Pathogen-derived Immunomodulatory Molecules

by Fallon, Padraic G., Ph.D.

• ISBN13: 9781441916006
• ISBN10: 1441916008
• Edition: 1st
• Format: Hardcover
• Copyright: 2009-12-30
• Publisher: Landes Bioscience

Summary

Pathogen-Derived Immunomodulatory Molecules is a book title that may require some explanation. Pathogens that are present today have evolved following a long association with man and have developed unique strategies that have been optimized by natural selection to subvert the host immunity. As we approach the 200th anniversary of Charles Darwin’s birth, it is appropriate to appreciate that Darwin recognized that pathogens (infections) play a significant and potent role in natural selection, encompassed by the concept infection begets natural selection”. This book therefore examines the molecules that pathogens produce, which can modulate or usurp the functions of the immune system.The idea of using molecules from pathogens as a therapeutic is an ancient concept in medicine. Such a strategy is exemplified by vaccination, with pathogen molecules employed to induce protective immunity against the given or related species of pathogen. The following chapters explore the concept of using pathogen-derived immune modulating molecules as a therapy. In doing so, they may provide the drug cabinet of the future for treating a spectrum of unrelated disease. Herein, a range of immune modulating molecules or strategies from various pathogens is examined in one volume.The intention of the book was to have chapters addressing immunomodulating molecules from different pathogens. The range of pathogens considered includes bacteria (chapters by Williams, van Strijp and Rooijakkers), viruses (chapters by Bowie, McFadden), protozoan parasites (Aliberti), helminths (Harnett, Fallon), fungi (Sorrell) and parasitic ticks (Anguita). Chapters also address specific immunomodulatory molecules or strategies. The diversity of aspects addressed in the book is highlighted by Lucas and colleagues review of the ‘saga’ of viral serine proteinase inhibitors, with a focus on Serp-1, the first new generation of pathogen immunomodulatory molecule currently in clinical trials. While Elliott and Weinstock have contributed a provocative chapter exploring the use of live parasitic helminth infections as a therapeutic strategy for immune-mediated diseases; indeed trials have already been completed for such an approach. With respect to pathogens usurping an immune pathway, Alcami and colleagues here reviewed the growing number of pathogens that have evolved a range of molecules that can modify many aspects of the chemokine system.This book is timely due to the need to expand the horizons of conventional drug discovery. A trend in the biopharmaceutical pipeline of fewer drugs to market is illustrated by USA FDA in 2007 approving the lowest number of new molecular entities since 1983. As the drug discovery and development industry broadens its search for new drugs to less traditional strategies, this book will be a reference to the potential for exploiting pathogen as a source of the anti-inflammatory drugs of the future.Finally, this book whets the appetite for the reader, whether in academia or industry, to explore opportunities for exploiting pathogens for the discovery of new processes in immunobiology and, ultimately, for development of new therapies for human inflammatory diseases.

Table of Contents

Bacterial Toxins as Immunomodulators	p. 1
Abstract	p. 1
Introduction	p. 1
Toxins Secreted by Bacillus Anthracis	p. 1
H. pylori Vacuolating Cytotoxin	p. 2
Toxins Produced by Clostridium Species	p. 3
Toxins Produced by S. pertussis	p. 3
Listeria monocytogenes Listeriolysin O	p. 5
The Cholera-Like Enterotoxins	p. 5
Concluding Remarks	p. 8
Innate Immune Evasion by Staphylococci	p. 19
Abstract	p. 19
Introduction	p. 19
Host Defense and the Battle against S. aureus and Its Products	p. 21
Complement	p. 21
Phagocytes	p. 21
Chemotaxis	p. 21
Phagocytosis and Killing	p. 22
Innate Immune Evasion	p. 23
Complement Evasion	p. 23
Rolling, Adhesion and Transmigration Inhibition	p. 24
Evading Neutrophil Chemotaxis and Activation	p. 25
Evading Phagocytosis and Killing	p. 26
Staphylococcal Innate Immune Evasion	p. 26
Bacterial Complement Escape	p. 32
Abstract	p. 32
Introduction	p. 32
Gram-Positive Pathogens	p. 34
Gram-Negative Pathogens	p. 38
Spirochetes	p. 41
Discussion	p. 42
Modulation of Innate Immune Signalling Pathways by Viral Proteins
Abstract	p. 49
Introduction	p. 49
PKR	p. 49
Toil-Like Receptors (TLRs)	p. 52
RIG-I-Like Helicases (RLHs)	p. 57
Viral Inhibition Proximal to Transcription Factors	p. 59
Conclusions	p. 60
Viral TNF Inhibitors as Potential Therapeutics	p. 64
Abstract	p. 64
Introduction	p. 64
TNF and TNF-Mediated Signaling	p. 65
PLAD Domain of TNFRs	p. 65
TNF-Mediated Diseases	p. 67
Current Anti-TNF Therapies in Humans	p. 67
Safety Issues with Current Anti-TNF Therapies	p. 67
Viral TNF Inhibitors as Alternative Therapeutics	p. 68
Viral TNF-Binding Proteins Unrelated to Host TNFRs	p. 71
Viral Proteins that Modulate TNF Receptors and Regulate Downstream Signaling	p. 72
Cell Signaling Inhibitors from Viruses that Inhibit Activation of NF-KB	p. 73
Conclusions	p. 74
Lipoxins as an Immune-Escape Mechanism	p. 78
Introduction	p. 78
Lipoxins	p. 79
Lipoxins and Toxoplasma Infection	p. 80
Experimental Model of Infection with T. gondii and Modulation of Immune Response	p. 81
Intracellular Mechanisms of Anti-Inflammatory Actions of LXs: SOCS Proteins	p. 82
LX-Induced SOCS2 Mediated TRAF2 and TRAF6 Proteosomal Degradation:A Major Pathway for the Anti-Inflammatory Actions of LXA, and ATL	p. 83
Concluding Remarks	p. 85
Immunomodulatory Activity and Therapeutic Potential of the Filarial Nematode Secreted Product, ES-62	p. 88
Abstract	p. 88
Introduction	p. 88
ES-62	p. 89
Immunomodulatory Properties of ES-62	p. 89
Therapeutic Potential of ES-62	p. 91
The Future	p. 92
Helminth-Derived Immunomodulatory Molecules	p. 95
Abstract	p. 95
Introduction	p. 95
Therapeutic Use of Helminth Infections	p. 96
Helminth IMs	p. 98
Helminth Glycans and Glycolipids as IMs	p. 102
LNFPII	p. 102
Lyso-PS	p. 102
Helminth Cytokine and Chemokine Homologues as IM	p. 103
Conclusions	p. 104
Fungal-Derived Immune Modulating Molecules	p. 108
Abstract	p. 108
Introduction	p. 108
Morphotypes of Yeasts, Moulds and Dimorphic Fungi Influence Pathogenicity and Innate Immune Responses	p. 109
Fungal PAMPs-The Fungal Cell Wall	p. 109
Phagocyte-Induced Exposure of PAMPS on the Fungal Cell Surface	p. 111
PAMP-PRR Interactions and Down-Stream Effects	p. 1ll
Toll-Like Receptors and Effects of Binding by Fungal PAMPs	p. 1ll
C-Type Lectin-Like Receptors and Effects of Binding by Fungal PAMPs	p. 113
S-Type Lectin-Galectin 3	p. 114
Cooperativity between Receptors	p. 114
PRR Arrays on Mononuclear Phagocytes	p. 114
Associations between PRR Polymorphisms and Fungal Diseases in Humans	p. 117
Conclusions and the Future	p. 117
The Immunosuppresive Tick Salivary Protein, Salpl5	p. 121
Abstract	p. 121
Introduction	p. 121
Interaction of Tick Saliva with, the Mammalian Host	p. 122
Immune Response to Tick Feeding and Tick Immunity	p. 122
Tick Modulation of the Host Immune Response	p. 123
Saliva Proteins and the Transmission of Human Pathogens	p. 123
Identification and Cloning of the Salivary Protein, Salpl5	p. 124
Salp15 Inhibits IL-2 Production and CD4+ T-Cell Proliferation	p. 124
Salp15 Specifically Interacts with the T-Cell Coreceptor CD4	p. 126
Salp15 Causes Conformational Rearrangements in CD4	p. 126
T-Cell Signaling Pathways Inhibited by Salp15	p. 127
In Vivo Function of Salp15	p. 128
Therapies Based on Salp15	p. 128
Concluding Remarks	p. 129
The Serpin Saga; Development Of A New Class Of Virus Derived Anti-Inflammatory Protein Immunotherapeutics	p. 132
Abstract	p. 132
Innate Immunity	p. 133
Serine Protease Inhibitors/Serpins	p. 134
Viral Serpins and Their Anti-Inflammatory Activities	p. 140
Preclinical Analysis of Serp-l	p. 141
SERP-1 Mechanism of Action	p. 148
Viral Serpins That Target Apoptotic Pathways:Preclinical Analysis of CRMA and SERP-2	p. 149
SERP-2 Preclinical Studies	p. 150
Other Mammalian Serpins	p. 150
Other Parasite Derived Serpins	p. 151
Clinical Study of SERP-1 Treatment in Acute Unstable Coronary Syndromes;Unstable Angina and Non-ST Elevation Myocardial Infarction (NSTEMI)	p. 152
Helminthic Therapy:Using Worms to Treat Immune-Mediated Disease	p. 157
Abstract	p. 157
Epidemiology of Immune-Mediated Disease and Worms	p. 157
Animal Models of Helminth Exposure	p. 158
Therapeutic Use of Helminths	p. 160
Controversy with Helminthic Therapy	p. 162
Conclusions	p. 164
Chemokine Binding Proteins Encoded by Pathogens	p. 167
Abstract	p. 167
Modulation of the Chemoldne System by Pathogens	p. 167
The M-T7 Protein Encoded by Myxoma Virus (MYXV)	p. 168
The 35-kDa CKBP Encoded by Poxviruses	p. 170
The A41 Family of Poxvirus CKBPs	p. 171
A Family of Poxvirus Proteins Containing the Smallpox Virus-Encoded Chemokine Receptor (SECRET) Domain	p. 171
The M3 Protein Encoded by Murine Gammaherpesvirus 68 (MHV-68)	p. 172
The Glycoprotein G (gG) Encoded by Alphaherpesviruses	p. 173
The Secreted CKBP from Human Cytomegalovirus (HCMV)	p. 174
A Schistosoma maiisoni-Encoded Secreted Chemokine Inhibitor	p. 174
Evasins, a Family of CKBPs in Ticks	p. 175
The Evolutionary Origin of CKBPs and Their Potential Therapeutic Applications	p. 175
Index	p. 181
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