reported by . It is not clear if the model of semi-immune status described in the current study might be a contributory factor. Furthermore, it is suspected that high IL-17 levels alone is not enough to contribute in the high survival, but in association with high levels of IL-12, IL-4 and IFN-γ. IL-10 in the current study was similar in the three mice strains used in the study. It is not clear what might have resulted in the differences between the results presented here and that of . It is tempting to speculate that pregnancy might have affected the extent of cytokine production, as pregnant mice were used in that study by . Significantly high levels of IL-4, IL-12 and IFN-γ together with IL-17 in the anaemic mice (Balb/c and F1) reported in the current study, suggests suppression of erythropoiesis and/or destruction of uRBC leading to the low Hb consistently observed. Similar observation was made in an earlier report concerning high levels of IFN-γ association with low Hb [24, 38]. Further studies are needed to clarify the mechanisms involved in this association. Similar levels of IL-10, TNF among the semi-immune anaemic mice (Balb/c and F1) in the current study was also observed in an earlier study . This observation was surprising since TNF and IL-10 are thought to contribute to the degree of anaemia in children with falciparum malaria [39, 40]. The results presented in this report also suggests that IL-1α, a protective cytokine, is not associated with protection in Balb/c and F1, even though an association of IL-1α with protection has been reported previously . Finally, since more of IL-12, IFN-γ (Th1 cytokines) were significantly higher in the semi-immune anaemic mice (Balb/c and F1), it is hypothesized that at low Hb (Hbm) mechanism of recovery or protection from the Plasmodium infection is shifted towards Th1 response.
From the data presented here it can concluded that certain genes are contributing to the extent of survival (protection) against Plasmodium infection through low Hb. And the mechanism employed in this protection against the Plasmodium infection may be more of a Th1 response at low Hb (Hbm) where F1 and Balb/c start clearing the parasites without treatment (Rec). Despite the strengths in this study, there were some limitations. These were the fact that pooled sera were used in analysing the IgG subtypes as well as T cell types analysis was done on pooled splenocytes. Also, the fact that Th17 cells were not assessed. Finally, even though the small number of CBA mice used might be a limitation, the results can still be valuable considering the fact that similar results were obtained in repeat experiments in this study. These can be areas for further studies. Further studies looking into the role of IL-17 in Balb/c will be informative in understanding the promising protective role of IL-17. In addition, further studies of F2 between the F1 and Balb/c will also be informative in evaluating if these genes are segregated or further apart.
NTH and KH designed the work with GKH. TY, MNS and MSC carried out animal experiment with GKH. GKH, MNS, MK, and MSC designed and carried out the ELISA and Flow Cytometry. GKH drafted the manuscript with MNS, NTH and KH, who were also involved with data analysis as well extensive revision of the manuscript for intellectual content. All authors read and approved the final manuscript.
GKH is a recipient of Ph.D. scholarship from the Japanese Government Ministry of Education, Science, Sports, and Culture. This work was supported in part by a “Grand-in-Aid for Young Scientists” (17301870, 2008–2009 for NTH) from Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and was supported in part by a “Grant-in-Aid for Scientific Research” from Nagasaki University to NTH (2007–2009). This study was also supported in part by Global COE Program for KH (2008–2012). This study was conducted (in part) at the Joint Usage/Research Center on Tropical Disease, Institute of Tropical Medicine, Nagasaki University, Japan.
The authors declare that they have no competing interests.
Availability of data and materials
The datasets supporting the findings of this article are available in this manuscript.
Ethics approval and consent to participate
The Fundamental Guidelines for Proper Conduct of Animal Experiment and Related Activities in Academic Research Institutions under the jurisdiction of the Ministry of Education, Culture, Sports, Science and Technology, Japan (Notice No. 71) was strictly followed during the study. All efforts were made to humanely minimize animal suffering. The Nagasaki University, Board of Animal Research approved all animal experiments, according to Japanese Guideline for use of Experimental animals (Permit Number 0811130716). Ethical approval for the study by the Board of Animal Research, Nagasaki University, Japan covers the consent by the study subjects to participate and for the publication of the manuscript and any accompanying image.
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- Calderaro A, Piccolo G, Gorrini C, Rossi S, Montecchini S, Dell’Anna ML, et al. Accurate identification of the six human Plasmodium spp. causing imported malaria, including Plasmodium ovale wallikeri and Plasmodium knowlesi. Malar J. 2013;12:321.View ArticlePubMedPubMed CentralGoogle Scholar
- Malaria, fact sheet. 2017. http://www.who.int/mediacentre/factsheets/fs094/en/. Accessed 20 Sept 2017.
- Mackillop L, Williamson C. Liver disease in pregnancy. Postgrad Med J. 2010;86:160–4.View ArticlePubMedGoogle Scholar
- Olliaro P. Mortality associated with severe Plasmodium falciparum malaria increases with age. Clin Infect Dis. 2008;47:158–60.View ArticlePubMedGoogle Scholar
- Miller KL, Silverman PH, Kullgren B, Mahlmann LJ. Tumor necrosis factor alpha and the anemia associated with murine malaria. Infect Immun. 1989;57:1542–6.PubMedPubMed CentralGoogle Scholar
- Mirghani HA, Eltahir HG, A-Elgadir TM, Mirghani YA, Elbashir MI, Adam I. Cytokine profiles in children with severe Plasmodium falciparum malaria in an area of unstable malaria transmission in central Sudan. J Trop Pediatr. 2011;57:392–5.View ArticlePubMedGoogle Scholar
- Lyke KE, Burges R, Cissoko Y, Sangare L, Dao M, Diarra I, et al. Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1beta), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in Malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls. Infect Immun. 2004;72:5630–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Peyron F, Caux-Menetrier C, Roux-Lombard P, Niyongabo T, Aubry P, Deloron P. Soluble intercellular adhesion molecule-1 and E-selectin levels in plasma of falciparum malaria patients and their lack of correlation with levels of tumor necrosis factor alpha, interleukin 1 alpha (IL-1 alpha), and IL-10. Clin Diagn Lab Immunol. 1994;1:741–3.PubMedPubMed CentralGoogle Scholar
- Kurtzhals JA, Adabayeri V, Goka BQ, Akanmori BD, Oliver-Commey JO, Nkrumah FK, et al. Low plasma concentrations of interleukin 10 in severe malarial anaemia compared with cerebral and uncomplicated malaria. Lancet. 1998;351:1768–72.View ArticlePubMedGoogle Scholar
- Dodoo D, Omer FM, Todd J, Akanmori BD, Koram KA, Riley EM. Absolute levels and ratios of proinflammatory and anti-inflammatory cytokine production in vitro predict clinical immunity to Plasmodium falciparum malaria. J Infect Dis. 2002;185:971–9.View ArticlePubMedGoogle Scholar
- Kwiatkowski D. Tumour necrosis factor, fever and fatality in falciparum malaria. Immunol Lett. 1990;25:213–6.View ArticlePubMedGoogle Scholar
- Luty AJ, Lell B, Schmidt-Ott R, Lehman LG, Luckner D, Greve B, et al. Interferon-gamma responses are associated with resistance to reinfection with Plasmodium falciparum in young African children. J Infect Dis. 1999;179:980–8.View ArticlePubMedGoogle Scholar
- Ishida H, Imai T, Suzue K, Hirai M, Taniguchi T, Yoshimura A, et al. IL-23 protection against Plasmodium berghei infection in mice is partially dependent on IL-17 from macrophages. Eur J Immunol. 2013;43:2696–706.View ArticlePubMedGoogle Scholar
- Bueno LL, Morais CG, Lacerda MV, Fujiwara RT, Braga EM. Interleukin-17 producing T helper cells are increased during natural Plasmodium vivax infection. Acta Trop. 2012;123:53–7.View ArticlePubMedGoogle Scholar
- Keswani T, Bhattacharyya A. Differential role of T regulatory and Th17 in Swiss mice infected with Plasmodium berghei ANKA and Plasmodium yoelii. Exp Parasitol. 2014;141:82–92.View ArticlePubMedGoogle Scholar
- Huang W, Na L, Fidel PL, Schwarzenberger P. Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis. 2004;190:624–31.View ArticlePubMedGoogle Scholar
- Cooper AM. IL-17 and anti-bacterial immunity: protection versus tissue damage. Eur J Immunol. 2009;39:649–52.View ArticlePubMedPubMed CentralGoogle Scholar
- Waisman A, Hauptmann J, Regen T. The role of IL-17 in CNS diseases. Acta Neuropathol. 2015;129:625–37.View ArticlePubMedGoogle Scholar
- Glenister FK, Coppel RL, Cowman AF, Mohandas N, Cooke BM. Contribution of parasite proteins to altered mechanical properties of malaria-infected red blood cells. Blood. 2002;99:1060–3.View ArticlePubMedGoogle Scholar
- McGilvray ID, Serghides L, Kapus A, Rotstein OD, Kain KC. Nonopsonic monocyte/macrophage phagocytosis of Plasmodium falciparum-parasitized erythrocytes: a role for CD36 in malarial clearance. Blood. 2000;96:3231–40.PubMedGoogle Scholar
- Stoute JA, Odindo AO, Owuor BO, Mibei EK, Opollo MO, Waitumbi JN. Loss of red blood cell-complement regulatory proteins and increased levels of circulating immune complexes are associated with severe malarial anemia. J Infect Dis. 2003;187:522–5.View ArticlePubMedGoogle Scholar
- Helegbe GK, Goka BQ, Kurtzhals JA, Addae MM, Ollaga E, Tetteh JK, et al. Complement activation in Ghanaian children with severe Plasmodium falciparum malaria. Malar J. 2007;6:165.View ArticlePubMedPubMed CentralGoogle Scholar
- Helegbe GK, Huy NT, Yanagi T, Shuaibu MN, Yamazaki A, Kikuchi M, et al. Rate of red blood cell destruction varies in different strains of mice infected with Plasmodium berghei-ANKA after chronic exposure. Malar J. 2009;8:91.View ArticlePubMedPubMed CentralGoogle Scholar
- Helegbe GK, Huy NT, Yanagi T, Shuaibu MN, Kikuchi M, Cherif MS, et al. Anti-erythropoietin antibody levels and its association with anaemia in different strains of semi-immune mice infected with Plasmodium berghei ANKA. Malar J. 2013;12:296.View ArticlePubMedPubMed CentralGoogle Scholar
- Giribaldi G, Ulliers D, Schwarzer E, Roberts I, Piacibello W, Arese P. Hemozoin- and 4-hydroxynonenal-mediated inhibition of erythropoiesis. Possible role in malarial dyserythropoiesis and anemia. Haematologica. 2004;89:492–3.PubMedGoogle Scholar
- Oyegue-Liabagui SL, Bouopda-Tuedom AG, Kouna LC, Maghendji-Nzondo S, Nzoughe H, Tchitoula-Makaya N, et al. Pro- and anti-inflammatory cytokines in children with malaria in Franceville Gabon. Am J Clin Exp Immunol. 2017;6:9–20.PubMedPubMed CentralGoogle Scholar
- Raballah E, Kempaiah P, Karim Z, Orinda GO, Otieno MF, Perkins DJ, et al. CD4 T-cell expression of IFN-gamma and IL-17 in pediatric malarial anemia. PLoS ONE. 2017;12:e0175864.View ArticlePubMedPubMed CentralGoogle Scholar
- Herbert F, Tchitchek N, Bansal D, Jacques J, Pathak S, Becavin C, et al. Evidence of IL-17, IP-10, and IL-10 involvement in multiple-organ dysfunction and IL-17 pathway in acute renal failure associated to Plasmodium falciparum malaria. J Transl Med. 2015;13:369.View ArticlePubMedPubMed CentralGoogle Scholar
- Marquet S, Conte I, Poudiougou B, Argiro L, Cabantous S, Dessein A, et al. The IL17F and IL17RA genetic variants increase risk of cerebral malaria in two African populations. Infect Immun. 2015;84:590–7.View ArticlePubMedGoogle Scholar
- Helegbe GK, Yanagi T, Senba M, Huy NT, Shuaibu MN, Yamazaki A, et al. Histopathological studies in two strains of semi-immune mice infected with Plasmodium berghei ANKA after chronic exposure. Parasitol Res. 2011;108:807–14.View ArticlePubMedGoogle Scholar
- Collicutt NB, Grindem CB, Neel JA. Comparison of manual polychromatophilic cell and automated reticulocyte quantification in evaluating regenerative response in anemic dogs. Vet Clin Pathol. 2012;41:256–60.View ArticlePubMedGoogle Scholar
- Evans KJ, Hansen DS, van Rooijen N, Buckingham LA, Schofield L. Severe malarial anemia of low parasite burden in rodent models results from accelerated clearance of uninfected erythrocytes. Blood. 2006;107:1192–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Price RN, Simpson JA, Nosten F, Luxemburger C, Hkirjaroen L, ter Kuile F, et al. Factors contributing to anemia after uncomplicated falciparum malaria. Am J Trop Med Hyg. 2001;65:614–22.View ArticlePubMedPubMed CentralGoogle Scholar
- Hassan DA, ElHussein AM, Abdulhadi NH. Cytokines and their role in modulating the severity of Plasmodium falciparum malaria. Khartoum Med J. 2010;3:373–6.Google Scholar
- Abrams ET, Brown H, Chensue SW, Turner GD, Tadesse E, Lema VM, et al. Host response to malaria during pregnancy: placental monocyte recruitment is associated with elevated beta chemokine expression. J Immunol. 2003;170:2759–64.View ArticlePubMedGoogle Scholar
- Sprangers B, Van der Schueren B, Gillard P, Mathieu C. Otelixizumab in the treatment of type 1 diabetes mellitus. Immunotherapy. 2011;3:1303–16.View ArticlePubMedGoogle Scholar
- Zainabur R, Sujarot DS, Budi S, Teguh WS, Loeki EF. Parasitemia induces high plasma levels of interleukin-17 (IL-17) and low levels of interleukin-10 (IL-10) and transforming growth factor-ß (TGF-ß) in pregnant mice infected with malaria. Malays J Med Sci. 2015;22:25–32.Google Scholar
- Zarychanski R, Houston DS. Anemia of chronic disease: a harmful disorder or an adaptive, beneficial response? CMAJ. 2008;179:333–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Akanmori BD, Kurtzhals JA, Goka BQ, Adabayeri V, Ofori MF, et al. Distinct patterns of cytokine regulation in discrete clinical forms of Plasmodium falciparum malaria. Eur Cytokine Netw. 2000;11:113–8.PubMedGoogle Scholar
- Othoro C, Lal AA, Nahlen B, Koech D, Orago AS, Udhayakumar V. A low interleukin-10 tumor necrosis factor-alpha ratio is associated with malaria anemia in children residing in a holoendemic malaria region in western Kenya. J Infect Dis. 1999;179:279–82.View ArticlePubMedGoogle Scholar
- Joost J, Feldmen MO. Cytokine reference: a compendium of cytokines and other mediators of host defense, 2 volumes set: ligands, receptors. Boston: Boston Academic Press; 2001.Google Scholar