final re portp Project code: B.BSC.0321 Prepared by: Professor Els Meeusen Monash University Date published: April 2013 PUBLISHED BY Meat & Livestock Australia Limited Locked Bag 991 NORTH SYDNEY NSW 2059 New ap proaches to innate immunity in livestock and the potential for manipulation - review Meat & Livestock Australia acknowledges the matching funds provided by the Australian Government to support the research and development detailed in this publication. This publication is published by Meat & Livestock Australia Limited ABN 39 081 678 364 (MLA). Care is taken to ensure the accuracy of the information contained in this publication. However MLA cannot accept responsibility for the accuracy or completeness of the information or opinions contained in the publication. You should make your own enquiries before making decisions concerning your interests. Reproduction in whole or in part of this publication is prohibited without prior written consent of MLA. PROJECT NO. B.BSC.0321 NEW APPROACHES TO INNATE IMMUNITY IN LIVESTOCK AND THE POTENTIAL FOR MANIPULATION – REVIEW RESEARCH ORGANISATION: Monash University PROJECT LEADER: Professor Els Meeusen PROJECT TEAM: 1. Els N Meeusen , ( [email protected] ), Monash University, School of Biomedical Sciences, Wellington Road, Clayton, Vic 3800, Australia. 2. Michael de Veer , ( [email protected] ), Monash University, School of Biomedical Sciences, Wellington Rd, Clayton, Vic 3800, Australia. 3. Paul J Hertzog , ( [email protected] ), Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, 27-31 Wright st., Clayton, Vic 3168, Australia. 4. Michael J Stear , ([email protected] ) University of Glasgow, College of Medical, Veterinary and Life Sciences, 464 Bearsden Rd, Glasgow, G61 1QH, UK. 5. Bonnie A Mallard , ( [email protected] ) University of Guelph, Department of Pathobiology, Guelph, Ontario, Canada, N1G 2W1 6. Nicholas N Jonsson , ( [email protected] , University of Glasgow, College of Medical, Veterinary and Life Sciences, 464 Bearsden Rd, Glasgow, G61 1QH, UK. CONTENT Chapter 1. Review of innate immunity literature in mice, man and livestock species. Chapter 2. The relationship between the innate immune system versus the acquired immune system and their proportional contribution to an animal’s response to disease Chapter 3. Prophylactic and therapeutic modulators to enhance innate immunity (including vaccines, stress) Chapter 4. Impact of nutrition on innate immune responses (including diet and food supplement, intestinal microflora). Chapter 5. Genetic contribution of immunity to resistance; breeding for disease resistance Chapter 6. Summary of recommendations for future research Appendix 1: Glossary of terms Appendix 2: Experts consulted Appendix 3: Relevant conferences attended Chapter 1 The Innate Immune System –sculpting the animal immune response Table of Contents OVERVIEW ............................................................................................................................................... 2 CYTOKINES MEDIATING INNATE IMMUNE RESPONSES.......................................................................... 5 PRIMARY CELL TYPES ASSOCIATED WITH THE INNATE IMMUNE SYSTEM: ............................................ 7 INNATE SCULPTING OF ADAPTIVE IMMUNE RESPONSES. ...................................................................... 9 PATTERN RECOGNITION RECEPTORS –INNATE RECOGNITION AND SIGNALLING ................................ 10 TOLL LIKE RECEPTORS (TLRs)............................................................................................................. 10 RIG-I LIKE HELICASES (RLHs). ............................................................................................................. 12 CYTOPLASMIC RNA SENSORS ............................................................................................................ 12 CYTOPLASMIC DNA SENSORS ........................................................................................................... 12 NOD –LIKE RECEPTORS (NLRs). ......................................................................................................... 13 C-TYPE LECTINS (CTLs) ....................................................................................................................... 16 PENTRAXINS –HUMORAL PRRs ......................................................................................................... 17 PREEXISTING CELLULAR IMMUNE ACTIVATORS OR “ALARMINS” ........................................................ 17 EFFECTOR TRIGGERED IMMUNITY ........................................................................................................ 18 GENERAL CONSIDERATIONS AND QUESTIONS ABOUT PRR SIGNALING............................................... 19 SUBCELLULAR LOCALISATION ........................................................................................................... 19 TISSUE /CELL SPECIFICITY – ORGAN SPECIFIC IMMUNITY ................................................................ 19 REGULATORS OF PRR SIGNALING ..................................................................................................... 20 PRACTICAL OUTCOMES ..................................................................................................................... 21 REFERENCES .......................................................................................................................................... 22 Chapter 1 - 1 The Innate Immune System –sculpting the animal immune response Paul Hertzog and Michael de Veer Monash University, Clayton, Vic. 3800, Australia [email protected] [email protected] OVERVIEW The innate immune response refers to the primitive, evolutionarily conserved, immune system that responds rapidly to a foreign stimulus. It has been long known to involve resident immune cells such as macrophages and dendritic cells (DC) and acts in consort with other “innate” protective mechanisms such as physical barriers (e.g. mucous), chemicals (e..g. free radicals), temperature controls, to form the body’s front-line defence systems. Not only does the innate immune response provide rapid defence, but also produces cytokines that amplify more innate responses, and importantly sculpts the ensuing adaptive immune response. These responses are mediated by cytokines and chemokines that are responsible for the development, recruitment and activation of infiltrating cells. Thus, the innate immune response is the basis of the inflammatory response. The cardinal signs of rubor (redness), tumor (swelling), calor (heat), dolor (pain) and functio laesa (loss of function), are the result of increased blood flow, vascular permeability and cell infiltration caused by the cytokines and chemical products released from stimulated innate immune cells. These signs have been known for centuries and the cellular and cytokine details elaborated in recent decades. However, is only in the last 14 years that our appreciation of the innate immune system has been shaken from the now apparently naïve notion of an essentially non- specific response, to one with a degree of specificity and structure, albeit not as elaborate as the adaptive immune response. The discoverers of this response won the 2011 Nobel Prize for this seminal contribution (http://www.nobelprize.org/nobel_prizes/medicine/laureates/2011 ). This revolution in our understanding of the innate immune system began with the discovery of the Drosophila Toll mutant as a developmental anomaly and subsequent demonstration of the role of the Toll receptor in protection from infection [1]. This was quickly followed by noting homology of the Toll gene with the interleukin-1 (IL1) cytokine family implicating a role in immune response [2], identification of mammalian homologues, designated Toll-like Chapter 1 - 2 Receptors (TLRs) and demonstration of TLR4 as mediating the sensing and response to the prototypical inflammatory stimulus, lipopolysaccharide (LPS) [3]. Since these discoveries were occurring at a time of enormous technological advances such as high throughput DNA and RNA sequencing, high density microarrays and generation of gene targeted mice for in vivo validation of function, there was an explosion of discovery in the ensuing years [4]. These led to the identification of a family of up to 13 TLRs in mammals and the rapid identification of the signal transduction components such as the adaptor molecules, kinases, transcription factors and sets of genes involved in the innate response (Fig.1). The families of receptors that initiate innate immune responses to pathogens grew as it was realised that the TLRs could not explain responses to all pathogens. These included RIG-I-Like Helicases (RLHs), DNA sensors [4], Nod-Like Receptors (NLRs) [5] and C –type Lectins [6]. The expanded family of receptors which co-evolved with pathogenic microorganisms are commonly known as Pathogen Recognition Receptors (PRRs). Accordingly, the molecules that trigger these receptors are known as Pathogen Associated Molecular Patterns (PAMPs) [7, 8]. PAMPs are present in almost all invasive organisms, from bacteria to viruses and fungi, and are derived from the major families of molecules found in these organisms, including cell surface glycolipids,, nucleic acids, lipids, proteins and chemicals (Fig.1). The innate receptors or PRRs also recognise endogenous non-pathogen ligands such as extracellular matrix components, nucleic acids from dying