Transcript Pathogen-Derived Immunomodulatory Molecules: Future

Pathogen-Derived
Immunomodulatory Molecules:
Future Therapeutics?
Padraic G. Fallon and Antonio Alcami (2006)
Rafael Sanchez
ABSTRACT
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Rapid developing area of research: Identifying molecules from various pathogens
that modulate the innate or adaptive immune systems.
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Immunomodulatory molecules: Have been optimized during pathogen/host coevolution and could be used as new immunotherapeutics. Immunomodulatory
molecules (IM) selectively mimic the desirable effects of infection.
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Main Focus: Demonstrate the use of these pathogen IM’s that have been produced
as recombinant proteins of which have different modes of modulatory activity, and
discuss their ability to change undesirable immune responses caused by human
diseases.
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Important Idea: Understanding the mechanisms that pathogens have evolved to
manipulate host immunity might help to result in new therapeutics for inflammatory
diseases.
Methods:
Address all Examples of
pathogen IM’s that come from
viruses, bacteria, and parasites.
Table 1. Examples of IM from various pathogens classified by mechanism of modulation
IM
Protease inhibitor
Serp-1
coronary syndrome)
[77]
Complement inhibitor
VCP
[15]
CHIPS
SCIN
Species
Myxoma virus
Vaccinia virus
Staphylococcus aureus
Staphylococcus aureus
Modulatory activity (therapeutic efficacy) Refs
Inhibits inflammation (in Phase II trials on patients with acute
Blocks complement activation (reduces transplant rejection and CNS damage in animal models)
Binds to C5a and formylated peptides [20]
Binds to C3 convertases [19]
Cytokine and chemokine homologues
vIL-10
Epstein-Barr virus IL-10 homologue
(suppression inflammation in various animal models) [21]
vMIP-II
Human herpesvirus 8 Chemokine homologue
(inhibits chemokine-mediated responses) [40]
C-18
Toxoplasma gondii CCR5 ligand
(blocks HIV infection of human cells in vitro) [34]
pTSP,
pMMP
Plasmodium species
Converts latent TGF-b to active form [30]
CKBPs
M-T7
Myxoma virus
Binds to CC, CXC and C chemokines (prevents atherosclerotic plaque formation) [48,49]
35 kDa
Vaccinia virus, myxoma
Binds to CC chemokines and inhibits chemokine-receptor interactions (prevents transplant
vasculopathy and airway inflammation
virus,
cowpox virus
Binds to CC chemokines and inhibits chemokine-receptor interactions (prevents transplant
vasculopathy and airway inflammation)
M3
SmCKBP
[60]
Cell signalling
A52R
YopJ
Murine gammaherpesvirus 68
Broad spectrum chemokine inhibitor, blocks interaction of chemokines with specific
receptors and GAGs (inhibits transplant vasculopathy, athersclerotic plaque formation and skin inflammation)
Schistosoma mansoni
Inhibits CC, CXC and C chemokines and binds to GAGs (suppresses acute inflammation in mice)
Vaccinia virus
Yersinia species
Inhibits TLR activation of NF-kB (blocks inflammation in mice) [65,67]
Blocks MAPK and NF-kB activation [70,71]
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Serp-1
Comes from the Myoxa virus,
poxvirus in rabbits.
encodes a secreted serine-protease
inhibitor (serpin)Serp-1.
Could be the first pathogen IM
available for patients.
Serp-1 blocks atheroscleroticplaque growth in models of arterial
trauma,
Has beneficial effects in aortic and
heart-transplant models, and also in
a model of antigen-induced
arthritis
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Studies have established that viral
IM can be effective at low doses,
and have the ability to reduce the
degree of the initial proinflammatory stimuli and the
ensuing chronic inflammatory
response that causes
immunopathology after physical
trauma.
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Currently in phase 2 of clinical
testing on patients with acute
coronary syndrome.
Other IM inhibitors
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Secreted vaccinia
complement-control
protein (VCP):
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Has anti-inflammatory property.
Prolongs survival after heart
transplants
VCP also shows an effect in animal
models of injury to the central
nervous system
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Orthologue encoded
by cowpox virus,
known as
inflammatory
modulatory protein:
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Has anti-inflammatory property
IM Modulation of Intracellular
Signaling
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IM can be directly released inside the cell by intracellular
pathogens and can alter different cellular processes such as
signaling pathways.
Any pathogen IM that can modulate cell signalling could have a
particular application as a therapeutic in inflammatory diseases.
(A52) –Tested in mice Reducing disease of bacterial induced
ear inflammation.
Viral pathogens can modulate intracellular processes readily, but
bacterial pathogens can’t.
Bacteria have developed multiple new mechanisms for
transporting IM into the host-cell cytosol.
Societal and Evolutionary Importance
and Future Studies
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Throughout the course of evolution pathogens have also evolved and learned
the molecular mechanisms which are essential to immunity and have
optimized approaches in counteracting immune pathways.
A better understanding of how pathogens modulate the immune response
should provide insights into the mechanisms of immunity and new strategies
for immune modulation.
Information can be used to design new therapeutic strategies to modulate
immunopathological reactions that cause human diseases, and in some
instances be able to use the IM’s produced by pathogens as therapeutic
reagents.
Development of pathogen IM’s as therapeutics is a new idea so there are
many IM’s encoded by pathogens that haven’t been identified.
May also look at non pathogen microbes as a source for IM’s such as IM
activity in symbiotic gut bacteria and cyanobacteria from blue-green algae.
References
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Padraic G. Fallon; Antonio Alcami (2006).
Pathogen-derived immunomodulatory
molecules: future immunotherapeutics?
TRENDS in Immunology: 27.10, 470-476.
Suzuki, Nobutaka; Saito, Takashi. IRAK-4- a
shared NF-kB activator in innate and acquired
immunity. TRENDS in Immunology: 27.12, 566572.