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U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated. Bacterial Toxin Repression of Nuclear Hormone Receptors: Host-Pathogen-Hormone Interactions and Implications for Therapy Esther M. Sternberg, M.D. National Institute of Mental Health National Institutes of Health Host Hormone-Immune-Bacterial Interactions: Implications for Susceptiblity to Inflammatory Sequelae of Bacterial Infections • Do hormones affect host inflammatory/immune responses? – Glucocorticoids – Estrogen – Progesterone • Do bacterial toxins interact with host hormone responses? – B. anthracis LeTx – C. difficile TcdA, TcdB – C. sordellii TcsL • Does blocking bacterial - host hormone - immune interactions predispose to inflammatory sequelae of bacterial exposure in vivo? Host Hormone-Immune-Bacterial Interactions: Implications for Susceptiblity to Inflammatory Sequelae of Bacterial Infections • Do hormones affect host inflammatory/immune responses? – Glucocorticoids – Estrogen – Progesterone • Do bacterial toxins interact with host hormone responses? – B. anthracis LeTx – C. difficile TcdA, TcdB – C. sordellii TcsL • Does blocking bacterial - host hormone - immune interactions predispose to inflammatory sequelae of bacterial exposure in vivo? Effects of Estrogen & Progesterone on T Helper Phenotypes: Cellular Humoral Glucocorticoids Lahita, 1999 Ovulation Relative Concentrations Estrogen & Progesterone Vary during the Menstrual Cycle 10-9M - 10-8M 10-11M - 10-10M 1 Follicular Phase Progesterone Estrogen 14 Day Luteal Phase 28 Changes in Immune Function during Menstrual Cycle No Immunologic effects Ovulation Relative Concentrations Ð T lymph chemokine receptors Ï Ab production Ï infection susceptibility • bacterial vaginosis, genital Herpes, chlamydia, HIV 10-9M - 10-8M 10-11M - 10-10M 1 Follicular Phase Progesterone Estrogen 14 Day Luteal Phase 28 Progesterone, Estrogen, Glucocortcoids during Pregnancy 10-8M - 10-7M Relative Concentrations Progesterone Glucocorticoids First Trimester Second Trimester Third Trimester Parturition Estrogen Changes in Immune Function during Pregnancy 10-8M - 10-7M Relative Concentrations Progesterone Glucocorticoids Strong immunosuppression Suppressor T cells Ï Cytotoxic T cell function greatly Ð NK cytotoxic function greatly Ð Ab production Ï Ï susceptibility T. gondii infection First Trimester Second Trimester Third Trimester Parturition Estrogen Dendritic Cells: bridge between innate inflammation and adaptive immune responses Innate Adaptive Hoebe, Janssenz & Beutler Nat. Immunol. (2004) 5:971-974 % Expression Steroid Hormone Receptor Expression in Cultured Dendritic Cells (CD11c+) GR AR PR FACS Analysis: % DCs expressing steroid hormone receptors (female rats). Fluorescent micrograph cultured DC cells expressing PR in cytoplasm Progesterone Receptor Nucleus Butts et al. unpublished data not for dissemination Progesterone Effects on DC Cell Function: ( C. Butts et al., submitted 2006) Progesterone has functional effects on mature but not immature DCs: • Does not affect Ag uptake by immature DCs • Suppresses pro-inflammatory (TNFα) but not anti-inflammatory (IL-10) cytokine production • Down-regulates co-stimulatory molecule expression (MHCII & CD80) Overall effect of progesterone on DCs is anti-inflammatory Host Hormone-Immune-Bacterial Interactions: Implications for Susceptiblity to Inflammatory Sequelae of Bacterial Infections • Do hormones affect host inflammatory/immune responses to bacterial infection/ bacterial products? – Glucocorticoids – Estrogen – Progesterone • Do bacterial toxins interact with host hormone responses? – B. anthracis LeTx – C. difficile TcdA, TcdB – C. sordellii TcsL • Does blocking bacterial - host hormone - immune interactions predispose to inflammatory sequelae of bacterial exposure in vivo? Selective B. anthracis LeTx repression of nuclear hormone receptors is both receptor and promoter dependent GRE GRE GRE MMTV MMTV GRE MMTV MMTV ARE ARE MMTV MMTV GRE GRE MMTV MMTV Webster & Sternberg Mol. Cell Endocrinol. (2005) 241. 21-31 Host Hormone-Immune-Bacterial Interactions: Implications for Susceptiblity to Inflammatory Sequelae of Bacterial Infections • Do hormones affect host inflammatory/immune responses to bacterial infection/ bacterial products? – Glucocorticoids – Estrogen – Progesterone • Do bacterial toxins interact with host hormone responses? – B. anthracis LeTx – C. difficile TcdA, TcdB – C. sordellii TcsL • Does blocking bacterial - host hormone - immune interactions predispose to inflammatory sequelae of bacterial exposure in vivo? Mortality in Animal Models where HPA Axis is Interrupted SCW Arthritis • RU-486 • cort EAE Sternberg et al. PNAS 89 100% mortality (F344 rats) 13% mortality MacPhee et al. J Exp Med 89 • ADX • cort Salmonella • hypophysect • cort MCMV 80% mortality 22% mortality Edwards et al. PNAS 91 100% mortality 5% mortality Ruzek et al. J. Immunol. 99 • ADX • cort Shiga toxin • ADX • cort 100% mortality 20% mortality Gomez et al. Clin. Exp. Immunol. 60% mortality 10% mortality Interruption of GC response affects LeTx mortality: Adx increases mortality in LeTx-resistant mice % SURVIVAL 100 BALB/cJ BALB/cJ-ADX C57BL/6J C57BL/6J-ADX DBA/2J DBA/2J-ADX 75 x d A 50 x d A 25 0 0 50 100 150 HOURS POST TOXIN INJECTION M Moayeri et al, Infect. Immunity, 73 (7) 4238-4244, (2005) 200 Dexamethasone did not Rescue Adrenalectomized LeTx-Treated Mice % SURVIVAL 100 DBA/2J-SAL+LT DBA/2J-DEX-NT DBA/2J-DEX300+LT DBA/2J-DEX100+LT DBA/2J-DEX10+LT DBA/2J (ADX)-SAL+LT DBA/2J (ADX)-DEX300+LT DBA/2J (ADX)-DEX10+LT 75 50 25 X E D 0 0 50 100 TIME (HRS) M Moayeri et al, Infect. Immunity, 73 (7) 4238-4244, (2005) 150 RU-486 had variable effects on B. anthracis LeTx mortality, suggesting that adrenal factors other than GC may play a role. M Moayeri et al, Infect. Immunity, 73 (7) 4238-4244, (2005) Summary • Glucocorticoids & progesterone suppress inflammatory responses. • Clostridia bacterial toxins partially repress GR transactivation. • Clostridia bacterial toxins partially reverse Dex suppression of TNFα production. HOST BACTERIAL PRODUCTS HOST IMMUNE/ INFLAMMATORY RESPONSE HORMONAL RESPONSE (HPG, HPA) BACTERIAL PRODUCTS Future Directions – What happens when these factors interact in vivo? – Do GR/PR antagonists (e.g. RU-486) prevent GC/P suppression of inflammatory responses in vivo? • Time-course after exposure to bacterial products? • Dose response? • Interactions with other drugs (prostaglandin)? – Are there host factors predisposing to susceptibility to infection/shock? • Hormone levels (pregnancy, menstrual cycle phase) • GR and PR resistance (receptor polymorphisms, mutations) Acknowledgements SNIB/NIMH/NIH Esther Sternberg A. Sasha Tait Cherie Butts Elena Belyavskaya Heather Gorby Andrea Marques-Deak Zhigang Kang Cash Horn Eve Bowers Jeanette Webster* Leonardo Tonelli* Farideh Eskandari* Shetha Shukair* Kristina Duncan* Monique Dalton* NIAID/NIH Steven Leppla Mahtab Moayeri CDC Lawrence McDonald Sherif Zaki NIAAA/NIH George Kunos Pal Pacher GSK, UK Stuart Farrow NIDDK/NIH S. Stoney Simons Giovanni Cizza Kenner Rice Institut Pasteur FR Michel Popoff OD/NIH Terry Phillips FDA Felice D’Agnillo