Dr. Smiley earned a B.Sc. from UConn (1985) and his PhD from Harvard University (1994), where he continued with a post-doc. He has worked as a scientist for Millennium BioTherapeutics, Inc. and LeukoSite, Inc. He currently is a Member of the Trudeau Institute, and an Adjunct Professor of Medicine with the University of Vermont.

The deposition of fibrin, a product of the blood coagulation pathway, accompanies many immune responses, including those that combat infection and those that cause multiple sclerosis, rheumatoid arthritis and allograft rejection. A major interest of my laboratory is to understand how and why fibrin is deposited during infection and immunity. Fibrin is widely perceived to exacerbate inflammation and disease in those settings. However, our work challenges that notion. Specifically, in collaboration with Dr. Larry Johnson (Trudeau Institute), we found that fibrin restrains hemorrhagic blood loss during infection by the protozoan parasite Toxoplasma gondii, thereby performing a host-protective function that is essential for survival. Remarkably, fibrin does not simply protect against vascular damage caused directly by the parasite, but rather, protects against hemorrhagic damage caused by IFN-gamma, a product of our immune systems. This finding, to our knowledge, was the first to decisively demonstrate a beneficial role for coagulation during immunity in vivo, and suggests that fibrin protects our tissue from collateral damage caused our immune systems as they combat infection. Follow-up studies have established that fibrin also functions protectively during bacterial infections. There, fibrin both limits hemorrhagic pathology and also suppresses growth/dissemination of bacteria. The means by which fibrin accomplishes this latter function is not yet entirely clear but, interestingly, the fibrin-mediated restraint of bacterial growth/dissemination applies both to infection by bacteria that predominantly replicate extracellularly (ex. Staphylococcus aureus) and intracellularly (ex. Listeria monocytogenes).

We are now working to define how immunity causes damage necessitating a protective coagulant response and how fibrin deposition is regulated during infection. This research is relevant to infections that evoke pathological hemorrhage (ex. Ebola virus, anthrax, plague), as well as to the large number of autoimmune, transplantation, and infectious disease settings (including septic shock) that are characterized by excessive activation of coagulation pathways. We recently discovered that host cytokines play primary roles in regulating the host-protective coagulation that accompanies infection. As prior studies suggest that these same cytokines also contribute to pathological coagulation, we hypothesize that pathological coagulation results from dysregulation of pathways that are meant to function protectively. We are now using a variety of models and methods to delineate precisely how cytokines regulate host-protective fibrin deposition during infection and immunity.

A second major project in my laboratory aims to improve vaccination against the bacterium that causes plague, Yersinia pestis. Plague has killed hundreds of millions of people during recorded history, and there is concern that terrorists may use aerosolized plague as a bioweapon. To date, plague vaccine efforts have focused largely on antibody-based humoral protection. Despite preliminary success in mouse models, recent studies by the US Army suggest that antibodies may not suffice in protecting humans against aerosolized plague, as vaccinated/challenged primates succumbed to plague despite evidence of robust humoral immunity. We suspect that cellular reservoirs of plague are not fully eradicated by humoral immunity and hypothesize that vaccines priming robust T cell-mediated cellular immunity will provide improved protection.

We began our Y. pestis vaccine studies by defining three CD4 T cell epitopes in the US Army’s currently favored vaccine antigen. We found that the T cells recognizing those epitopes failed to defend against plague in our mouse model. To evaluate whether cellular immunity directed at other antigens can protect against plague, we vaccinated B cell-deficient with live attenuated Y. pestis. We reasoned that vaccination with live Y. pestis should prime T cells against many plague antigens, and that successful vaccination of B cell-deficient mice would indicate that cellular immunity can defend against plague, since B cell-deficient mice cannot generate humoral immunity. We found that B cell-deficient mice vaccinated with live attenuated Y. pestis are protected against plague. Depleting T cells at the time of challenge abrogated protection and transferring vaccine-primed T cells to naïve mice provided protection. Together, these experiments establish that cellular immunity mediated by vaccine-primed T cells can indeed protect against plague. Current efforts are aimed at (i) identifying the Y. pestis antigens that elicit protective cellular immunity, (ii) defining the mechanisms by which T cells mediate that protection, and (iii) evaluating whether cellular and humoral immunity can synergize to provide superior protection against plague. We are simultaneously working to develop vaccination protocols that prime robust cellular immunity against plague. Basic research in these areas should aid the development of effective vaccines against plague, as well as a variety of other pulmonary bacterial infections.

Please feel welcome to contact me if you may be interested in joining my group, or if you have questions or suggestions regarding the projects described above.

Infection by Toxoplasma gondii causes hepatocellular necrosis in fibrin-sufficient mice (A), but causes hemorrhagic pathology in fibrin-deficient mice (B).

Depletion of CD4 and CD8 T cells abrogates vaccine-mediated protection against pneumonic plague (A) and specific T cells transfer protection to naive B cell-deficient mice (B).

Szaba, F.M. and Smiley, S.T. Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo. Blood. 2002 99:1053-59.

Johnson, L.L., Berggren, K.N., Szaba, F.M., Chen, W. and Smiley, S.T. Fibrin-mediated protection against infection-stimulated immunopathology. Journal of Experimental Medicine. 2003 197:801-6.

Parent, M.A., Berggren, K.N., Mullarky, I.K., Szaba, F.M., Kummer, L.W., Adamovicz, J.A. and Smiley, S.T. Yersinia pestis V protein epitopes recognized by CD4 T cells. Infection and Immunity 2005 73:2197-204.

Mullarky, I.K., Szaba, F.M., Berggren, K.N., Parent, M.A., Kummer, L.W., Chen, W., Johnson, L.L. and Smiley, S.T. Infection-stimulated fibrin deposition controls hemorrhage and limits hepatic bacterial burdens during listeriosis. Infection and Immunity 2005 73:3888-95.

Parent, M.A., Berggren, K.N., Kummer, L.W., Wilhelm, L.B., Szaba, F.M., Mullarky, I.K., and Smiley, S.T. Cell-mediated protection against pulmonary Yersinia pestis infection. Infection and Immunity 2005 73:7304-10.

Mullarky, I.K., Szaba, F.M., Berggren, K.N., Kummer, L.W., Wilhelm, L.B., Parent, M.A., Johnson, L.L. and Smiley, S.T. Tumor necrosis factor-alpha and interferon-gamma, but not hemorrhage or pathogen burden, dictate levels of protective fibrin deposition during infection. Infection and Immunity 2006 74:1181-8.

Parent, M.A., Wilhelm, L.B., Kummer, L.W., Szaba, F.M., Mullarky, I.K. and Smiley, S.T. Interferon-gamma, tumor necrosis factor-alpha and nitric oxide synthase 2, key elements of cellular immunity, perform critical protective functions during humoral defense against lethal pulmonary Yersinia pestis infection. Infection and Immunity 2006 74:3381-6.