Biography:

Abstract:

Wild koala populations continue to experience serious declines as a result of several threatening factors including: loss of habitat; motor vehicle trauma; dog attacks and; chlamydial disease. Chlamydial infections are associated with diseases ranging from ocular disease leading to blindness, as well as urinary and genital tract disease, leading to female infertility. Modeling shows that targeting chlamydial disease would have a major impact on stabilizing population decline. Our previous studies have demonstrated that koalas can be safely immunized with a vaccine containing a mixture of chlamydial major outer membrane protein (MOMP) antigens combined with a single or three-dose subcutaneous regime. In our most recent, large scale, field trial of the vaccine, we vaccinated 30 koalas that were outwardly clinically healthy but either chlamydia PCR negative or chlamydia PCR positive, and followed them for 1-2 years to assess the protective effect of the vaccine (compared to a control group of unvaccinated koalas). We observed strong, specific and long-lasting immune responses in the vaccinated koalas; high titer antibody responses (as measured by ELISA and also in vitro neutralization) as well as chlamydia-specific cytokine responses (interferon-gamma and IL-17 in particular). For animals which were chlamydia PCR positive at the time of vaccination, we observed a significant reduction in their infection PCR load (at both the ocular and urogenital tract sites). We also observed protection from progression to clinical disease in the vaccinated animals. We have also conducted a small trial to vaccinate animals which already have clinical signs of ocular disease. Instead of the normal practice of administering antibiotics (chloramphenicol, daily for 28 days, which severely disrupts the animal’s gut microbiome) we vaccinated four animals with a single dose, 3-MOMP vaccine. For all vaccinated animals, their chlamydia PCR load decreased, often to zero, and in two animals at least, we observed a decrease in their clinical disease score. These results are promising for the future development of an effective chlamydial vaccine for use in captive as well as wild koalas.

Biography:

Zlatko Dembic is a Professor of Immunology, Cell-Biology and Microbiology at University of Oslo. He has been working in science at various institutions in Academia (Medical Faculty, Zagreb, Croatia; Max-Planck Institute for Immunogenetics, Tubingen, Germany; Basel Institute for Immunology, Switzerland; Institute of Immunology, Oslo, Norway) and industry (Roche, Switzerland). He has his expertise in molecular biology shown by over 100 publications to date and a monograph about cytokines in immunology. He is co-inventor of the US patent (Roche) covering the production and use of etanercept (Enbrel), which is a successful (anti-TNF) biological used to treat several autoimmune diseases including rheumatoid arthritis. He was the president of the Norwegian Society for Immunology and Editor-in-chief of the Scand J Immunol (at present, Associate Editor). He is a Visiting Professor of Medicine at medical school in his hometown Rijeka (Croatia).

Abstract:

Statement of the Problem: Heritable susceptibility to tuberculosis (TB) is complex and polygenic in nature. Only five to ten percent of humans that come in contact with the bacterium Mycobacterium tuberculosis (Mt) will manifest the disease, provided no acquired- or congenital immunodeficiency were present. We still lack a viable explanation for the observed epidemiologic fact. Method: Activation of macrophages via proinflammatory cytokines IFN-v and interleukin (IL)-17 can kill intracellular bacteria such as Mt. Instead, macrophages stimulated by the Toll-like receptor (TLR)-10 agonists show an anti-inflammatory effect. The TLR-10 acts by inhibiting the TLR-2 signaling from the cell membrane. The TLR-2 is the Mt-binding protein by which activated macrophages can internalize (and kill) Mt. Inactivation of the TLR-2 protein might convey a risk for developing the disease. This was supported by our finding that TLR2 gene polymorphisms, which either inactivate the TLR2 gene product or have a dominantnegative role in TLR-2-signaling, associated with elevated risk for tuberculosis in the Croatian Caucasian population. Findings: The genome-wide study found that three single nucleotide polymorphisms (SNPs) within the HLA class II loci were significantly associated with TB; suggesting that adaptive immunity is of paramount importance for defense against TB. In our studied population, SNP in the TLR10 gene was associated with risk for TB, analyzed by the dominant model of inheritance. However, this was contrasted by the fact that SNPs in the IL17A&F genes were not. Conclusion & Significance: Studying genetic risk by association analyses or genome-wide screening led us to propose that clinical manifestation of TB is a state above certain risk-threshold. Threshold is reached by accumulation of seemingly minor susceptibilities divided between the hallmarks of the disease (Fig 1). The model suggests that every human population has its own mosaic of genetic risks for TB.