Abstract

The long-term goal of this research is to advance knowledge of the mechanism by which malaria interacts with the host immune system and Epstein-Barr virus (EBV) to promote the development of endemic Burkitt?s lymphoma (eBL). An association between holoendemic malaria, EBV infection and eBL during childhood is well established in Africa. EBV -specific HLA class I-restricted CD8+ cytotoxic T lymphocyte responses limit proliferation of B cells infected with EBV. These and other findings suggest that malaria suppresses EBV- specific immunity and thereby promotes the emergence of eBL. The mechanisms by which malaria alters immunity to EBV and its role in the pathogenesis of eBL are poorly understood. This mentored-training award builds upon collaborations between Case Western Reserve University and the Kenya Medical Research Institute. The proposal will test the hypothesize that EBV -specific T cell immunity is not altered by malaria exposure per se but that viral immunity is transiently and profoundly suppressed during episodes of acute malaria morbidity, thereby providing the opportunity for latently infected B cells to undergo malignant transformation. Thus, in children presenting with eBL, EBV -specific T cell immunity will be intact since suppression of such preceded development of eBL.
The specific aims will test the following hypotheses:
Aim 1 : EBV-specific T cell IFN-y and IL-I0 responses are stable over time and not influenced by the pattern of malaria transmission in a population of healthy children.
Aim 2 : EBV-specific IFN-y T cell responses are transiently suppressed while IL-I0 T cell responses are induced during an attack of malaria morbidity.
Aim 3 : EBV-specific T cell IFN-y and IL-I0 responses in children with eBL are qualitatively and quantitatively similar to that of age-matched controls. Characterization of EBV-driven T cell responses associated with malaria will have implications for EBV vaccine trials to be conducted in populations where this lymphoma has a high prevalence.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI051565-03
Application #
6741484
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Beisel, Christopher E
Project Start
2002-08-01
Project End
2007-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
3
Fiscal Year
2004
Total Cost
$123,525
Indirect Cost

  Institution

Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106

  Publications

Moormann, Ann M; Bailey, Jeffrey A (2016) Malaria - how this parasitic infection aids and abets EBV-associated Burkitt lymphomagenesis. Curr Opin Virol 20:78-84
Bowman, Natalie M; Juliano, Jonathan J; Snider, Cynthia J et al. (2016) Longevity of Genotype-Specific Immune Responses to Plasmodium falciparum Merozoite Surface Protein 1 in Kenyan Children from Regions of Different Malaria Transmission Intensity. Am J Trop Med Hyg 95:580-7
Buckle, Geoffrey; Maranda, Louise; Skiles, Jodi et al. (2016) Factors influencing survival among Kenyan children diagnosed with endemic Burkitt lymphoma between 2003 and 2011: A historical cohort study. Int J Cancer 139:1231-40
Chattopadhyay, Pratip K; Chelimo, Kiprotich; Embury, Paula B et al. (2013) Holoendemic malaria exposure is associated with altered Epstein-Barr virus-specific CD8(+) T-cell differentiation. J Virol 87:1779-88
Snider, Cynthia J; Cole, Stephen R; Chelimo, Kiprotich et al. (2012) Recurrent Plasmodium falciparum malaria infections in Kenyan children diminish T-cell immunity to Epstein Barr virus lytic but not latent antigens. PLoS One 7:e31753
Moormann, Ann M; Snider, Cynthia J; Chelimo, Kiprotich (2011) The company malaria keeps: how co-infection with Epstein-Barr virus leads to endemic Burkitt lymphoma. Curr Opin Infect Dis 24:435-41
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
Moormann, Ann M; Heller, Kevin N; Chelimo, Kiprotich et al. (2009) Children with endemic Burkitt lymphoma are deficient in EBNA1-specific IFN-gamma T cell responses. Int J Cancer 124:1721-6
Munz, Christian; Moormann, Ann (2008) Immune escape by Epstein-Barr virus associated malignancies. Semin Cancer Biol 18:381-7
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

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