Timothy J. Sellati, PhD
Distinguished Fellow & Chair Department of Infectious Diseases Drug Discovery Division, Southern Research
Southern Research Institute, Birmingham, AL
“Controlling the Inflammatory Response in Lyme Arthritis–What the Mouse Model teaches Us About Human Disease”
Timothy J. Sellati joined the Southern Research Institute as a Senior Research Fellow and Chair of the Department of Infectious Diseases in the Drug Discovery Division November 2015. He received a BA degree in Biology from Dowling College in 1985 and a PhD degree in Cellular and Developmental Biology from the State University of New York at Stony Brook in 1996. Dr. Sellati began postdoctoral training in 1996 at the University of Texas Southwestern Medical Center in Dallas and completed his training in 1999 at the University of Connecticut Health Science Center in Farmington. After joining the Center for Immunology and Microbial Disease at Albany Medical College as an Assistant Professor in December 2000 he was promoted to Associate Professor in 2005 and earned tenure in 2010. In July 2013 through October 2015 Dr. Sellati served as an Associate Member at the Trudeau Institute in Saranac Lake, NY.
During both his graduate and postdoctoral training he studied host responses to the spirochetal pathogens Borrelia burgdorferi and Treponema pallidum, the respective causative agents of Lyme disease and syphilis. Currently the major focus of the Sellati laboratory is to delineate the role of CD14 and TLR2 signaling in innate immunity to B. burgdorferi and Francisella tularensis, the causative agent of tularemia and a CDC Category A biological threat agent. Dr. Sellati was the Immunology Scientific Councilor for the International Endotoxin and Innate Immunity Society, the past President of the Eastern New York Branch of the American Society for Microbiologists, and has served as ad hoc member of a number of NIAID Study Section review panels and reviewer for several scientific journals in the areas of immunology and microbiology.
Conference Lecture Summary
Genotype profoundly influences disease severity in the murine model of Lyme borreliosis, caused by the spirochetal bacterium Borrelia burgdorferi. Infected C57BL/6 (B6) and C3H/HeN (C3H) mice develop very mild and severe Lyme arthritis, respectively. Expression of the immunosuppressive cytokine interleukin-10 (IL-10) by B6, but not C3H mice has long been associated with these strain differences in disease presentation. However, the underlying mechanism(s) of genotype-specific IL-10 regulation remained elusive. Herein, we reveal a cyclic AMP (cAMP)-mediated mechanism of IL-10 regulation in B6 mice that is absent in C3H mice, which provides insight into the clinical spectrum of human Lyme disease, particularly those suffering from treatment-refractory arthritis. We show that bone marrow-derived monocytes (BMDMs) from B6 mice mount a more tempered, protective immune response to borrelial infection by virtue of the action of cAMP and CD14-p38-MAPK signaling; which, in combination, is responsible for increased production of the anti-inflammatory cytokine IL-10 and decreased production of potent pro-inflammatory and arthritogenic cytokines, including TNF. cAMP relaxes chromatin structure through modification of histones while CD14-dependent p38 MAPK activity increases binding of STAT3 and SP1 to their cognate sites on the now accessible IL-10 promoter, facilitating increased IL-10 production. Thus, cAMP and CD14 regulate IL-10 production and dampen the release of pro-inflammatory mediators elicited by B. burgdorferi by changing the epigenetic ‘landscape’. In stark contrast, arthritis-susceptible C3H mice lack basal levels of cAMP comparable to those of their disease-resistant B6 counterparts and thus are ill equipped to mitigate the damaging consequences of B. burgdorferi-induced TNF through production of IL-10. Intriguingly, reciprocal regulation of IL-10 and TNF by cAMP- and CD14-dependent mechanisms are operative in primary human peripheral blood monocytes and cAMP-enhancing drugs show therapeutic efficacy in our mouse model of Lyme arthritis.