Research:

Expertise

Research Interests:

Pediatric immunity to infectious diseases focusing on Plasmodium falciparum malaria and Epstein Barr Virus (EBV), molecular epidemiology, Global Health Research, and the etiology of endemic Burkitt lymphoma in Africa.

Professor Ann M. Moormann
is leading a study which aims to shed light on endemic Burkitt lymphoma. Here, she talks about her studies to date and her hopes for the future of her research: Understanding Endemic Burkitt Lymphoma

Description of Research Projects

Pediatric immunity and malaria
Understanding the development and maintenance of adaptive immunity to Plasmodium falciparum malaria in pediatric populations residing in African countries, where this parasitic infection is responsible for 1-2 million deaths each year, is the underlying them to the research conducted in my lab. Our studies of cellular and humoral immune responses to various malaria antigens from naturally infected humans help inform malaria vaccine design. Understanding the evolution of protective T cell memory to malaria also involves genotyping immunologically relevant malaria protein epitopes.

Malaria and EBV co-infections in the etiology of endemic Burkitt lymphoma
Endemic Burkitt lymphoma (eBL) is the most common pediatric cancer in sub-Saharan African and has been linked to early-age Epstein-Barr virus (EBV) infection and geographically to regions with high malaria transmission intensity (ie holoendemic malaria). Uncovering the etiologic mechanisms that explain how these pediatric co-infections lead to eBL is the another area of research in my laboratory.

Pediatric immunity to other infections and vaccine preventable diseases (ie measles)
Other co-infections of interest to our group include schistosomiasis, measles virus, and cytomegalovirus (CMV) due to either their immune-modulating potential or their ability to induce antigen-specific T cell immunity not associated with cancer that can serve as a positive control for our eBL studies. Such studies also provide a better understanding of fundamental aspects of T cell immunity in infants and young children.

Immunologic and viral predictors of survival for children with endemic Burkitt lymphoma
This project aims to establish non-invasive, readily measured correlates of long-term survival in pediatric patients diagnosed with endemic Burkitt lymphoma (eBL); that in turn can be used within the context of a future clinical trial aimed at improving the chemotherapeutic regimen used to cure this pediatric cancer. The kinetics and clinical usefulness of biomarkers such as EBV viral loads, the function and phenotype of EBV-specific T cell immunity and EBV serological profiles will be evaluated as diagnostic predictors within the context of our longitudinal study.

Potential rotation projects
My lab primarily investigates Plasmodium falciparum malaria-induced dysregulation of EBV-specific T cell immunity and its role in the etiology of endemic Burkitt lymphoma (eBL), the most prevalent pediatric cancer in Equatorial Africa. Within the context of our ongoing studies of healthy Kenyan children with divergent malaria exposure histories (chronic/repeated infections in a holoendemic area versus low infection rates in a nearby highland, malaria hypoendemic area) and by examining children diagnosed with eBL we have established a repository of samples that can be used to address this question.

1. One avenue of exploration involves homeostatic cytokine regulation of memory T cells. IL-15 and/or IL-7 responsiveness of EBV-specific memory T cells may be impaired in children with chronic malaria exposure and in children with endemic Burkitt lymphoma (eBL). We would like to investigate IL-15Ra and IL-7Ra surface expression, and CFSE proliferation of EBV-specific T cells in response to cognate antigen with and without IL-15 or IL-7 stimulation and compared children with divergent malaria exposure histories and children diagnosed with eBL. T cell responsiveness to IL-15 and IL-7 can be measured by STAT5 phosphorylation and the specificity of this effect for EBV-specific T cells can be evaluated by comparing IL-15Ra and IL-7Ra expression and responsiveness on other lymphocyte subsets and CMV-specific T cells.

2. Another putative mechanism by which malaria may interfere with the development of immunologic memory and influence EBV-specific T cell immunity is through the Programmed death-1 (PD-1) pathway. PD-1 is an immune inhibitory molecule that negatively regulates activated immune cells upon interacting with its ligands, programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2) resulting in down-regulation of immune responses. Previous studies in murine and primate viral and parasitic diseases have reported the up-regulation of PD-1 and soluble PD-1 (sPD-1) but no studies have reported the expression of PD-1 in individuals from areas with divergent malaria transmission dynamics or in children presenting with endemic Burkitt lymphoma (eBL). In addition the PD-1 pathway has been suggested to be involved in the evasion of antitumor immunity by the host immune system. Preliminary studies in my lab suggest that PD-1 expression is significantly increased on CD4, CD8 T cells, B cells and NK cells in those residing in high malaria transmission areas compared to age-matched individuals without a history of malaria exposure. Future studies will explore the kinetics of this effect, the impact of antigen dose and how malaria exploits PD-1 mediated regulation to impair the development of immunologic memory.

3. Another area of interest is the role of Th17 cells in pediatric immunity. Because of the naturally delayed production of T_H1 mediated pro-inflammatory cytokines (i.e. IL-12 and IFN-g) in utero, neonatal immunity is thought to be ‘suppressed’. However, more recent studies have shown that neonatal monocytes and antigen-presenting cells do express pro-inflammatory and regulatory cytokines (i.e. IL-6, IL-10 and IL-23) and at higher levels than adults. Thus T_H17 cells appear to be an early, sequential response to pathogens prior to the induction of a T_H1 or T_H2 response. T_H17 cells are also stimulated with IL-21 and IL-22 in an autocrine and paracrine fashion by natural killer cells. Exploring Th17 cell responses within the context of early-age human infections with malaria and EBV would be an exciting new avenue of investigation in my laboratory.