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P3 - Malaria Pathogenesis: Infection Progression, Infection Extremes

1) Infection Progression: Identify the host and parasite factors associated with the three possible outcomes of asymptomatic infection – clearance, maintenance, or progression.

2) Infection Extremes: Compare the host and parasite factors associated with persistent asymptomatic parasitemia and life-threatening cerebral malaria.



By using two approaches, an observational cohort study and a case/control study, we will identify host and parasite factors that affect the outcome of P. falciparum infections in Malawian children.


The vast majority of malaria infections are either asymptomatic (creating a reservoir for infection (see P2)) or they progress to an uncomplicated febrile illness. What determines which asymptomatic infections become illnesses is not known. 

We plan to study this progression over time by following cohorts of asymptomatically infected children for two months and observing the evolution of their infections.


Only a small proportion of infections progress to life-threatening cerebral malaria.  We would like to understand the host and parasite factors associated with the extremes of the infection à disease progression.

In this case control study, we will compare children who are persistently asymptomatically infected with children who meet a very stringent definition of cerebral malaria.

Parasite:
  • Cycle time
  • Parasite multiplication rate
  • Merozoite production
  • Complexity of infection


Host:
  • Immunophenotyping
  • Cytokine staining
  • NK cell phenotypes
  • Var seroreactivity
  • Stool microbiota


Investigators

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Karl Seydel M.D., Ph.D.  
Professor
Department of Osteopathic Medical Specialties
Michigan State University

Study Team

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Josephine Banda
Project Intern
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Albert Mlenga
Research Assistant

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Patricia Mawindo
Study nurse

Project Locations

  • Machinga
  • Balaka
  • Queen Elizabeth Central Hospital, Blantyre District

Project Duration

  • 2020-2024

Project Publications

    1. Seydel KB, Milner DA, Kamiza SB, Molyneux ME, Taylor TE. The distribution and intensity of parasite sequestration in comatose Malawian children.  J Infect Dis 2006;194(2):208-15. PMID: 16779727 Link to pubmed

    2. Francischetti IM, Seydel KB, Monteiro RQ, Whitten RO, Erexson CR, Noronha AL, Ostera GR, Kamiza SB, Molyneux MB, Ward JM, Taylor TE. Plasmodium falciparum-infected erythrocytes induce tissue factor expression in endothelial cells and support the assembly of multimolecular coagulation complexes. J Thromb Haemost 2007;5(1)155-65. https://pubmed.ncbi.nlm.nih.gov/17002660/

    3. Conroy AL, Phiri H, Hawkes M, Glover S, Mallewa M, Seydel KB, Taylor TE, Molyneux ME, Kain KC.  Endothelium-based biomarkers are associated with cerebral malaria in Malawian children: a retrospective case-control study. PLoS One 2010;5(12):e15291. PMID  23209923 https://pubmed.ncbi.nlm.nih.gov/21209923/

    1. Herricks T, Seydel KB, Turner G, Molyneux M, Heyderman R, Taylor T, Rathod PK. A microfluidic system to study cytoadhesion of Plasmodium falciparum infected erythrocytes to primary brain microvascular endothelial cells. Lab Chip. 2011;11(17):2994-3000. PMID: 21743938

    2. Phiri HT, Bridges DJ, Glover SJ, van Mourik JA, de Laat B, M'baya B, Taylor TE, Seydel KB, Molyneux ME, Faragher EB, Craig AG, Bunn JE. Elevated plasma von Willebrand factor and propeptide levels in Malawian children with malaria. PLoS One. 2011;6(11):e25626. Epub 2011 PMID: 22125593

    3. Seydel KB, Fox LL, Glover SJ, Reeves MJ, Pensulo P, Muiruri A, Mpakiza A, Molyneux ME, Taylor TE. Plasma Concentrations of Parasite Histidine-Rich Protein 2 Distinguish Between Retinopathy-Positive and Retinopathy-Negative Cerebral Malaria in Malawian Children. J Infect Dis. 2012 ;3:309-18. PMID: 22634877

    4. MilnerDA Jr, Vareta J, Valim C, Montgomery J, Daniels RF, Volkman SK, Neafsey DE, Park DJ, Schaffner SF, Mahesh NC, Barnes KG, Rosen DM, Lukens AK, Van Tyne D, Wiegand RC, Sabeti PC, Seydel KB, Glover SJ, Kamiza S, Molyneux ME, Taylor TE,   Wirth DF. Human cerebral malaria and Plasmodium falciparum genotypes in Malawi.  Malar J. 2012 ;11:35.PMID:22314206

    5. MilnerDA Jr, Valim C, Luo R, Playforth KB, Kamiza S, Molyneux ME, Seydel KB, Taylor Supraorbital postmortem brain sampling for definitive quantitative confirmation of cerebral sequestration of Plasmodium falciparum parasites. J Infect Dis. 2012;205(10):1601-6. PMID: 22291197

    6. Conroy AL, Glover SJ, Hawkes M, Erdman LK, Seydel KB, Taylor TE, Molyneux ME, Kain KC. Angiopoietin-2 levels are associated with retinopathy and predict mortality in Malawian children with cerebral malaria: a retrospective case-control study. Crit Care Med. 2012;40(3):952-9. PMCID: PMC3284252 https://pubmed.ncbi.nlm.nih.gov/22343839/

    7. PotchenMJ, Kampondeni SD, Seydel KB, Birbeck GL, Hammond CA, Bradley WG, Demarco JK, Glover SJ, Ugorji JO, Latourette MT, Siebert JE, Molyneux ME, Taylor  Acute Brain MRI Findings in 120 Malawian Children with Cerebral Malaria: New Insights into an Ancient Disease. Am J Neuroradiol. 2012;9:1740-6.  PMID: 22517285

    8. Fox LL, Taylor TE, Pensulo P, Liomba A, Mpakiza A, Varela A, Glover SJ, Reeves MJ, Seydel KB. Histidine-rich protein 2 levels predict progression to cerebral malaria in Malawian children with Plasmodium falciparum J Infect Dis 2013; 208(3):500-3.

    9. Fox LL, Taylor TE, Pensulo P, Liomba A, Mpakiza A, Varela A, Glover SJ, Reeves MJ, Seydel KB. Histidine-rich protein 2 levels predict progression to cerebral malaria in Malawian children with Plasmodium falciparum J Infect Dis 2013; 208(3):500-3.

    10. Moxon CA, Wassmer SC, Milner DA Jr, Chisala NV, Taylor TE, Seydel KB, Molyneux ME, Faragher B, Esmon CT, Downey C, Toh CH, Craig AG, Heyderman RS. Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children.  Blood 2013;122(5):842-51.  PMID: 

    11. Moxon CA, Chisala NV, Wassmer SC, Taylor TE, Seydel KB, Molyneux ME, Faragher B, Kennedy N, Toh CH, Craig AG, Heyderman RS. Persistent Endothelial Activation and Inflammation After Plasmodium falciparum Infection in Malawian Children. J Infect Dis. 2013 Sep 17. PMID: 24048963

    12. Sisya TJ, Kamn’gona RM, Vareta JA, Fulakeza JM, Mukaka MF, Seydel KB, Laufer MK, Taylor TE, Nkhoma SC.  Subtle changes in Plasmodium falciparum infection complexity following enhanced intervention in Malawi.  Acta Trop 2014;142C:108-114.  PMID 25460345

    13. Seydel KB, Kampondeni SD,Valim C, Potchen MJ, Milner DA, Muwalo FW, Birbeck GL, Bradley WG, Fox LL, Glover SJ, Hammond CA, Heyderman RS, Chilingulo CA, Molyneux ME, Taylor TE. Brain swelling and death in pediatric cerebral malaria, N Engl J Med 2015; 72(12):1126-37. PMID: 2578590.

    14. Pelle KG, Oh K, Buchholz K, Narasimhan V, Joice R, Milner DA, Brancucci NM, Ma S, Voss TS, Ketman K, Seydel KB, Taylor TE, Barteneva NS, Huttenhower C, Marti M. Transcriptional profiling defines dynamics of parasite tissue sequestration during malaria infection. Genome Med. 2015; 7(1):19.PubMed PMID: 25722744; PubMed Central PMCID: PMC4342211.

    15. Walldorf JA, Cohee LM, Coalson JE, Bauleni A, Nkanaunena K, Kapito-Tembo A, Seydel KB, Ali D, Mathanga D, Taylor TE, Valim C, Laufer MK. School-age children are a reservoir of malaria Infection in Malawi. PLoS One. 2015; 24;10(7):e0134061. PubMed PMID: 26207758; PubMed Central PMCID: PMC4514805.

    16. Kessler A, Dankwa S, Bernabeu M, Harawa V, Danziger SA, Duffy F, Kampondeni SD, Potchen MJ, Dambrauskas N, Vigdorovich V, Oliver BG, Hochman SE, Mowrey WB, MacCormick IJC, Mandala WL, Rogerson SJ, Sather DN, Aitchison JD, Taylor TE, Seydel KB, Smith JD, Kim K. Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria. Cell Host Microbe. 2017;22(5):601-614.e5. PubMed PMID: 29107642.

    17. Buchwald AG, Sixpence A, Chimenya M, Damson M, Sorkin D, Wilson ML, Seydel S, Hochman S, Mathanga DP, Taylor TE, Laufer MK. Clinical implications of asymptomatic Plasmodium falciparum infections in Malawi.  Clin Inf Dis 2019;68(1):106-112.

    18. Buchwald AG, Sorkin JD, Sixpence A, Chimenya M, Damson M, Wilson ML, Seydel K, Hochman S, Mathanga D, Taylor TE, Laufer MK. Association Between Age and Plasmodium falciparum Infection Dynamics. Am J Epidemiol 2019;188(1):169-176. PMID:30252032

    19. Buchwald AG, Sixpence A, Chimenya M, Damson M, Sorkin JD, Wilson ML, Seydel K, Hochman S, Mathanga DP, Taylor TE, Laufer MK. Clinical Implications of Asymptomatic Plasmodium falciparum Infections in Malawi. Clin Infect Dis. 2019;68(1):106-112. PMID:297880

    20. Bernabeu M, Gunnarsson C, Vishnyakova M, Howard CC, Nagao RJ, Avril M, Taylor TE, Seydel KB, Zheng Y, Smith JD. Binding Heterogeneity of Plasmodium falciparum to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1. 2019;10(3). PMID: 31138740

    21. Earland D, Buchwald AG, Sixpence A, Chimenya M, Damson M, Seydel KB, Mathanga DP, Taylor TE, Laufer MK. Impact of Multiplicity of Plasmodium falciparumInfection on Clinical Disease in Malawi. Am J Trop Med Hyg 2019;101(2):412-415. PMID: 31219007 

    22. Vareta J, Buchwald AG, Barrall A, Cohee LM, Walldorf JA, Coalson JE, Seydel K, Sixpence A, Mathanga DP, Taylor TE, Laufer MK. Submicroscopic malaria infection is not associated with fever in cross-sectional studies in Malawi. Malar J. 2020 Jun 29;19(1):233. PMID: 32600362