Albany Medical Center
 Search
Home / About Us / Caring / Educating / Discovering / Directories / Maps & Directions / Ways to Give / News & Publications / Find a Doctor / Careers
College Phone Directory Maps & Directions

Discovering

INDIVIDUAL RESEARCHER

Timothy J. Sellati , Ph.D.
Associate Professor
e-mail: sellatt@mail.amc.edu


Education

1996 - Ph.D. from State University of New York at Stony Brook


Current Research

The overall goal of our research program is to understand how host responses are "tailored" to the specific pathogens they encounter, in particular, pathogens that represent re-emerging and emerging infectious agents. In pursuit of this goal, studies in the laboratory focus on two distinct, yet interrelated, aspects of bacterial pathogenesis  disease development and resolution. In both instances, we believe that innate immunity, a pre-programmed first-line defense against invading pathogens, plays a defining role in the disease process. A fundamental question we hope to answer is why some individuals present with more severe and/or persistent inflammation during infection than others. How does the immune system see bacterial pathogens? The tick-borne spirochetal bacterium Borrelia burgdorferi causes Lyme disease (LD), a multisystem chronic inflammatory disorder that affects the skin, joints, heart, and nervous system. Although many aspects of LD pathogenesis remain ill defined, it is generally accepted that clinical manifestations result primarily from the host's local immune response to spirochetes in infected tissues. Research efforts in my laboratory are designed to improve our understanding of how B. burgdorferi interacts with the body's immune system and identify constituents of the bacterium that trigger immune responses. A variety of cellular, molecular and biophysical methodologies has been applied to demonstrate that the lipid-modified membrane immunogens (e.g., lipoproteins) of spirochetes are the principal pro-inflammatory agonists during natural infection. In doing so, we have identified key players in the signal transduction pathway responsible for the immune cell activation that likely contributes to clinical manifestations. One such player is CD14, a 55-kilodalton polypeptide anchored to the surface of monocytes/macrophages via a glycosylphophatidylinositol moiety. Lipoprotein binding to CD14 results in communication of a danger signal through a down-stream signaling element, Toll-like receptor 2 (TLR2), that leads to secretion of several pro-inflammatory cytokines and chemokines; these events are thought to play a critical role in LD pathogenesis. How does the immune system temper its response to bacterial pathogens? Surprisingly, however, infected mice genetically deficient for CD14 present with more severe and persistent arthritis, a hallmark of disease in Lyme patients. One project in the laboratory seeks to define the signaling events responsible for controlling the intensity and duration of inflammation with emphasis on the PI3K/AKT/p38-MAPK cascade which serves to negatively regulate TLR2 signaling in macrophages. A second project in the lab focuses on the molecular basis for differences in clinical outcome (i.e. survival versus death) in sepsis syndrome. In collaboration with physicians in the Emergency Department at Albany Medical Center Hospital CD14 expression on peripheral blood leukocytes and in serum and the release of several pro-inflammatory biomarkers are being evaluated as prognostic tools. These studies will further our understanding of LD pathogenesis and identify novel therapeutic strategies to preserve those inflammatory responses to B. burgdorferi that are protective while hopefully reducing or eliminating those that are destructive. How does the immune system coordinate its response to bacteria that reside both outside and inside the cell Tularemia is a vector-borne zoonosis caused by Francisella tularensis, a Gram-negative facultative intracellular bacterium. F. tularensis is responsible for lethal disease in humans with as few as 10 organisms capable of causing pulmonary infection and death. These features coupled with its ability to contaminate food and water and its ease of dissemination by aerosol have resulted in F. tularensis being listed as a category A biothreat agent by the CDC. The overall objective of this project is to elucidate the cellular and molecular mechanism(s) responsible for the development of innate immunity necessary to control F. tularensis proliferation and mitigate inflammation-mediated tissue damage. Following entry into the pulmonary system, F. tularensis proliferate within alveolar macrophages and the ensuing inflammatory response is characterized by a dense neutrophilic infiltrate and focal necrosis. Like in Lyme disease pathogenesis, TLR2 plays an essential role in the initiation of host responses to F. tularensis membrane and capsular constituents (e.g., recognition of lipoproteins and ß-glucans by TLR2 and LPS by TLR4). Internal components (e.g., DNA, RNA, muramyl dipeptide, etc.) may be recognized by the intracytosolic equivalent of the TLRs, namely NOD-like receptor proteins (NLRPs). One project in the laboratory focuses on determining whether infected hosts orchestrate innate and adaptive immune response to F. tularensis through coordinating the communication of signals via TLRs and NLRs at the cellular level. The double-edged sword: What role do neutrophils play in clearing bacterial pathogens versus causing collateral damage? A second project is based upon our recent findings that mice deficient for matrix metalloproteinase 9 (MMP-9) exhibit greater resistance to lethal challenge with F. tularensis than their wild-type counterparts, even the SchuS4 strain that was weaponized by both the former Soviet Union and the U.S. Investigation of the role of MMP-9 in tularemia pathogenesis led to the discovery that fragments of extracellular matrix (e.g., collagen) generated by the action of this collagen-degrading enzyme are potent chemoattractants for neutrophils. While these cells typically function to kill and clear bacteria F. tularensis is virtually immune to their antimicrobial action. Instead, neutrophils that are activated following invasion by F. tularensis release a variety of lytic enzymes and other reactive species that damage surrounding tissue. As such, attempts to diminish the influx of these cells may hold therapeutic promise in the fight against this respiratory pathogen. We currently are evaluating the ability of small molecule antagonists to block excessive neutrophil recruitment into the lungs of F. tularensis-infected mice. How do environmental cues influence the nature of the host-pathogen relationship with respect to bacterial virulence and immune evasion? Finally, a nascent project in the lab seeks to uncover what distinguishes the early or acute phase of tularemia pathogenesis (during which little inflammation develops despite exponential bacterial replication) from the later and more severe inflammatory changes that occur shortly before mice succumb to respiratory infection. Presently, we are exploring how growth conditions (e.g., medium, isolated host cell, infected tissues) influence the pro-inflammatory capacity of F. tularensis and whether what distinguishes early and late disease reflects changes in the bacterium and/or the host. The rationale underlying this work is the belief that defining immune mechanisms that engender clinical manifestations and disease resolution is an essential first step towards development of immunotherapeutic strategies and identification of appropriate vaccine targets to combat this highly virulent contagion.


References

  1. Tupin, E., M. R. Benhnia, Y. Kinjo, R. Patsey, C. Lena, M. C. Haller, M. J. Caimano, M. Imamura, C-H. Wong, S. Crotty, J. D. Radolf, T. J. Sellati*, and M. Kronenberg*. NKT cells prevent chronic joint inflammation following infection with Borrelia burgdorferi. Proc. Natl. Acad. Sci. U.S.A., In Press. *Senior/corresponding authorship is shared by both T. J. Sellati and M. Kronenberg. (Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19863-8. Epub 2008 Dec 5.).


  2. Hazlett KR, Caldon SD, McArthur DG, Cirillo KA, Kirimanjeswara GS, Magguilli ML, Malik M, Shah A, Broderick S, Golovliov I, Metzger DW, Rajan K, Sellati TJ, Loegering DJ. Adaptation of Francisella tularensis to the mammalian environment is governed by cues which can be mimicked in vitro. (Infect Immun. 2008 Oct;76(10):4479-88. Epub 2008 Jul 21).


  3. Malik, M., C. S. Bakshi, K. McCabe, S. V. Catlett, A. Shah, R. Singh, P. L. Jackson, A. Gaggar, D. W. Metzger, J. A. Melendez, J. E. Blalock, and T. J. Sellati. Matrix Metalloproteinase 9 (MMP-9) activity enhances host susceptibility to pulmonary infection with Type A and B strains of Francisella tularensis. (J. Immunol., 178:1013-1020, 2007).


  4. Bakshi, C. S., M. Malik, K. Regan, J. A. Melendez, D. W. Metzger, V. Pavlov and T. J. Sellati. Superoxide dismutase-B (sodB) deficient mutants of Francisella tularensis demonstrate hypersensitivity to oxidative stress and attenuated virulence. (J. Bact., 188:6443-6448, 2006)


  5. Kinjo, Y., E. Tupin, D. Wu, M. Fujio, R. Garcia-Navarro, M. Rafii-El-Idrissi Benhnia, D. M. Zajonc, G. Ben-Menachem, G. D. Ainge, G. F. Painter, A. Khurana, K. Hoebe, S. M. Behar, B. Beutler, I. A. Wilson, M. Tsuji, T. J. Sellati, C.-H. Wong and M. Kronenberg. NKT cells recognize diacylglycerol antigens from pathogenic bacteria. (Nat. Immunol., 7:978-986, Epub Aug 20, 2006).