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Fasciola hepatica and Host Responses – A Network of
Intrigue
Grace Mulcahy UCD School of Veterinary Medicine
Oh what a tangled web we weave, When first we practise to deceive!
Sir Walter Scott, Marmion, Canto vi. Stanza 17.
Knowledge of Host Immune Responses
Vaccine Technology
Immunoregulation
Immune Responses of Cattle
• Aged cows can be readily re-infected
• Lymphocyte responsiveness correlates positively with fluke burden
(Clery et al., 1996)
• After initial stimulation, lymphocyte and γ-INF responses are suppressed
(Clery and Mulcahy., 1996)
Cows
Heifers
Immune Responses of Cattle • IgG1 is the dominant antibody class
• Th0 and then Th2 clones are detected following infection (Brown et al. 1994)
• Restimulation of PBMC induces IL-4 and IL-10
• Multiple antigens recognised – ES antigens (Cathepsin L1) dominant
Log
Tit
re
Weeks post Infection
IgG1
IgG2
Vaccination using Cathepsin L1 Alters Antibody Isotype and Avidity
IgG1 IgG2
V V
C C
Macrophage Activation
Protection in low-challenge field trial
15
5.38 4.85
0
2
4
6
8
10
12
14
16
Control Adj A Adj B
Flukes
Fluk
e Num
bers
Summary
• Immune responses of cattle infection permit chronic infection and do not prevent re-infection
• Responses are associated with suppression of lymphocyte responsiveness, IgG1 dominance, altered macrophage phenotype and regulatory cytokine production
• Vaccination with recombinant FhCL1 can induce balanced IgG1 and IgG2 responses, alter macrophage function, and induce partial protection.
What are the mechanisms of Fh-mediated Immunoregulation?
Macrophage Phenotypes and Pathways
Fh can induce AAMφ
• Alternative Macrophage activation (Donnelly et al., 2005 – FhPrx)
• AAMφ Ruminant-derived Macrophage cell line (Flynn et al., 2007)
Macrophage Activation
• Regulatory cytokines IL-10 and TGF-β suppressing IFN-γ production
Regulatory cytokine induction
• F. hepatica infection induces immune responses that permit persistence and re-infection
• Alternative-activation of macrophages and the regulatory cytokines TGF-β and IL-10 are implicated in Fh-mediated immunoregulation
• Some vaccine protocols can disrupt this process and deliver partial immunity
Is Fh-mediated immunoregulation important to anyone other than vaccinologists?
Recap
Potential Global Implications 0f Macroparasite-mediated Immunoregulation
Hygiene Hypothesis and inflammatory disease
Bystander Immunoregulation and Chronic infection
Helminth inflammatory/Immune effects in Animal Health
• Salmonella? • Clostridial Diseases? • Mycobacterial
infection • Disease diagnosis • Response to Vaccines
Is the Immunoregulatory Effect of Practical Significance?
F. hepatica/M. bovis co-infection
Wk 0 Wk 4 Wk 13 Wk 14
F.h M.b SCITT PME
Group-1 F. Hepatica
150 metacercariae Aerosol M. bovis
5x102 cfu n = 6
Aerosol M. bovis 5x102 cfu
n = 6
Group-2
Fh Mb
Reduction of INF-γ Production
Co-infection increases IL-10 Response to M. bovis
Intradermal Response to PPD Challenge
0
5
10
15
20
25
30
Mb Fh/Mb
Series1
PPDB-
PPDA
M Bovis M Bovis/Fh
Role of Granulomatous Inflammation?
• In vitro bovine granuloma model
• Effect of Fh products
Macrophage phenotype
Granuloma morphology
Bacterial fate
Fh products
Thanks to…..
Rob Flynn Olwen Golden Elaine McCarthy Olwen Golden Lindsey Cox
Jim McNair Michael Welsh Sam Strain
Diana Williams