Endemic Burkitt's lymphoma (BL)-the most prevalent childhood cancer in Equatorial Africa-is a rapidly growing B-cell malignancy that is ultimately fatal if untreated. While there is a consensus that infection with Epstein-Barr virus (EBV) and repeated infections with Plasmodium falciparum malaria in childhood (e.g. holoendemic malaria) are essential components in the etiology of BL, the mechanisms of malaria and EBV interactions that increase the risk for endemic BL remain to be elucidated. The long-term goal of our research is to identify the events that initiate B cell oncogenesis in BL. The overall objective of this proposal is to continue our investigations of EBV and malaria interactions in Kenyan infants at risk for endemic BL. In our current R01 (CA102667), we followed a prospective cohort of children with divergent malaria exposures from 2 months through 36 months of age. We observed that children born in the malaria holoendemic region had a significantly earlier age of primary infection with EBV, with ~35% infected by 6 months of age. Importantly, children infected early in life maintained a chronic viral load. These studies support the long-held hypothesis that early age of EBV infection is a risk factor for BL. What we do not know however, is why these infants are infected early in life and how early age of infection limits control of EBV. Based on our data and the data of others, we propose a model whereby susceptibility of infants to infection with EBV by 6 months of age is linked to placental malaria. Infants infected early in life while they have under-developed immune responses will have poor immunologic control of the virus. The long term consequences of poor immunologic control is a greater number of latently infected cells which can ultimately exhaust the immune response against EBV and increase the risk for a malignant clone to emerge from the latently infected B cell. Our central hypothesis is that placental malaria alters an infants ability to control primary EBV infection resulting in infection earlier in life and failure to develop effective EBV immunity. We will establish an infant cohort by enrolling pregnant women attending an antenatal clinic at Chulaimbo Hospital in Kisumu District, Kenya where malaria is holoendemic, and follow infants prospectively from birth to their second birthday. To test our hypothesis, we determine the effects of placental malaria on transfer of maternal EBV-specific neutralizing antibodies and in utero sensitization to EBV antigens;determine the factors influencing susceptibility of infants to EBV by 6 months of age;determine the effects of early age of EBV infection on the development of EBV-specific immune responses, the frequency of atypical exhausted memory B cells, and the emergence of pre-malignant B cells. If our model proves valid, the implications are that prevention of BL should focus on delaying the age of EBV infection by focusing on pregnant women with placental malaria, or on blocking transmission to infants.

Public Health Relevance

Endemic Burkitt's lymphoma (BL), the most prevalent childhood cancer in Equatorial Africa, is a rapidly growing B-cell malignancy that is ultimately fatal if untreated. The knowledge gained by this study will improve the understanding of the etiology of endemic BL which will ultimately allow for the design of programs aimed at the prevention of BL.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Daschner, Phillip J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Upstate Medical University
Schools of Medicine
United States
Zip Code
Daud, Ibrahim I; Ogolla, Sidney; Amolo, Asito S et al. (2015) Plasmodium falciparum infection is associated with Epstein-Barr virus reactivation in pregnant women living in malaria holoendemic area of Western Kenya. Matern Child Health J 19:606-14
Korir, Anne; Mauti, Nathan; Moats, Pamela et al. (2014) Developing clinical strength-of-evidence approach to define HIV-associated malignancies for cancer registration in Kenya. PLoS One 9:e85881
Wilmore, Joel R; Maue, Alexander C; Lefebvre, Julie S et al. (2013) Acute Plasmodium chabaudi infection dampens humoral responses to a secondary T-dependent antigen but enhances responses to a secondary T-independent antigen. J Immunol 191:4731-9
Molyneux, Elizabeth M; Rochford, Rosemary; Griffin, Beverly et al. (2012) Burkitt's lymphoma. Lancet 379:1234-44
Piriou, Erwan; Asito, Amolo S; Sumba, Peter O et al. (2012) Early age at time of primary Epstein-Barr virus infection results in poorly controlled viral infection in infants from Western Kenya: clues to the etiology of endemic Burkitt lymphoma. J Infect Dis 205:906-13
Spring, Michele D; Chelimo, Kiprotich; Tisch, Daniel J et al. (2010) Allele specificity of gamma interferon responses to the carboxyl-terminal region of Plasmodium falciparum merozoite surface protein 1 by Kenyan adults with naturally acquired immunity to malaria. Infect Immun 78:4431-41
Sumba, P O; Kabiru, E W; Namuyenga, E et al. (2010) Microgeographic variations in Burkitt's lymphoma incidence correlate with differences in malnutrition, malaria and Epstein-Barr virus. Br J Cancer 103:1736-41
Piriou, Erwan; Kimmel, Rhonda; Chelimo, Kiprotich et al. (2009) Serological evidence for long-term Epstein-Barr virus reactivation in children living in a holoendemic malaria region of Kenya. J Med Virol 81:1088-93
Asito, Amolo S; Moormann, Ann M; Kiprotich, Chelimo et al. (2008) Alterations on peripheral B cell subsets following an acute uncomplicated clinical malaria infection in children. Malar J 7:238
Moormann, Ann M; Chelimo, Kiprotich; Sumba, Peter O et al. (2007) Exposure to holoendemic malaria results in suppression of Epstein-Barr virus-specific T cell immunosurveillance in Kenyan children. J Infect Dis 195:799-808