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Vaccine development against chronic bacterial infections

Monday 2 December 2013

Dr. A.P. (Ad) Koets
Department of Farm Animal Health, UU

Ad Koets has obtained his DVM degree in 1994 and his PhD in immunology in 2000. He is an associate professor at the department of Farm Animal Health. (http://www.uu.nl/staff/APKoets/0 ) Ad enjoys working on veterinary infection biology and vaccinology in general and specifically on prevalent diseases of dairy cattle (paratuberculosis and mastitis). Ad has experience and affinity with immunogenetics (molecular and population level), molecular biology, immunology, microbiology, epidemiology and mathematical modeling of with-in host dynamics of (chronic) infections. Of special interest are bacterial pathogens with an intracellular lifestyle which in various ways subverts the hosts innate and specific immune system to establish a niche for persistence and replication. Examples of such (often zoonotic) pathogens are Staphylococcus aureus, Mycobacterium spp (eg bovis and paratuberculosis) and Coxiella burnetii.

Current group members:
Susanne Eisenberg (Post-doc), Ineke Daemen (technician), PhD students Lindert Benedictus, Manouk Vrieling, Eveline Boerhout, Kim Poppe (Honours Program student), Sanne van Zalen (Master student) in close collaboration with Prof. dr. Victor Rutten (Veterinary Immunology)

Current research projects are:
‘Evasion Molecules in Staphylococcal Bovine Mastitis Vaccines’ (EVAC) is a collaborative project between Merck Animal Health and the Department of Medical Microbiology of the University Medical Center (UMC) Utrecht, and the Faculty of Veterinary Medicine of Utrecht University. The objective of EVAC is to develop a series of vaccines against difficult to treat infections with certain bacteria known to cause bovine mastitis. Examples of such bacteria are Staphylococcus aureus, Streptococcus uberis and Escherichia coli.
In the EVAC project, bacterial evasion molecules are identified and characterized, and subsequently recombinant versions of these proteins are produced. Combinations of such evasion molecules and adjuvants will be used in candidate vaccines. Different vaccination strategies are explored aiming to raise neutralizing antibodies against bacterial immune evasion molecules in the animal to reduce the pathogenicity of the bacteria.
‘The role of Coxiella burnetii (Cb) in unexplained subfertility in dairy cattle’ is collaborative project between . Cb is the causative agent of Q-fever and a zoonotic pathogen. A recent outbreak of Q-fever in dairy goats has spiked interest in this pathogen. In cattle infection with Cb is common but the infection has few if any symptoms and progresses mostly subclinical. This project explores basic aspects of the pathogenesis of subclinical Cb infection in dairy cattle in a field study setting.
‘Bovine Neonatal Pancytopenia’ is a syndrome in new born calves which first occurred in 2007. Following epidemiological studies it was established that this syndrome was a rare side-effect of a successful commercially available vaccine against bovine viral diarrhea. This project uses genetic and immunological techniques to elucidate the pathogenicity of this syndrome in order to explain the molecular mechanisms that lead to vaccine response which is harmless for the vaccinated dairy cows but leads to a fatal bone marrow hypoplasia in calves born to dairy cows vaccinated with the vaccine.
‘Within-host modeling of Mycobacterium avium subsp. paratuberculosis (MAP) infections.’ The international NIMBioS working group on mathematical modeling of the within-host response to a Mycobacterium avium subsp paratuberculosis (MAP) infection ( http://www.nimbios.org/workinggroups/WG_map ) highlighted the current state of our knowledge and clearly identified our lack of understanding of the within-host infection process of MAP. Empirical data on infection progression is present and multiple distinct infection patterns are present in MAP infected cattle. However, the immunological and microbiological attributes of infection and disease patterns are not well understood. There is a large amount of piece-meal immunological data available in previous publications and in the hands of MAP scientists. However these data have not resulted in a comprehensive understanding of the infection process. The objective of this working group is to develop a within-host MAP infection model, using observational data on infection patterns and within-host immune response data. The ultimate goal of the model is to provide an understanding of progression of disease in response to MAP infection and to devise better mitigation strategies for Johne’s disease.

Focus areas
Infection and Immunity
Life Sciences (strategic theme)

Selected references:
Santema, W.I., Rutten, V.P.M.G., Segers, R.P.A.M., Poot, J., Hensen, S., Heesterbeek, J.A.P. & Koets, A.P. (2013). Postexposure Subunit Vaccination against Chronic Enteric Mycobacterial Infection in a Natural Host. Infection and Immunity, 81(6), 1990-1995

Vrieling, M., Santema, W.J., Rhijn, I. van, Rutten, V.P.M.G. & Koets, A.P. (2012). γd T Cell Homing to Skin and Migration to Skin-Draining Lymph Nodes Is CCR7 Independent. Journal of Immunology, 188(2), 578-584.

Benedictus, L., Thomas, A.J., Jorritsma, R., Davies, C.J. & Koets, A.P. (2012). Two-Way Calf to Dam Major Histocompatibility Class I Compatibility Increases Risk for Retained Placenta in Cattle. American Journal of Reproductive Immunology, 67(6), 179-183.

Hulzen, K.J.E. van, Schopen, G.C.B., Arendonk, J.A.M. van, Nielen, M., Koets, A.P., Schrooten, C. & Heuven, H.C.M. (2012). Genome-wide association study to identify chromosomal regions associated with antibody response to Mycobacterium avium subspecies paratuberculosis in milk of Dutch Holstein-Friesians. Journal of Dairy Science, 95(5), 2740-2748.

Eisenberg, S.W., Koets, A.P., Nielen, M., Heederik, D., Mortier, R., Buck, J. & Orsel, K. (2011). Intestinal infection following aerosol challenge of calves with Mycobacterium avium subspecies paratuberculosis. Veterinary Research, 42(1)

Rhijn, I. van, Nguyen, T.K.A., Michel, A.L., Cooper, D., Govaerts, M., Cheng, T.Y., Eden, W. van, Moody, D.B., Coetzer, J.A., Rutten, V.P.M.G. & Koets, A.P. (2009). Low cross-reactivity of T cell responses against lipids from Mycobacterium bovis and M. avium paratuberculosis during natural infection. European Journal of Immunology, 39(11), 3031-3041.