1. Pathogen-Derived Immunomodulatory Molecules: Future Therapeutics? Padraic G. Fallon and Antonio Alcami (2006) Rafael Sanchez

2. ABSTRACT Rapid developing area of research: Identifying molecules from various pathogens that modulate the innate or adaptive immune systems. Rapid developing area of research: Identifying molecules from various pathogens that modulate the innate or adaptive immune systems. Immunomodulatory molecules: Have been optimized during pathogen/host co- evolution and could be used as new immunotherapeutics. Immunomodulatory molecules (IM) selectively mimic the desirable effects of infection. Immunomodulatory molecules: Have been optimized during pathogen/host co- evolution and could be used as new immunotherapeutics. Immunomodulatory molecules (IM) selectively mimic the desirable effects of infection. 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. 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. Important Idea: Understanding the mechanisms that pathogens have evolved to manipulate host immunity might help to result in new therapeutics for inflammatory diseases. Important Idea: Understanding the mechanisms that pathogens have evolved to manipulate host immunity might help to result in new therapeutics for inflammatory diseases.

3. Methods: Address all Examples of pathogen IM’s that come from viruses, bacteria, and parasites.

4. Table 1. Examples of IM from various pathogens classified by mechanism of modulation IM Species Modulatory activity (therapeutic efficacy) Refs Protease inhibitor Serp-1 Myxoma virus Inhibits inflammation (in Phase II trials on patients with acute coronary syndrome) [77] Complement inhibitor VCP Vaccinia virus Blocks complement activation (reduces transplant rejection and CNS damage in animal models) [15] CHIPS Staphylococcus aureus Binds to C5a and formylated peptides [20] SCIN Staphylococcus aureus 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 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) SmCKBP Schistosoma mansoni Inhibits CC, CXC and C chemokines and binds to GAGs (suppresses acute inflammation in mice) [60] Cell signalling A52R Vaccinia virus Inhibits TLR activation of NF-kB (blocks inflammation in mice) [65,67] YopJ Yersinia species Blocks MAPK and NF-kB activation [70,71]

5. Serp-1 Comes from the Myoxa virus, poxvirus in rabbits. Comes from the Myoxa virus, poxvirus in rabbits. encodes a secreted serine-protease inhibitor (serpin)  Serp-1. encodes a secreted serine-protease inhibitor (serpin)  Serp-1. Could be the first pathogen IM available for patients. Could be the first pathogen IM available for patients. Serp-1 blocks atherosclerotic- plaque growth in models of arterial trauma, Serp-1 blocks atherosclerotic- plaque growth in models of arterial trauma, Has beneficial effects in aortic and heart-transplant models, and also in a model of antigen-induced arthritis Has beneficial effects in aortic and heart-transplant models, and also in a model of antigen-induced arthritis Studies have established that viral IM can be effective at low doses, and have the ability to reduce the degree of the initial pro- inflammatory stimuli and the ensuing chronic inflammatory response that causes immunopathology after physical trauma. Currently in phase 2 of clinical testing on patients with acute coronary syndrome.

6. Other IM inhibitors Secreted vaccinia complement-control protein (VCP): Secreted vaccinia complement-control protein (VCP): Has anti-inflammatory property. Has anti-inflammatory property. Prolongs survival after heart transplants Prolongs survival after heart transplants VCP also shows an effect in animal models of injury to the central nervous system VCP also shows an effect in animal models of injury to the central nervous system Orthologue encoded by cowpox virus, known as inflammatory modulatory protein: Has anti-inflammatory property

7. IM Modulation of Intracellular Signaling IM can be directly released inside the cell by intracellular pathogens and can alter different cellular processes such as signaling pathways. 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. 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. 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. Bacteria have developed multiple new mechanisms for transporting IM into the host-cell cytosol.

8. Societal and Evolutionary Importance and Future Studies 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. 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. 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. 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. 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. 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.

9. References Padraic G. Fallon; Antonio Alcami (2006). Pathogen-derived immunomodulatory molecules: future immunotherapeutics? TRENDS in Immunology: 27.10, 470-476. 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, 566- 572. Suzuki, Nobutaka; Saito, Takashi. IRAK-4- a shared NF-kB activator in innate and acquired immunity. TRENDS in Immunology: 27.12, 566- 572.