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.
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. Project Narrative: 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.
|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|
Showing the most recent 10 out of 28 publications