Browsing by Author "Tetteh, J.K.A."

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Age-related pattern and monocyte-acquired haemozoin associated production of erythropoietin in children with severe malarial anaemia in Ghana
(2014-08-20) Abugri, J.; Tetteh, J.K.A.; Oseni, L.A.; Mensah-Brown, H.E.; Delimini, R.K.; Obuobi, D.O.; Akanmori, B.D.
Abstract Background Malaria continues to be a global health challenge, affecting more than half the world’s population and causing approximately 660,000 deaths annually. The majority of malaria cases are caused by Plasmodium falciparum and occur in sub-Saharan Africa. One of the major complications asscociated with malaria is severe anaemia, caused by a cycle of haemoglobin digestion by the parasite. Anaemia due to falciparum malaria in children has multifactorial pathogenesis, which includes suppression of bone marrow activity. Recent studies have shown that haemozoin, which is a by-product of parasite haemoglobin digestion, may play an important role in suppression of haemoglobin production, leading to anaemia. In this study we correlated the levels of erythropoietin (EPO), as an indicator of stimulation of haemoglobin production, to the levels of monocyte acquired haemozoin in children with both severe and uncomplicated malaria. There was a significantly negative correlation between levels of haemozoin-containing monocytes and EPO, which may suggest that haemozoin suppresses erythropoiesis in severe malaria. A multiple linear regression analysis and simple bar was used to investigate associations between various haematological parameters. Methods To examine the levels of erythropoietin in the age categories, the levels of erythropoietin was measured using a commercial Enyme-Linked Immunosorbent Assay (ELISA). Giemsa-stained blood smears were used to determine percentage pigment containing monocytes. The haemozoin containing monocytes was expressed as a percentage of the total number of monocytes. To obtain the number of haemozoin containing monocytes/μL the percentage of haemozoin containing monocytes was multiplied by the absolute number of monocytes/μL from the automated haematology analyzer. Results The levels of erythropoietin in younger children (<3 years) was significantly higher than in older children with a similar degree of malaria anaemia (Hb levels) (p < 0.005). Haemozoin-containing monocytes were relatively higher in severe malaria anaemia patients compared to those with uncomplicated malaria (p < 0.001). Conclusions Age purportedly has a direct effect on background levels of erythropoietin. With corresponding decreased levels of erythropoietin in older children with the same degree of severe malarial anaemia, conceivably, the bone marrows of younger children with acute malaria may be less sensitive to erythropoietin.
Comparison of the impact of allelic polymorphisms in PfAMA1 on the induction of T Cell responses in high and low malaria endemic communities in Ghana
(Malaria Journal, 2021) Ofori, E.A.; Tetteh, J.K.A.; Frimpong, A.; Geneshan, H.; Belmonte, M.; Peters, B.; Villasante, E.; Sedegah, M.; Ofori, M.F.; Kusi, K.A.
Background: Malaria eradication requires a combined efort involving all available control tools, and these eforts would be complemented by an efective vaccine. The antigen targets of immune responses may show polymor phisms that can undermine their recognition by immune efectors and hence render vaccines based on antigens from a single parasite variant inefective against other variants. This study compared the infuence of allelic polymor phisms in Plasmodium falciparum apical membrane antigen 1 (PfAMA1) peptide sequences from three strains of P. fal ciparum (3D7, 7G8 and FVO) on their function as immunodominant targets of T cell responses in high and low malaria transmission communities in Ghana. Methods: Peripheral blood mononuclear cells (PBMCs) from 10 subjects from a high transmission area (Obom) and 10 subjects from a low transmission area (Legon) were tested against 15 predicted CD8+T cell minimal epitopes within the PfAMA1 antigen of multiple parasite strains using IFN-γ ELISpot assay. The peptides were also tested in simi lar assays against CD8+enriched PBMC fractions from the same subjects in an efort to characterize the responding T cell subsets. Results: In assays using unfractionated PBMCs, two subjects from the high transmission area, Obom, responded pos itively to four (26.7%) of the 15 tested peptides. None of the Legon subject PBMCs yielded positive peptide responses using unfractionated PBMCs. In assays with CD8+enriched PBMCs, three subjects from Obom made positive recall responses to six (40%) of the 15 tested peptides, while only one subject from Legon made a positive recall response to a single peptide. Overall, 5 of the 20 study subjects who had positive peptide-specifc IFN-γ recall responses were from the high transmission area, Obom. Furthermore, while subjects from Obom responded to peptides in PfAMA1 from multiple parasite strains, one subject from Legon responded to a peptide from 3D7 strain only. Conclusions: The current data demonstrate the possibility of a real efect of PfAMA1 polymorphisms on the induc tion of T cell responses in malaria exposed subjects, and this efect may be more pronounced in communities with higher parasite exposure.
Comparison of the impact of allelic polymorphisms in PfAMA1 on the induction of T Cell responses in high and low malaria endemic communities in Ghana
(Springer Nature, 2021) Ofori, E.A.; Tetteh, J.K.A.; Frimpong, A.; Ganeshan, H.; Belmonte, M.; Peters, B.; Villasante, E.; Sedegah, M.; Ofori, M.F.; . Kusi, K.A.
Background: Malaria eradication requires a combined effort involving all available control tools, and these efforts would be complemented by an effective vaccine. The antigen targets of immune responses may show polymorphisms that can undermine their recognition by immune effectors and hence render vaccines based on antigens from a single parasite variant ineffective against other variants. This study compared the influence of allelic polymorphisms in Plasmodium falciparum apical membrane antigen 1 (PfAMA1) peptide sequences from three strains of P. falciparum (3D7, 7G8 and FVO) on their function as immunodominant targets of T cell responses in high and low malaria transmission communities in Ghana. Methods: Peripheral blood mononuclear cells (PBMCs) from 10 subjects from a high transmission area (Obom) and 10 subjects from a low transmission area (Legon) were tested against 15 predicted CD8 + T cell minimal epitopes within the PfAMA1 antigen of multiple parasite strains using IFN-γ ELISpot assay. The peptides were also tested in similar assays against CD8 + enriched PBMC fractions from the same subjects in an effort to characterize the responding T cell subsets. Results: In assays using unfractionated PBMCs, two subjects from the high transmission area, Obom, responded positively to four (26.7%) of the 15 tested peptides. None of the Legon subject PBMCs yielded positive peptide responses using unfractionated PBMCs. In assays with CD8 + enriched PBMCs, three subjects from Obom made positive recall responses to six (40%) of the 15 tested peptides, while only one subject from Legon made a positive recall response to a single peptide. Overall, 5 of the 20 study subjects who had positive peptide-specific IFN-γ recall responses were from the high transmission area, Obom. Furthermore, while subjects from Obom responded to peptides in PfAMA1 from multiple parasite strains, one subject from Legon responded to a peptide from 3D7 strain only. Conclusions: The current data demonstrate the possibility of a real effect of PfAMA1 polymorphisms on the induction of T cell responses in malaria exposed subjects, and this effect may be more pronounced in communities with higher parasite exposure.
Complement activation in Ghanaian children with severe Plasmodium falciparum malaria
(2007-12-17) Helegbe, G.K.; Goka, B.Q.; Kurtzhals, J.A.L.; Addae, M.M.; Ollaga, E.; Tetteh, J.K.A.; Dodoo, D.; Ofori, M.F.; Obeng-Adjei, G.; Hirayama, K.; Awandare, G.A; Akanmori, B.D.
Abstract Background Severe anaemia (SA), intravascular haemolysis (IVH) and respiratory distress (RD) are severe forms of Plasmodium falciparum malaria, with RD reported to be of prognostic importance in African children with malarial anaemia. Complement factors have been implicated in the mechanism leading to excess anaemia in acute P. falciparum infection. Methods The direct Coombs test (DCT) and flow cytometry were used to investigate the mean levels of RBC-bound complement fragments (C3d and C3bαβ) and the regulatory proteins [complement receptor 1 (CD35) and decay accelerating factor (CD55)] in children with discrete clinical forms of P. falciparum malaria. The relationship between the findings and clinical parameters including coma, haemoglobin (Hb) levels and RD were investigated. Results Of the 484 samples tested, 131(27%) were positive in DCT, out of which 115/131 (87.8%) were positive for C3d alone while 16/131 (12.2%) were positive for either IgG alone or both. 67.4% of the study population were below 5 years of age and DCT positivity was more common in this age group relative to children who were 5 years or older (Odds ratio, OR = 3.8; 95%CI, 2.2–6.7, p < 0.001). DCT correlated significantly with RD (β = -304, p = 0.006), but multiple regression analysis revealed that, Hb (β = -0.341, p = 0.012) and coma (β = -0.256, p = 0.034) were stronger predictors of RD than DCT (β = 0.228, p = 0.061). DCT was also not associated with IVH, p = 0.19, while spleen size was inversely correlated with Hb (r = -402, p = 0.001). Flow cytometry showed similar mean fluorescent intensity (MFI) values of CD35, CD55 and C3bαβ levels on the surfaces of RBC in patients and asymptomatic controls (AC). However, binding of C3bαβ correlated significantly with CD35 or CD55 (p < 0.001). Conclusion These results suggest that complement activation contributed to anaemia in acute childhood P. falciparum malaria, possibly through induction of erythrophagocytosis and haemolysis. In contrast to other studies, this study did not find association between levels of the complement regulatory proteins, CD35 and CD55 and malarial anaemia. These findings suggest that complement activation could also be involved in the pathogenesis of RD but larger studies are needed to confirm this finding.
Generation of HIV-1 primary isolates representative of plasma variants using the U87.CD4 cell line
(Journal of Virological Methods, 2010) Heeregrave, E.J.; Ampofo, W.K.; Tetteh, J.K.A.; Ofori, M.; Ofori, S.B.; Shah, A.S.; Pollakis, G.; Paxton, W.A.
In order to obtain HIV-1 primary isolates in settings with limited access to donor PBMCs, a culture method was developed where patient PBMCs infected with HIV-1 were cultured together with U87.CD4 cells. Using this non-laborious method, it is possible to harvest virus solely on the basis of syncytia formation and circumventing monitoring of viral replication by CA-p24 ELISA. Primary isolates from 23 out of 33 patients (70%) were isolated successfully. From PCR amplification and sequencing of the V1V5 region of the viral gp120 envelope gene, primary isolates were compared with variants obtained from plasma and PBMCs of 13 patients. The primary isolates of seven patients (54%) resembled closely the plasma viral quasispecies, whereas different variants were isolated from the other patients (46%). Three patients harboured a dual infection, while this remained unnoticed from sequencing the plasma or PBMC compartment. The primary isolates were highly infectious for TZM-bl cells and could infect CD4-enriched lymphocytes. This study demonstrates that it is possible to grow viral isolates using a non-laborious and simple method. These isolates may be used in the field for studies on antiretroviral therapy or for vaccine trials.
High CD4/CD45RO+ and CD8/CD45RO+ frequencies in children with vaccine-modified measles
(Pediatrics International, 2006) Addae, M.M.; Tetteh, J.K.A.; Ishiwada, N.; Komada, Y.; Yamaguchi, S.; Ofori-Adjei, D.; Kamiya, H.; Akanmori, B.D.
BACKGROUND: Despite availability and wide vaccine coverage, measles infections still occur especially in developing countries. An outbreak of measles occurred among previously immunized older Ghanaian children who had milder clinical symptoms with measles-specific IgG antibodies that could have been attributed to secondary vaccine failure, suggesting that the infection was vaccine-modified measles (VMM). METHODS: Two-color immunophenotyping of the peripheral blood mononuclear cells was performed at acute, recovery and convalescence phases for 19 VMM patients (mean age 6.2 +/- 3.5 years) using flow cytometry, and compared with that of 20 healthy, sex- and age-matched controls. RESULTS: The results showed a significantly higher memory helper (CD4(+)/CD45RO(+)) cell frequency and increased suppressor cell (CD8(+)/CD45R0(+)) frequency in VMM patients compared to healthy controls. There were no complications and all the patients recovered completely. CONCLUSIONS: These findings show that the mild symptoms in patients with VMM may have correlated with the increase of memory T cells, which is in sharp contrast with previous reports on acute measles infection. This may suggest that the intact immunologic memory cells could have been crucial for the resolution of VMM.
High Plasma Levels of Soluble Intercellular Adhesion Molecule (ICAM)-1 Are Associated with Cerebral Malaria
(PLoS ONE, 2017-12-27) Adukpo, S.; Kusi, K.A.; Ofori, M.F.; Tetteh, J.K.A.; Amoako-Sakyi, D.; Goka, B.Q.; Adjei, G.O.; Edoh, D.A.; Akanmori, B.D.; Gyan, B.A.; Dodoo, D.
Background: Cerebral malaria (CM) is responsible for most of the malaria-related deaths in children in sub-Saharan Africa. Although, not well understood, the pathogenesis of CM involves parasite and host factors which contribute to parasite sequestration through cytoadherence to the vascular endothelium. Cytoadherence to brain microvasculature is believed to involve host endothelial receptor, CD54 or intercellular adhesion molecule (ICAM)-1, while other receptors such as CD36 are generally involved in cytoadherence of parasites in other organs. We therefore investigated the contributions of host ICAM- 1 expression and levels of antibodies against ICAM-1 binding variant surface antigen (VSA) on parasites to the development of CM. Methodology/Principal Findings: Paediatric malaria patients, 0.5 to 13 years were recruited and grouped into CM and uncomplicated malaria (UM) patients, based on well defined criteria. Standardized ELISA protocol was used to measure soluble ICAM-1 (sICAM-1) levels from acute plasma samples. Levels of IgG to CD36- or ICAM-1-binding VSA were measured by flow cytometry during acute and convalescent states. Wilcoxon sign rank-test analysis to compare groups revealed association between sICAM-1 levels and CM (p,0.0037). Median levels of antibodies to CD36-binding VSA were comparable in the two groups at the time of admission and 7 days after treatment was initiated (p.0.05). Median levels of antibodies to CD36-binding VSAs were also comparable between acute and convalescent samples within any patient group. Median levels of antibodies to ICAM-1-binding VSAs were however significantly lower at admission time than during recovery in both groups. Conclusions/Significance: High levels of sICAM-1 were associated with CM, and the sICAM-1 levels may reflect expression levels of the membrane bound form. Anti-VSA antibody levels to ICAM-binding parasites was more strongly associated with both UM and CM than antibodies to CD36 binding parasites. Thus, increasing host sICAM-1 levels were associated with CM whilst antibodies to parasite expressing non-ICAM-1-binding VSAs were not.
Increased levels of inflammatory mediators in children with severe Plasmodium falciparum malaria with respiratory distress
(Journal of Infectious Diseases, 2006-12) Awandare, G.A.; Goka, B.; Boeuf, P.; Tetteh, J.K.A.; Kurtzhals, J.A.L.; Behr, C.; Akanmori, B.D.
Background. Respiratory distress (RD), a symptom of underlying metabolic acidosis, has been identified as a major risk factor for mortality in children with severe malaria in Africa, yet the molecular mediators involved in the pathogenesis of RD have not been identified. Methods. We studied circulating levels of mediators of inflammation-including the cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-10; the chemokines macrophage inflammatory protein (MIP)-1α, MIP-1β, and IL-8; and the immune activation marker neopterin-in children with RD, severe malarial anemia (SMA), cerebral malaria (CM), and uncomplicated malaria (UM). Results. Children with RD had significantly higher plasma levels of TNF-α, IL-10, and neopterin and a significantly higher TNF-α:IL-10 ratio than those without RD. In addition, the results demonstrated that, relative to UM, CM was associated with increased levels of TNF-α and decreased levels of MIP-1α, whereas SMA was associated with decreased levels of IL-10. Circulating levels of neopterin were inversely correlated with hemoglobin, whereas levels of MIP-1β were positively correlated with parasitemia. Conclusions. We conclude that distinct clinical presentations of severe malaria are associated with specific patterns of inflammatory mediators. In particular, we show, to our knowledge for the first time, that patients with malaria and RD have a strong and unbalanced proinflammatory response that may be involved in the pathogenesis of the underlying metabolic acidosis. © 2006 by the Infectious Diseases Society of America. All rights reserved.
Leishmanicidal Potential of Hardwickiic Acid Isolated From Croton sylvaticus
(Frontiers in Pharmacology, 2020-05-25) Crentsil, J.A.; Yamthe, L.R.T.; Anibea, B.Z.; Broni, E.; Kwofie, S.K.; Tetteh, J.K.A.; Osei-Safo, D.
Leishmania is a parasitic protozoon responsible for the neglected tropical disease Leishmaniasis. Approximately, 350 million people are susceptible and close to 70,000 death cases globally are reported annually. The lack of effective leishmanicides, the emergence of drug resistance and toxicity concerns necessitate the pursuit for effective antileishmanial drugs. Natural compounds serve as reservoirs for discovering new drugs due to their chemical diversity. Hardwickiic acid (HA) isolated from the stembark of Croton sylvaticus was evaluated for its leishmanicidal potential against Leishmania donovani and L. major promastigotes. The susceptibility of the promastigotes to HA was determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide/phenazine methosulfate colorimetric assay with Amphotericin B serving as positive control. HA showed a significant antileishmanial activity on L. donovani promastigotes with an IC50 value of 31.57± 0.06 µM with respect to the control drug, amphotericin B with IC50 of 3.35 ± 0.14 µM). The cytotoxic activity was observed to be CC50 = 247.83 ± 6.32 µM against 29.99 ± 2.82 µM for curcumin, the control, resulting in a selectivity index of SI = 7.85. Molecular modeling, docking and dynamics simulations of selected drug targets corroborated the observed antileishmanial activity of HA. Novel insights into the mechanisms of binding were obtained for trypanothione reductase (TR), pteridine reductase 1 (PTR1), and glutamate cysteine ligase (GCL). The binding affinity of HA to the drug targets LmGCL, LmPTR1, LdTR, LmTR, LdGCL, and LdPTR1 were obtained as -8.0, -7.8, -7.6, -7.5, -7.4 and -7.1 kcal/mol, respectively. The role of Lys16, Ser111, and Arg17 as critical residues required for binding to LdPTR1 was reinforced. HA was predicted as a Caspase-3 stimulant and Caspase-8 stimulant, implying a possible role in apoptosis, which was shown experimentally that HA induced parasite death by loss of membrane integrity. HA was also predicted as antileishmanial molecule corroborating the experimental activity. Therefore, HA is a promising antileishmanial molecule worthy of further development as a biotherapeutic agent
Macrophage susceptibility to infection by Ghanaian Mycobacterium tuberculosis complex lineages 4 and 5 varies with self-reported ethnicity
(Frontiers in Cellular and Infection Microbiology, 2023) Osei-Wusu, S.; Tetteh, J.K.A.; Arthur, N.; et al.
Background: The epidemiology of Mycobacterium tuberculosis complex (MTBC) lineage 5 (L5) infections in Ghana revealed a significantly increased prevalence in Ewes compared to other self-reported ethnic groups. In that context, we sought to investigate the early phase of tuberculosis (TB) infection using ex vivo infection of macrophages derived from the blood of Ewe and Akan ethnic group volunteers with MTBC L4 and L5 strains. Methods: The study participants consisted of 16 controls, among which self reported Akan and Ewe ethnicity was equally represented, as well as 20 cured TB cases consisting of 11 Akans and 9 Ewes. Peripheral blood mononuclear cells were isolated from both healthy controls and cured TB cases. CD14+ monocytes were isolated and differentiated into monocyte-derived macrophages (MDMs) before infection with L4 or L5 endemic strains. The bacterial load was assessed after 2 hours (uptake) as well as 3 and 7 days post-infection. Results: We observed a higher capacity of MDMs from Ewes to phagocytose L4 strains (p < 0.001), translating into a higher bacillary load on day 7 (p < 0.001) compared to L5, despite the higher replication rate of L5 in Ewe MDMs (fold change: 1.4 vs. 1.2, p = 0.03) among the controls. On the contrary, within macrophages from Akans, we observed a significantly higher phagocytic uptake of L5 (p < 0.001) compared to L4, also translating into a higher load on day 7 (p = 0.04). However, the replication rate of L4 in Akan MDMs was higher than that of L5 (fold change: L4 = 1.2, L4 = 1.1, p = 0.04). Although there was no significant difference in the uptake of L4 and L5 among cured TB cases, there was a higher bacterial load of both L4 (p = 0.02) and L5 (p = 0.02) on day 7 in Ewe MDMs. Conclusion: Our results suggest that host ethnicity (driven by host genetic diversity), MTBC genetic diversity, and individual TB infection history are all acting together to modulate the outcome of macrophage infections by MTBC.
Phenotypic Characterization of Host-Pathogen Interaction on Mycobacterium Africanum
(University of Ghana, 2015-12) Tetteh, J.K.A.; Newman, M.J.; Yeboah-Manu, D.; Gyan, B.; University of Ghana, College of Health Sciences School of Biomedical and Allied Health Sciences Department of Medical Microbiology
Background: Mycobacterium africanum (MAF) and Mycobacterium tuberculosis sensu strico (MTBss) are two members of a closely related bacterial species of Mycobacterium tuberculosis complex (MTBC) that causes tuberculosis (TB) in humans. However MAF is known to cause up to 50% of human pulmonary TB in West Africa only. MAF has been sub-divided into MAF West African 1 (MAF1) (Lineage 5) and MAF West African 2 (MAF2) (Lineage 6), as two distinct phylogenetical lineages within MTBC. Subsequently the absence of Mycobacterium tuberculosis deletion gene (TbD1) strains in MTBss has been referred to as modern lineage whilst ancient lineage (MAF1 and MAF2) have the presence of TbD1. Ghana represents one of the few countries within Central West Africa known to have this unique genetic diversity of MAF1, MAF2 and MTBss that causes TB cases in significant proportions. While previously it was thought MAF is genetically very closely related to MTBss such that there are no important phenotypic differences between the two species, current advance in molecular biology indicate that substantial genetic difference exit between the two that can translate into significant phenotypic differences including immunogenicity and virulence. Aim: The aim of the study was to analyze the phenotypic features of host-pathogen interaction in Mycobacterium africanum and compared to Mycobacterium tuberculosis sensu strico strains. Methodology: The study was embedded in 2 different projects. Retrospective archived cryopreserved peripheral blood mononuclear cells (PBMCs) of MAF-infected and MTBss-infected patients were stimulated with growth medium (negative control), Staphylococcus enterotoxin B (SEB, positive control) and recombinant early secreted antigenic protein 6 kiloDalton/culture filtrate protein 10 kiloDalton fusion protein (rESAT-6/CFP-10), surface stained for T-subsets (CD4 and CD8) and intracellular cytokine, interferon gamma (IFN-), and acquired with FACS Calibur flow cytometer. The second study used characterized large sequence polymorphism (LSP) clinical isolates identified as MAF1, MAF2 and MTBss to determine intracellular growth assay in human monocyte–derived macrophages (MDM), mean doubling time and pro-inflammatory tumour necrosis factor–alpha (TNF-α), interleukin 6 (IL-6) and 12p70 cytokines by enzyme-linked immunosorbent assay (ELISA). Results: The percentage frequencies of CD4+IFN-+ and CD8+ IFN-+ T cells of MAF-infected patients did not differ from the percentage frequencies CD4+ IFN-+ and CD8+ IFN-+ T cells of MTB-infected patients in response to rESAT-6/CFP-10 fusion protein (p>0.05). Uptake of MAF1, MAF2 and MTBss representing modern and ancient strains respectively at 4hours was not significant (p>0.05). Mean intracellular growth index from 24hours to 72hours was significantly rapid for MTBss (modern) lineage compared to MAF1 and MAF2 (ancient) lineages (p<0.05). In contrast the mean doubling time of MTBss (modern) lineage was significantly lower compared to MAF1 and MAF2 (ancient) lineages (p<0.05). Levels of pro-inflammatory cytokines released into the supernatants by MTBss, MAF1 and MAF2 at 4hours was not statistically significant (p>0.05). However at 24hours to 72hours levels released by MAF1 and MAF2 (ancient) lineages was significantly higher than MTBss (modern) lineage (p<0.05). Conclusion: The study has shown that MAF-infected patients had similar T subset response to rESAT-6/CFP-10 fusion protein relative to MTBss-infected patients. Furthermore MAF had reduced uptake, low intracellular growth rate and a higher doubling time in MDM. Likewise MAF (ancient) lineages have hyper-inflammatory response thereby inducing a ‘slow growth’ phenotype highlighting the point that MAF indeed has lower virulence and longer latency leading to slower progression to active disease in the host.
Plasma levels of Th1 and Th2 cytokines in Ghanaian children with vaccine-modified measles.
(2003) Tetteh, J.K.A.; Addae, M.M.; Commey, J.O.O.; Ishiwada, N.; Yempewu, S.M.; Yamaguchi, S.; Ofori-Adjei, D.
To understand the pathogenesis of vaccine-modified measles (VMM), we measured plasma levels of IFN-gamma and IL-2 (Th1 cytokines), IL-4 and IL-10 (Th2 cytokines), IL-12, TNF-alpha and TGF-beta1 in children with uncomplicated measles, who had anti-measles IgG antibodies and with a history of immunization on admission (day 0), day 14 and day 60. We compared these to levels in healthy, age-matched, immunized children. Plasma levels of IFN-gamma, IL-2 and IL-12 were significantly higher in VMM patients on day 0 compared to healthy controls (p = 0.023; p = 0.018; p = 0.001) respectively. In contrast, plasma IL-4 was lower in VMM patients on day 0 when compared to the controls (p = 0.009). Plasma levels of IL-12 remained consistently high on days 14 and 60 (p = 0.001; p = 0.04), whilst IL-10 levels fell significantly on the same days (p = 0.002; p = 0.001) respectively. Kinetically, IFN-gamma and IL-10 levels decreased consistently from day 0 to days 14 and 60 in VMM patients. In contrast, IL-4 levels increased from day 0 to day 14 and day 60. Our results therefore suggest that VMM is associated with an early up-regulation of Th1 cytokine production and a down-regulation of Th2 cytokine production. The strong Th1 response may be associated with the induction of IL-12 and memory cells, thus contributing to the early resolution of the infection and lack of complications.
Selective activation of TCR gamma delta +ve cells in endemic Burkitt's lymphoma
(2007-05-23) Futagbi, G.; Welbeck, J.E.; Tetteh, J.K.A.; Hviid, L.; Akanmori, B.D.
Abstract Background The overlap in geographical distribution of Plasmodium falciparum malaria and endemic Burkitt's lymphoma (eBL) – an aggressive Epstein-Barr virus (EBV)-associated B-cell tumour occurring almost exclusively in the tropics – strongly suggests a link between the two diseases. It is suspected that the polyclonal B-cell activation in P. falciparum malaria may precipitate a breakdown in homeostatic T-cell control of EBV-immortalized B-cell proliferation. Previous studies have suggested that a particular T-cell subset, characterized by expression of Vδ1+ γδ T-cell receptors, is important for maintaining B-cell homeostasis, both in P. falciparum- exposed populations and in individuals subject to polyclonal B-cell activation of other aetiology. The objective of the present study was, therefore, to characterize lymphocyte phenotypes and to investigate possible differences in T-cell subset composition and activation status in P. falciparum-exposed Ghanaian children with and without eBL. Methods Venous blood samples in heparin from 21 eBL patients (mean age: 7.0 years; range: 3–11 years), referred to the Burkitt's Tumour Centre at Korle-Bu Teaching Hospital, Accra and 15 healthy, age and sex matched children, were stained with fluorescein isothiocyanate (FITC)-, phycoerythrin (PE)-, R-phycoerythrin (RPE)- and RPE-Cy5-conjugated antibodies (CD3, CD4, CD8, CD25, CD69, CD95, HLA-DR, TCR-γδ, Vδ1, Vδ3, Vγ9 and B-cells) and acquired on a flow cytometer. Results A reduction in the proportion of CD3+ cells in eBL patients, due mainly to perturbations among TCR-γδ+ cells was observed. In contrast, the proportions of CD4+ or CD8+ cells were relatively unaffected, as were the mean numbers of peripheral blood mononuclear cells. Conclusion Selective changes in numbers and activation status of TCR-γδ+ cells occurs in Ghanaian children with eBL, a pattern which is similar to P. falciparum-induced changes. The data supports the hypothesis of a regulatory role for Vδ1+ TcR-γδ T-cells in maintaining B-cell homeostasis and provides insights into the pathogenesis of eBL.
Vaccine-modified measles in previously immunized children in Accra, Ghana: Clinical, virological and serological parameters.
(2001) Ishiwada, N.; Addae, M.M.; Tetteh, J.K.A.; Yempewu, S.M.; Ofori-Adjei, D.; Kamiya, H.; Akanmori, B.D.
Despite rapidly increasing measles immunization coverage, epidemics of measles occurred from January to March 2000 in some parts of Accra, the capital of Ghana. 44 cases of acute measles were diagnosed at three health facilities during the outbreaks, which we examined clinically and serologically. The peak incidence occurred among 6-12-year-olds, clinical symptoms were milder than the typical symptoms of measles, and fever was significantly less common. None of the cases developed complications and all recovered completely. Thirty-eight (86.4%) were tested serologically; IgM antibodies were detected in 73.7% and IgG antibodies in 84.2% during the acute phase. Milder symptoms in a significant number of cases with measles IgG antibodies suggest that these are vaccine-modified measles, attributable to waning antibodies and low circulation of wild type virus in an area of high vaccine coverage. Serological confirmation will be required for accurate diagnosis, if measles is to be eradicated or kept under control. It also seems likely that multiple dose immunization schedules will be needed in the future to maintain protective antibody levels and to protect children against measles in Ghana. This will eliminate the frequent outbreaks of measles involving immunized children.