Alina Boesteanu Research Assistant Professor Microbiology and Immunology Ph.D., Pennsylvania State University, 1999 2900 Queen Lane Philadelphia, PA 19129 Tel: 215-991-8386 Fax: 215-848-2271 Email: alina.boesteanu@drexelmed.edu

Keywords:

innate immunity, immune response, influenza virus, CD4+ T cells, CD8+ T cells.

Research Interests:

Seasonal influenza virus infections affect 5-15% of the human population and 250,000-500,000 deaths occur each year, due to severe pneumonia, multiple organ failure, or acute respiratory distress-like syndrome.  Although the exact mechanism of influenza pathogenicity is unknown, the induction of an overreacting immune response is the primary suspect. In mice, infection with sub-lethal doses of influenza virus type A induces morbidity manifested as extensive weight loss, labored breathing, and loss of appetite. A recent study on the mechanisms of pathogenicity of influenza virus that caused the 1918 pandemic revealed that mice infected with this virus manifested an early activation of pro-inflammatory and cell-death pathways. What induces the cytokine storm in severe influenza disease is however currently unknown.  

My research covers three areas related to influenza virus infection:

• analysis of the role played by the innate and the adaptive immune responses in the pathogenicity associated with influenza virus immune response
• identification of chemical compounds that can attenuate the morbidity induced by viral infection
• development of a “universal” vaccine against influenza virus that elicits a potent CD8+ T cell immune response against viral epitopes that are conserved across different flu virus strains.  

Using as a model the immune response mounted by C57BL/6 mice experimentally infected with influenza virus type A, we examine the very early events of the immune response that may trigger the cytokine storm associated with flu pathogenesis (Toll like receptor signaling, production of type I interferon and tumor necrosis factor, activation of dendritic cells, NK and NKT cells, B cells, CD8+ and CD4+ T cells). Short oligonucleotides have been shown to inhibit pro-inflammatory cytokine production by cells infected with influenza virus. Based on this observation, we are currently examining in vivo the mechanism by which oligonucleotides can block the pro-inflammatory cytokines, lung cellular infiltration, and the weight loss in mice infected with influenza virus.

Conferring protection to multiple strains of influenza virus by vaccination is another way to reduce morbidity associated with this viral infection. We are currently testing in mice a biogel-encapsulated live influenza virus vaccine that generates a strong memory CD8+ T cell immune response to an epitope derived from the nucleoprotein of influenza virus which is conserved across multiple strains of this virus. The efficiency of this vaccine will be further tested in ferrets because of the similarity of the flu infection symptoms between humans and ferrets. 

Selected Research Publications:

1. Joyce, S., Negishi, I., Boesteanu, A., DeSilva, A. D., Sharma, P., Chorney, M. J, Loh, D. Y., and Van Kaer, L.  Expansion of natural (NK1+) T cells that express alpha/beta T cell receptors in transporters associated with antigen presentation-1 null and thymus leukemia antigen positive mice. Journal of Experimental Medicine, 184, 1579 - 1584, 1996.

2. Sanjeev K. Mendiratta, Martin, W. D., Hong, S., Boesteanu, A., Joyce, S., and Van Kaer, L.  CD1d1 mutant mice are deficient in natural T cells that promptly produce IL-4. Immunity, 6, 469 - 477, 1997.

3. Boesteanu, A., DeSilva, A.D., Nakajima, H., Leonard, W.J., Peschon, J.J., and Joyce, S.  Distinct roles for signals relayed through the common cytokine receptor gamma chain and interleukin 7 receptor alpha -chain in natural T cell development. Journal of Experimental Medicine, 186, 331 - 336, 1997.

4. Joyce, A., Woods, A. S., Yewdell, J. W., Benick, J., DeSilva, A. D., Boesteanu, A., Balk, S. P., Cotter, R. J., and Brutkiewicz, R. R..  Natural ligand of Mouse CD1d1: cellular glycosylphosphatidylinositol.  Science, 279, 1541 - 544, 1998.

5. Boesteanu, A., Brehm, M., Mylin, L.M., Christianson, G.J., Tevethia, S.S., Roopenian, D.C., and Joyce, S. A molecular basis for how a single T cell receptor interfaces multiple ligands. Journal of Immunology, 161, 4719 - 4727, 1998.

6. De Silva, D., Boesteanu, A., Song, R., Nagy, N., Harhaj, E., Harding, C. V., and Joyce, S.  Thermolabile H-2Kb molecules expressed by transporter associated with antigen processing-deficient RMA-S cells are occupied by low-affinity peptides. Journal of Immunology, 163, 4413 - 4420, 1999.

7. Mylin, L. M., Schell, T.D., Roberts, D., Epler, M., Boesteanu, A., Collins, E.J., Frelinger, J.A., Joyce, S., and Tevethia, S.S. Quantitation of CD8(+) T-lymphocyte responses to multiple epitopes from simian virus 40 (SV40) large T antigen in C57BL/6 mice immunized with SV40, SV40 T-antigen-transformed cells, or vaccinia virus recombinants expressing full-length T antigen or epitope minigenes.  2000. Journal of Virology, 74(15), 6922 -6934.
   

8. Jordan, M. S., Boesteanu, A., Reed, A. J., Petrone, A. L., Holenbeck, A. E., Lerman, M. A., Naji, A., and Caton, A.J. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nature Immunology, 2(4), 301 - 306, 2001.

9. Yadav, R., Yoshimura, Y., Boesteanu, A., Christianson, G.J., Ajayi, W.U., Shashidharamurthy, R., Stanic, A.K., Roopenian, D.C., and Joyce, S. The H4b minor histocompatibility antigen is caused by a combination of genetically determined and posttranslational modifications. Journal of Immunology, 170(10), 5133-5142, 2003.
   
   
10. Caton, A. J., Cozzo, C., Larkin, J. 3rd, Lerman, M.A., Boesteanu, A., Jordan, M.S. CD4(+) CD25(+) regulatory T cell selection. Ann N Y Acad Sci., 1029, 101-114, 2004.
    
    
11. Cozzo, C., Lerman, M.A. Boesteanu, A, Larkin, J 3rd, Jordan, M.S., and Caton A.J. Selection of CD4+CD25+ regulatory T cells by self-peptides. Curr Top Microbiol Immunol., 293, 3 - 23, 2005.
    
    
12. Boesteanu, A., A. L. Rankin, and Caton, A.J. Impact of effector cell differentiation on CD4+ T cells that evade negative selection by a self-peptide. International Immunology, 18(7), 1017-27, 2006.
    
    
13. Cozzo, C., Larkin, J. 3rd, Boesteanu, A., Lerman, M.A., Rankin, A. L., and Caton, A.J.  Role of TCR specificity in CD4CD25 regulatory T-cell selection. Immunological Reviews, 212, 74-85, 2006.
    
    
14. Borowski, A. B., Boesteanu, A. C., Mueller, Y. M., Carafides, C., Topham, D. J., Altman, J. D., Jennings, S. R., and P. D. Katsikis. Memory CD8+ T cells require CD28 costimulation. J. Immunol, 179 (10): 6494-6503, 2007.
    


15. Douglas, V., Dolfi, D., Boesteanu, A. C., Petrovas, C., Xia, D., Butz, E. A. and P. D. Katsikis. Late signals from CD27 prevent Fas dependent apoptosis of primary CD8+ T cells. J. Immunol., 180: 2912–2921, 2008.