Endemic Burkitt's lymphoma (eBL) is the most common childhood cancer in Equatorial Africa. Two cofactors are linked to the etiology of this pediatric cancer: Epstein-Barr virus (EBV) infection, and sustained and intense exposure to Plasmodium falciparum malaria (holoendemic malaria). While there is a wealth of epidemiologic data establishing both EBV and P. falciparum as co-carcinogens necessary for the emergence of eBL, the mechanisms by which these pathogens interact and their unique roles in the etiology of this malignancy remain unknown. In this application, we will test three inter-related hypotheses: 1) children infected with P. falciparum before primary EBV infection will have a higher viral load and increases in viral load will occur throughout infancy and early childhood and correlate with the frequency and intensity of malaria exposure;2) repeated P. falciparum infections throughout infancy and early childhood results in the loss of an established EBV-specific anti-viral CD8+ T cell response and 3) repeated P. falciparum infections throughout infancy and early childhood result in the expansion of the peripheral B cell pool and the emergence of a pre-malignant BL B-cell phenotype. We will test these hypotheses by determining how P. falciparum infections modulate EBV immunity and persistence in a longitudinal study of children followed from 1 month through 3 years of age. To examine the effects of malaria exposure, two populations of children with divergent exposures to malaria (e.g. holoendemic and sporadic) living in Western Kenya will be compared to achieve the objectives of this study which are: 1) to identify the age of EBV and P. falciparum infections, and determine the effects of repeated P. falciparum infections on the establishment and maintenance of EBV infection;2) to determine the EBV-specific CD8+ T cell response of children with divergent malaria exposures and 3) to determine the influence of holoendemic malaria on blood B cell subpopulations and homeostasis in children.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102667-05
Application #
7617125
Study Section
Special Emphasis Panel (ZRG1-IDM-P (03))
Program Officer
Daschner, Phillip J
Project Start
2005-07-01
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2011-04-30
Support Year
5
Fiscal Year
2009
Total Cost
$269,426
Indirect Cost
Name
Upstate Medical University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
Ayers, Leona W; Barbachano-Guerrero, Arturo; McAllister, Shane C et al. (2018) Mast Cell Activation and KSHV Infection in Kaposi Sarcoma. Clin Cancer Res 24:5085-5097
Wohlford, Eric M; Baresel, Paul C; Wilmore, Joel R et al. (2018) Changes in Tonsil B Cell Phenotypes and EBV Receptor Expression in Children Under 5-Years-Old. Cytometry B Clin Cytom 94:291-301
Falanga, Yves T; Frascoli, Michela; Kaymaz, Yasin et al. (2017) High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells. JCI Insight 2:
Toko, Eunice N; Sumba, Odada P; Daud, Ibrahim I et al. (2016) Maternal Vitamin D Status and Adverse Birth Outcomes in Children from Rural Western Kenya. Nutrients 8:
Wilmore, Joel R; Maue, Alexander C; Rochford, Rosemary (2016) Plasmodium chabaudi infection induces AID expression in transitional and marginal zone B cells. Immun Inflamm Dis 4:497-505
Reynaldi, Arnold; Schlub, Timothy E; Piriou, Erwan et al. (2016) Modeling of EBV Infection and Antibody Responses in Kenyan Infants With Different Levels of Malaria Exposure Shows Maternal Antibody Decay is a Major Determinant of Early EBV Infection. J Infect Dis 214:1390-1398
Reynaldi, Arnold; Schlub, Timothy E; Chelimo, Kiprotich et al. (2016) Impact of Plasmodium falciparum Coinfection on Longitudinal Epstein-Barr Virus Kinetics in Kenyan Children. J Infect Dis 213:985-91
Ogolla, Sidney; Daud, Ibrahim I; Asito, Amolo S et al. (2015) Reduced Transplacental Transfer of a Subset of Epstein-Barr Virus-Specific Antibodies to Neonates of Mothers Infected with Plasmodium falciparum Malaria during Pregnancy. Clin Vaccine Immunol 22:1197-205
Daud, Ibrahim I; Coleman, Carrie B; Smith, Nicholas A et al. (2015) Breast Milk as a Potential Source of Epstein-Barr Virus Transmission Among Infants Living in a Malaria-Endemic Region of Kenya. J Infect Dis 212:1735-42
Wilmore, Joel R; Asito, Amolo S; Wei, Chungwen et al. (2015) AID expression in peripheral blood of children living in a malaria holoendemic region is associated with changes in B cell subsets and Epstein-Barr virus. Int J Cancer 136:1371-80

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