RS–IAP-ICSU international workshop on science & technology developments relevant to the Biological & Toxin Weapons Convention 4 – 6 September 2006

Defences Under Attack: The Potential Misuse of Innate Immunity Kathryn Nixdorff Department of Microbiology and Genetics Darmstadt University of Technology, Germany nixdorff@bio.tu-darmstadt.de

The immune system plays a crucial role in protecting against infectious diseases. The ability of a microorganism to cause disease can only rightly be defined within the scope of its interaction with the immune system.

Two types of immunity Innate Immunity: Acquired (Adaptive) Immunity:  Requires little or no induction  Relatively non-specific (generic)  All-important first line of immune defence  Keeps an infection in check until adaptive immunity is induced Acquired (Adaptive) Immunity:  Requires induction  Specific (reacts to specific antigens)  Affords a long-lasting, high degree of specific protection

The macrophage is a cell central to innate immunity Cytokines Regulate immune responses Proinflammatory Cytokines Makrophage

Proinflammatory Cytokines In moderate amounts, these contribute greatly to immune defence and healing processes When overproduced, these can lead to severe inflammatory disorders, autoimmunity, shock and even death

Toll-like Receptors (TLRs) and NOD Receptors of Innate Immunity Source: Strober, Murray, Kitani, Watanabe (2006) Nature Reviews Immunology Vol. 6, pp. 9-20.

Toll-like Receptors (TLRs) react to Pathogen-associated molecular Patterns (PAMPs) Receptor TLR2 TLR4 TLR8 TLR9 PAMPs (Ligands/Agonists) Lipoproteins, Peptidoglycan Lipoteichoic Acid, Lipoarabinomannan Lipopolysaccharide HSP60 (G+U)-rich single-stranded RNA Bacterial DNA, Viral DNA Synthetic Analogues – Synthetic lipid A, E5564 Imidazole quinolines (Imiquimod, Resiquimod) CpG oligodeoxynucleotides

NOD (Nucleotide-binding Oligomerization Domain) Receptors PAMPs (Ligand/Agonist) Peptidoglycan structures Synthetic Analogues Tripeptides with terminal diaminopimelic acid Muramyl-dipeptide structures

Targeting the Innate Immune System for Therapeutic Purposes:  Imidazole quinolones to target TLR7 and TLR8 for treatment of genital warts and other diseases caused by human papillomaviruses  CpG oligodeoxynucleotides to target TLR9 for treatment of patients for asthma  CpG oligodeoxynucleotides afford generic immunoprotection in rodents against:: - many different bacteria (e.g. agents of anthrax, tularemia, glanders) - many viruses (e.g. pox viruses, Ebola, VEE, influenza) - parasites (e.g. agents of malaria, toxoplasmosis) Targeting the Innate Immune System for Biodefence Purposes:

The possibilities for therapy and defence are great, but at the same time the potential for misuse is huge. Use of such bioactive substances for good or evil depends to a great extent on the feasibility of targeted delivery.

Growing potential for greatly improved methods of aerosol delivery of bioactive substances: Advances in nanotechnology combined with new methods for making substances absorbable through the nasal and respiratory tracts represent such growing potential for delivery.

Workshop Report of the National Research Council of the National Academies, USA 2005: An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks www.nap.edu. “A major theme that emerged from these discussions is that pathogens are not the only potential bioterrorists agents. …bioregulators, which are non-pathogenic organic compounds, may pose a more serious dual-use risk than had been previously perceived, particularly as improved targeted delivery technologies have made the potential dissemination of these compounds much more feasible than in the past.”

The immune system does not act alone! The immune system interacts interdependently with the nervous and endocrine systems through biochemical bioregulators (cytokines, hormones, neurotransmitters). Manipulation of one system will also profoundly affect the functions of the others. This raises the dual-use dilemma to a whole new order of complexity.

With such rapid advances occurring in the life sciences, dealing with this complexity becomes an enormous task. The five-year review mechanism for S&T of relevance to the BTWC at the review conferences is increasingly inadequate. States Parties will have to devise and implement a better mechanism for review, with a more coherent assessment of the ongoing S&T relevant to the Convention.