Abstract
Purpose
During malarial infection, both parasites and host red blood cells (RBCs) come under severe oxidative stress due to the production of free radicals. The host system responds in protecting the RBCs against the oxidative damage caused by these free radicals by producing antioxidants. In this study, we investigated the antioxidant enzyme; superoxide dismutase (SOD) activity and cytokine interactions with parasitaemia in Ghanaian children with severe and uncomplicated malaria.
Methodology
One hundred and fifty participants aged 0–12 years were administered with structured questionnaires. Active case finding approach was used in participating hospitals to identify and interview cases before treatment was applied. Blood samples were taken from each participant and used to quantify malaria parasitaemia, measure haematological parameters and SOD activity. Cytokine levels were measured by commercial ELISA kits. DNA comet assay was used to evaluate the extent of parasite DNA damage due to oxidative stress.
Results
Seventy – Nine (79) and Twenty- Six (26) participants who were positive with malaria parasites were categorized as severe (56.75 × 103 ± 57.69 parasites/µl) and uncomplicated malaria (5.87 × 103 ± 2.87 parasites/µl) respectively, showing significant difference in parasitaemia (p < 0.0001). Significant negative correlation was found between parasitaemia and SOD activity levels among severe malaria study participants (p = 0.0428). Difference in cytokine levels (IL-10) amongst the control, uncomplicated and severe malaria groups was significant (p < 0.0001). The IFN-γ/IL-10 /TNF-α/IL-10 ratio differed significantly between the malaria infected and non- malaria infected study participants. DNA comet assay revealed damage to Plasmodium parasite DNA.
Conclusion
Critical roles played by SOD activity and cytokines as anti-parasitic defense during P. falciparum malaria infection in children were established.
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Data availability
All data used in the preparation of this manuscript are duly included (captured) in this manuscript (in the results section).
Code availability
Not applicable.
References
WHO (2020) Meeting Report of the WHO Evidence Review Group on Malaria Burden Estimation Methods WHO Headquarters. World Health Organisation, Geneva, Switzerland
WHO (2020) World malaria report 2020: 20 years of global progress and challenges. Geneva: World Health Organization,
President’s malaria (2020) initiative, Ghana. Malaria Operational Plan
Postma NS, Mommers EC (1996) Eling W.M.C. oxidative stress in malaria; implications for prevention and therapy. Pharm World Sci 18:121–129
Beutler B (2004) Innate immunity: an overview. Mol Immunol 40:845–859
Iwanaga S, Lee BL (2005) Recent advances in the innate immunity of invertebrates animals. Journ Biochem Mol Biol 38:128
Hemmer CJ, Lehr HA, Westphal K, Unverricht M, Kratzius M, Reisinger EC (2005) Plasmodium Falciparum malaria: reduction of endothelial cell apoptosis in vitro. Infect Immun 73:1764–1770
Kern P, Hemmer CJ, Van Damme J, Gruss HJ, Dietrich M (1989) Elevated tumor necrosis factor alpha and interleukin-6 serum levels as markers for complicated Plasmodium falciparum malaria. Am Journ Med 87:139–143
Rockett KA, Awburn MM, Rockett EJ (1994) Clark I.A. Tumor necrosis factor and interleukin-1 synergy in the context of malaria pathology. Am Journ Trop Med Hyg 50:735–742
Phawong C, Ouma C, Tangteerawatana P, Thongshoob J, Were T, Mahakunkijcharoen Y, Wattanasirichaigoon D, Perkins DJ, Khusmith S (2010) Haplotypes of IL12B promoter polymorphisms condition susceptibility to severe malaria and functional changes in cytokine levels in Thai adults. Immunogenet 62:345–356
Lyke KE, Burges R, Cissoko Y, Sangare L, Dao M, Diarra I, Kone A, Harley R, Plowe CV, Doumbo OK (2004) Sztein M.B. Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1β), 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 72:5630–5637
Malaguarnera L, Imbesi RM, Pignatelli S, Simporè J, Malaguarnera M, Musumeci S (2002) Increased levels of interleukin-12 in Plasmodium Falciparum malaria: correlation with the severity of disease. Para Immunol 24:387–389
Chaisavaneeyakorn S, Othoro C, Shi YP, Otieno J, Chaiyaroj SC, Lal AA (2003) Udhayakumar V. relationship between plasma Interleukin-12 (IL-12) and IL-18 levels and severe malarial anemia in an area of holoendemicity in western Kenya. Clin Diag Lab Immunol 10:362–366
Perera MK, Herath NP, Pathirana SL, Phone-Kyaw M, Alles HK, Mendis KN, Premawansa S, Handunnetti SM (2013) Association of high plasma TNFΑ-alpha levels and TNFΑ-alpha/IL-10 ratios with TNFΑ2 allele in severe P. falciparum malaria patients in Sri Lanka. Pathog Global Heal 107:21–29
Kremsner PG, Winkler S, Brandts C, Wildling E, Jenne L, Graninger W, Prada J, Bienzle U, Juillard P (1995) Grau G.E. Prediction of accelerated cure in Plasmodium Falciparum malaria by the elevated capacity of tumor necrosis factor production. Am Journ Trop Med Hyg 53:532–538
Chotivanich K, Udomsangpetch R, Dondorp A, Williams T, Angus B, Simpson JA, Pukrittayakamee S, Looareesuwan S, Newbold CI (2000) White N.J. The mechanisms of parasite clearance after antimalarial treatment of Plasmodium Falciparum malaria. J Infect Dis 182:629–633
Clark IA, Chaudhri G, Cowden WB (1989) Some roles of free radicals in malaria. Free Radic Biol Med 6(3):315–321
Guha M, Kumar S, Choubey V, Maity P, Bandyopadhyay U (2006) Apoptosis in liver during malaria: role of oxidative stress and implication of mitochondrial pathway. FASEB J 20:E439–E449
Percário S, Moreira DR, Gomes BA, Ferreira ME, Gonçalves ACM, Laurindo PS, Vilhena TC, Dolabela MF, Green MD (2012) Oxidative stress in malaria. Int J Mol Sci 13(12):16346–16372
Atamna H, Ginsburg H (1993) Origin of reactive oxygen species in erythrocytes infected with Plasmodium Falciparum. Mol Biochem Parasitol 61:231–234
Kumar S, Bandyopadhyay U (2005) Free heme toxicity and its detoxification systems in human. Toxicol Lett 157(3):175–188
Sobolewski P, Gramaglia I, Frangos JA, Intaglietta M, Van Der Heyde H (2005) Plasmodium Berghei resists killing by reactive oxygen species. Infect Immun 73:6704–6710
Segal AW (2008) The function of the NADPH oxidase of phagocytes and its relationship to other NOXs in plants, invertebrates, and mammals. Internat Journ Biochem Cell Biol 40(4):604–618
Ighodaro OM, Akinloye OA (2018) First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): their fundamental role in the entire antioxidant defence grid. Alexan Journ Med 54(4):287–293
Prah DA, Amoah LE, Gibbins MP, Bediako Y, Cunnington AJ, Awandare GA (2020) Hafalla J.C.R. comparison of leucocyte profiles between healthy children and those with asymptomatic and symptomatic Plasmodium falciparum infections. Mal Journ 19(1):1–12
Squire DS (2013) Malaria parasitaemia levels in relation to antioxidant enzyme levels in severe Malaria Amongst Ghanaian Children. https://ugspace.ug.edu.gh/handle/123456789/5261?show = full
Nsiah K, Bahaah B, Afranie BO, Acheampong E (2020) Evaluation of red blood cell count as an ancillary index to hemoglobin level in defining the severe falciparum malarial anemia among Ghanaian children in low-resource communities. Heliyon 6(8):e04605
Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journ Royal Stat Soc: Ser B (Methodological) 57(1):289–300
Delmas-Beauvieux MC, Peuchant E, Dumon MF, Reuveur MC, Le Bras M (1995) Relationship between red blood cell antioxidant enzymatic system status and lipoperoxidation during acute phase of malaria. Clin Biochem 28:163–169
Vasquez M, Zuniga M, Rodriguez A (2021) Oxidative stress and Pathogenesis in Malaria. Front Cell Infect Microbiol 11:768182
Oyewole I, Anyasor G, Ogunwenmo K, Ayodele S (2011) Antioxidant and oxidative stress status in human Plasmodium malaria. Der Pharm Lett 3(2):91–96
Stocker R, Hunt NA, Buffinton GD, Wiedemann MJ, Lewis-Hughes PH, Clark IA (1985) Oxidative stress and protective mechanisms in erythrocytes in relation to Plasmodium vinckei load. Proc Natl Acad Sci 82:548–551
Kharazmi A, Jepsen S, Andersen BJ (1987) Generation of reactive oxygen radicals by human phagocytic cells activated by Plasmodium Falciparum. Scand Journ Immunol 25:335–341
Greve B, Lehman LG, Lell B, Luckner D, Schmidt- Ott R, Kremsner PG (1999) High Oxygen Radical production is associated with fast parasite clearance in children with Plasmodium Falciparum malaria. Journ Infect Dis 179:1584–1586
Rodrigues J, Charris J, Domínguez J, Ángel J, Gamboa N (2009) Modification of oxidative status in Plasmodium berghei-infected erythrocytes by E-2-chloro-8-methyl-3-[(4’-methoxy-1’-indanoyl)-2’-methyliden]-quinoline compared to chloroquine. Mem Inst Oswaldo Cruz Rio De Janeiro 104(6):865–870
Ezzi AAA, Al Salahy MB, Shnawa BH, Abed GH, Mandour AM (2017) Changes in levels of antioxidant markers and status of some enzyme activities among Falciparum Malaria patients in Yemen. Journ Microbiol Exp 4(6):119–122
Narsaria N, Mohanty C, Das BK, Mishra SP, Prasad R (2012) Oxidative stress in children with severe malaria. Journ Trop Paed 58(2):147–150
Ackerman HC, Beandry SD, Fairhurst RM (2009) Antioxidant therapy: reducing malaria severity? Crit Care Med 37:758–760
Becker K, Koncarevic S, Hunt NH (2005) Oxidative stress and antioxidant defense in malarial parasites. In: Sherman IW (Ed.). Molecular Approaches to Malaria, Herndon: Am. Soc. Microbiol. Press, 365–83
Chandra P, D’Souza V, D’Souza B (2006) Comparative study on lipid peroxidation and antioxidant vitamins E and C in falciparum and vivax malaria. Ind Journ Clin Biochem 21:103–106
Prasad R, Das BK, Pengoria R, Mishra OP, Shukla J, Singh TB (2009) Coagulation status and platelet functions in children with severe malaria and their correlation of outcome. Journ Trop Pediatr 55:374–378
Nathan C (2006) Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 6:173–182
Hafalla JC, Cockburn IA, Zavala F (2006) Protective and pathogenic roles of CD8 + T cells during malaria infection. Para Immunol 28(1–2):15–24
Rzepczyk CM, Anderson K, Stamatiou S, Townsend E, Allworth A, McCormack J (1997) Whitby M. Gamma delta T cells: their immunobiology and role in malaria infections. Int Journ Parasitol 27(2):191–200
Allison AC, Eugui EM (1983) The role of cell-mediated immune responses in resistance to malaria, with special reference to oxidant stress. Annu Rev Immunol 1:361–392
Kremsner PG, Winkler S, Brandts C, Wildling E, Jenne L, Graninger W, Prada J, Bienzle U, Juillard P, Grau GE (1995) Prediction of accelerated cure in Plasmodium Falciparum malaria by the elevated capacity of tumor necrosis factor production. Am Journ Trop Med Hyg 53:532–538
Klebanoff SJ, Vadas MA, Harlan JM, Sparks LH, Gamble JR, Agosti JM, Waltersdorph AM (1986) Stimulation of neutrophils by tumor necrosis factor. Journ Immunol 136:4220–4225
Kwiatkowski D, Hill AVS, Sambou I, Twumasi P, Greenwood AVS, Hill KR, Manogue KR, Cerami A (1990) Brewster D.R. TNF concentration in fatal, non-fatal cerebral and uncomplicated Plasmodium falciparum malaria. Lancet 336:1201–1204
Popa GL, Popa IP (2021) Recent advances in understanding the inflammatory response in Malaria: a review of the dual role of cytokines. Journ Immunol Res. https://doi.org/10.1155/2021/7785180
Dodoo D, Omer FM, Todd J, Akanmori BD, Koram KA, Riley EM (2002) Absolute levels and ratios of Proinflammatory and anti-inflammatory cytokine production in Vitro Predict Clinical immunity to Plasmodium Falciparum Malaria. Journ Infect Dis 185:971–979
Frimpong A, Amponsah J, Adjokatseh AS, Agyemang D, Bentum-Ennin L, Ofori EA, Kyei-Baafour E, Akyea-Mensah K, Adu B, Mensah GI, Amoah LE, Kusi KA (2020) Asymptomatic Malaria infection is maintained by a balanced Pro- and anti-inflammatory response. Front Microbiol 11:559255
Kurtzhals JAL, Adabayeri V, Goka BQ, Akanmori BD, Oliver-Commey JO, Nkrumah FK, Behr C (1998) Hviid L. Low concentrations of interleukin10 in severe malarial anaemia compared with cerebral and uncomplicated malaria. Lancet 351:1768–1772
Othoro C, Lal A, Nahlen B, Koech D, Orago A (1999) 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. Journ Infect Dis 179:279–282
Day NPJ, Hien TT, Schollaardt T, Loc PP, Chuong LV, Hong Chau TT, Hoang Mai NT, Phu NH, Sinh DX, White NJ, Ho M (1999) The prognostic and pathophysiologic role of pro- and antiinflammatory cytokines in severe malaria. Journ Infect Dis 180:1288–1297
Kumar S, Guha M, Choubey V, Maity P, Srivastava K, Puri SK, Bandyopadhyay U (2008) Bilirubin inhibits Plasmodium falciparum growth through the generation of reactive oxygen species. Free Rad Biol Med 2008, 44(4), 602–613
Paiva CN, Bozza MT (2014) Are reactive oxygen species always detrimental to pathogens? Antioxid red Signal 20(6):1000–1037
Raza A, Varshney SK, Khan HM, Malik MA, Mehdi AA (2015) Shukla I. Superoxide dismutase activity in patients of cerebral malaria. As Pac Journ Trop Dis 5:S51–S53
Acknowledgements
Manuscript was curled from author’s (Daniel Sai Squire) postgraduate thesis titled “Malaria Parasitaemia Levels in Relation to Antioxidant Enzyme Levels in Severe Malaria Amongst Ghanaian Children” submitted to the University of Ghana in partial fulfilment of the requirement for the award of the MPhil microbiology degree (https://ugspace.ug.edu.gh/handle/123456789/5261?show=full). All data generated or analyzed during the study are included in this manuscript. We thank the study participants and their parents/guardians for providing us with the samples to work with. We also thank Princess Marie hospital, Achimota hospital and Ussher polyclinic, all in Accra, Ghana for their support throughout the study period. Also, staff of Medical Laboratory Science Department, School of Biomedical and Allied Health Sciences, University of Ghana, are thanked for their technical support.
Funding
The study was supported by a grant from the University of Ghana Research Fund (No. URF/4/007/2011–2012) awarded to Richard Harry Asmah. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Richard H. Asmah and Daniel S. Squire both contributed equally to the paper, especially on the conceptualisation and performance of the assay. Selorme Adupko, David Adedia, and Eric Kyei-Baafour helped on data analysis. Ebenezer K. Aidoo and Patrick F. Ayeh-Kumi helped on the writing of the paper. Richard H. Asmah, Daniel S. Squire and Patrick F. Ayeh-Kumi worked on the study design as well as on the writing of the paper.
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Asmah, R.H., Squire, D.S., Adupko, S. et al. Host-parasite interaction in severe and uncomplicated malaria infection in ghanaian children. Eur J Clin Microbiol Infect Dis (2024). https://doi.org/10.1007/s10096-024-04804-z
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DOI: https://doi.org/10.1007/s10096-024-04804-z