Download U.S. Food and Drug Administration Notice: Archived Document

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 It was current when produced, but is no longer maintained and may be outdated.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