James Burns Associate Professor, Microbiology and Immunology Ph.D., 1989, Hahnemann University, Philadelphia, PA 2900 Queen Lane Philadelphia, PA 19129 Tel: 215-991-8490 Fax: 215-848-2271 Email: jburns@drexelmed.edu

Research Staff: Michelle Lynch
Graduate Students: Patricia Petritus, Swati Thorat, Amy Cernetich-Ott, James Alaro, Kristen Weaver

Keywords:

malaria, vaccines, immunity to blood-stage malaria, rodent models of malaria

Research Interests

Extensive studies in humans and animal models indicate that acquired immunity to malaria develops.  Nevertheless, the goal of reducing malaria morbidity and mortality through active immunization has not been achieved. As such, Plasmodium falciparum malaria remains one of the most significant public health problems in the world today. The long-term goal of our research is to maximize the protective immunity against blood-stage malaria induced by immunization with defined subunit vaccines. We utilize the Plasmodium yoelii and Plasmodium chabaudi rodent models of malaria to gain in vivo experimental data on protective antigens and immune mechanisms. We apply these data to the investigation of human malaria in parallel in vitro studies of P. falciparum blood-stage parasites.

Merozoites are the extracellular forms of malaria parasites that invade host red blood cells and merozoite surface proteins (MSPs) that engage receptors on host erythrocytes are clear vaccine targets. One leading vaccine candidate is MSP-1, which contains conserved EGF-like domains within its C-terminus that are targets of invasion-inhibitory antibodies. Our first project is focused on MSP-8, a second GPI-anchored membrane protein identified in studies of P. yoelii that also contains two C-terminal EGF-like domains. Immunization with recombinant P. yoelii MSP-8 protects mice against an otherwise lethal P. yoelii infection. The expression, localization and erythrocyte binding activity of MSP-8 as well as the T and B cell responses that correlate with protection induced by immunization are under investigation. We are particularly interested in how responses induced upon exposure to viable blood-stage parasites affect the efficacy of MSP-based vaccines. Vaccine formulations and delivery systems are being manipulated to optimize protection against P. yoelii malaria induced by immunization with recombinant P. yoelii MSP-8 antigens formulated in combination with MSP-1. Based on our studies in the P. yoelii model, we are pursing the production and testing of a chimeric P. falciparum MSP vaccine antigen designed to promote the production of antibodies to protective B cell epitopes of both MSP-1 and MSP-8.

In the course of our P. yoelii studies, we also observed that parasites which preferentially invade young reticulocytes as opposed to mature erythrocytes escape neutralization by antibodies induced by MSP-8 immunization. We examined changes in gene expression in reticulocyte-restricted P. yoelii 17XL parasites that escaped neutralization by PyMSP-8 specific antibodies using P. yoelii DNA microarrays. Changes in the expression of a subset of merozoite and rhoptry protein genes were noted. Breakthrough parasites also exhibited increases in the expression of a subset of yir and pyst-a genes that are predicted to encode polymorphic antigens expressed on the surface of infected erythrocytes. Studies are ongoing to test the hypothesis that parasite proteins expressed on the surface of infected erythrocytes direct the localization of parasitized RBCs to sites of erythropoiesis prior to merozoite release, facilitating the efficient invasion of newly formed reticulocytes and reducing exposure to merozoite neutralizing antibodies.

In collaborative studies with Dr. William P. Weidanz, University of Wisconsin-Madison and Dr. Carole A. Long, NIH-NIAID, we are investigating cell-mediated mechanisms of immunity that lead to the resolution of acute malaria in a naïve host and in vitro correlates of protective immunity induced by defined subunit vaccines (AMA-1, MSP-1, MSP-8). In particular we are interested in IFNγ-dependent mechanisms of immunity and role of multifunctional CD4+ T cells. For these studies, we utilize both the Plasmodium chabaudi and Plasmodium yoelii murine models. Correlates of protective T cell and B cell responses defined in vitro are then validated in vivo by passive immunization studies and through the immunization and infection of selected immunological knockout mice deficient in the expression of components of antibody-mediated and/or cell-mediated immunity. 

Selected Research Publications

1. Burns, Jr., J.M., P.D. Dunn and D.M. Russo. Protective immunity against Plasmodium yoelii malaria induced by immunization with particulate blood-stage antigens. Infect. Immun., 65: 3138, 1997.
   
   
2. Russo, D.M., P. Chakrabarti, and J.M. Burns, Jr. Naive human T cells develop into Th1 or Th2 effectors and exhibit cytotoxicity early after stimulation with Leishmania infected macrophages. J. Infect. Dis., 177: 1345, 1998.
   
   
3. Burns, Jr., J.M., E.K. Adeeku, and P.D. Dunn. Protective immunization with a novel membrane protein of Plasmodium yoelii - infected erythrocytes. Infect. Immun., 67: 675, 1999.
   
   
4. Burns, Jr., J.M., E.K. Adeeku, C.C. Belk, and P.D. Dunn. An unusual tryptophan-rich domain characterizes two secreted antigens of Plasmodium yoelii infected erythrocytes. Mol. Biochem. Parasitol., 110: 11, 2000.
   
   
5. Burns, Jr., J.M., C.C. Belk, and P.D. Dunn. A protective GPI-anchored membrane protein of Plasmodium yoelii trophozoites and merozoites contains two epidermal growth factor-like domains.  Infect. Immun., 68: 6189, 2000.
   
   
6. Burns, Jr., J.M., P.R. Flaherty, and W.P. Weidanz. Immunization against Plasmodium chabaudi malaria using combined formulations of apical membrane antigen-1 and merozoite surface protein-1.  Vaccine, 21: 1843, 2003.
   
   
7. Batchelder, J.M., J. M. Burns, Jr., F. K. Cigel, H. Lieberg, D. D. Manning, B. J. Pepper, D. M. Yanez, H. van der Heyde, W. P. Weidanz. Plasmodium chabaudi: IFN-γ but not IL-2 is essential for the expression of cell-mediated immunity against blood-stage parasites in mice. Exp. Parasitol. 105:159, 2003.
   
   
8. Mello, K., T. M. Daly, C. A. Long, J. M. Burns, Jr. and L. W. Bergman. MSP-7 family members with similar expression patterns differ in ability to immunize against Plasmodium yoelii malaria. Infect. Immun. 72:1010, 2004.
   
   
9. Burns, Jr., J.M., P. R. Flaherty, P. Nanavati, and W.P. Weidanz. Protection against Plasmodium chabaudi malaria induced by immunization with apical membrane antigen-1 and merozoite surface protein-1 does not require IFN-γ or IL-4.  Infect. Immun. 72:5605, 2004.
   
   
10. Rummel, T., J. Batchelder, P. Flaherty, G. Lafleur, P. Nanavati, J. M Burns, Jr. and W. P. Weidanz. CD28 co-stimulation is required for the expression of T cell dependent, cell-mediated immunity against blood-stage Plasmodium chabaudi malaria parasites. Infect. Immun. 72:5768, 2004
    
    
11. Shi, Q., A. Cernetich, T. M. Daly, G. Galvan, A. B. Vaidya, L. W. Bergman and J. M. Burns, Jr. Alteration in host cell tropism limits the efficacy of immunization with a surface protein of malaria merozoites. Infect. Immun. 73:6363, 2005.
    
    
12. Shi, Q., A. Cernetich-Ott,  M. M. Lynch and J. M. Burns, Jr. Expression, localization and erythrocyte binding activity of Plasmodium yoelii merozoite surface protein-8. Mol. Biochem. Parasitol. 149:231, 2006.
    
    
13. van der Heyde, H.C., J. Horn,  J .M.  Burns, Jr., W. P. Weidanz, I. Gramaglia, J. P. Nolan. Analysis of antigen-specific antibodies and their isotypes in experimental malaria. Cytometry 71:242, 2007.
    
    
14. Shi, Q., M. M. Lynch, M. Romero and J. M. Burns, Jr. Enhanced protection against malaria by a chimeric merozoite surface protein vaccine. Infect. Immun. 75:1349, 2007.
    
    
15. Petritus, P. M. and J. M. Burns, Jr. Suppression of lethal Plasmodium yoelii malaria following protective immunization requires antibody-, IL-4-, and IFN-γ-dependent responses induced by vaccination and/or challenge infection. J. Immunol., 180: 444, 2008.