|Institution||College of Medicine|
|Address||500 University Drive Hershey PA 17033|
Physician, Associate Professor of Medicine, and Microbiology and Immunology
GRADUATE PROGRAM AFFILIATIONS:
Microbiology and Immunology
Fellowship, Infectious Disease, Walter Reed Army Medical Center (District of Columbia) (1994)
Residency, Internal Medicine, Emory University School of Medicine (Georgia) (1988)
M.D., University of Miami School of Medicine (Florida) (1985)
My laboratory focuses on the study of malaria, in particular Plasmodium falciparum. I have three areas of interest: pathogenesis, mechanisms of red cell invasion, and development of novel treatment strategies.
P. falciparum malaria kills close to one million people per year. Most of these deaths occur in children in sub-Saharan Africa and are due to complications such as severe anemia and cerebral malaria. We do not have a complete understanding of the mechanisms that lead to these complications and we are also in need of better treatment strategies to decrease their mortality.
Severe Malarial Anemia (SMA):
Uninfected red cells are cleared from the circulation in greater numbers than infected red cells. The reasons for this are unknown. My laboratory has concentrated in understanding the role of complement and complement regulatory proteins in the destruction of uninfected red cells during P. falciparum malaria. We have documented that red cells from children with SMA have decreased complement receptor 1 (CR1/CD35) and decay accelerating factor (CD55/DAF). These two proteins act to protect red cells from complement activation. In addition, we have observed that these red cells have increased surface IgG and complement (C3) which can mark them for destruction when they interact with macrophages in the liver or spleen. We are currently developing a novel mouse model of SMA in which to test these ideas and develop novel strategies for treatment.
Cerebral Malaria (CM):
CM manifests itself as coma or seizures. It usually occurs in older children and adults. The pathognomonic lesion of CM in postmortem studies is sequestration of parasites in cerebral capillaries by adherence to endothelial cells. One school of thought is that this sequestration leads to decreased perfusion and CM. Ohters believe that local inflammation leading to production of cytokines and other inflammatory mediators can interfere with neurotransmitters. Other data from mice and human studies suggest that complement activation also plays a role here. Because there is a clear age differential predisposition to CM vs. SMA, we have concentrated in identifying differences in the expression of complement receptors on red cells. We have documented that CR1 and CD55 expression on red cells is high after birth and it dips to a nadir between 6-24 months and increases thereafter into adulthood. Therefore, it is possible that higher expression of complement receptors later in life places patients at risk. Data from other laboratories are supportive of this hypothesis. Our current work is concentrating on testing the role of complement and complement receptors using mouse knockouts in a model of cerebral malaria.
Mechanisms of Red Cell Invasion:
The mechanisms by which P. falciparum invades red cells are complex. The parasite has multiple ligands that can bind to a variety of red cell receptors. There is significant redundancy which is felt to be intended to evade the immune responses of the host. These factors have prevented the development of an effective vaccine that prevents red cell invasion. We recently demonstrated that the complement receptor 1 (CR1) is a red cell receptor of P. falciparum and is used for invasion. Our work is currently concentrated on understanding how this receptor is used and on identifying P. falciparum ligands that interact with it.
Development of Immunomodulators:
It is clear that effective immunomodulators are needed as adjunct therapy of SMA and CM, diseases in which the immune response of the host against the parasite is central to their pathogenesis. Children with SMA frequently required blood transfusions but in endemic countries they are seldom available when needed. Therefore, we need better ways to preserve the red cell mass in these children.
With funding from the Gates Foundation, we are currently exploring the use of low power microwaves as potential treatment for malaria.
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