Hannover Medical School (MHH) was founded in 1965, and since then has remained the only freestanding state funded medical university in Germany. MHH is the top ranked medical faculty in Germany with respect to peer-reviewed grant funding. MHH has approximately 3.000 students and more than 7.000 employees, of which 1.222 are employed in scientific positions; the MHH hospital has 1,400 inpatient beds. One important characteristic of research at MHH, which is centered around topics of biomedicine, human medical sciences, biochemistry and structural biology, is the close collaboration between basic and clinical research (“bench to bedside“). Some basic and clinical research highlights at MHH include: Infections (mainly bacterial and viral), immunology and inflammation Transplantation and stem cell research Oncology and cancer Cardiovascular and pulmonary medicine Tissue engineering, and research on implants Public health Research within INCA is performed in the Institute for Virology and the Institute for Medical Microbiology and Hospital Epidemiology.

Helicobacter pylori, geographical diversity, immune response and malignancy groups, Institute of Medical Microbiology, Hannover Medical School (Groups Prof. Dr. Sebastian Suerbaum and P.D. Dr. Christine Josenhans) Research background: Helicobacter pylori, Helicobacter hepaticus and related Helicobacter species are pathogenic bacterial species, causing chronic infections in their mostly mammalian hosts and may induce or promote the development of malignant tumours. H. pylori is the second-most frequent bacterial pathogen of humans, infecting more than 50% of the whole world population for a lifetime and causing stomach diseases and stomach cancer. Every year, appr. 500,000 humans worldwide are affected by H. pylori-associated stomach carcinoma. H. pylori is also one of the most variable bacteria found to date, displaying a high capacitiy of microevolution. There are a number of animal-infecting Helicobacter species, which are causing malignancies in their host animals and serve as model systems for carcinogenesis and chronic inflammation. Research goals within INCA (in close collaboration with other INCA partners): A multilocus sequence analysis study of strains from patients with MALT lymphoma and controls is being performed The role of H. pylori genes in DNA repair, recombination, mutagenesis in host adaptation, microevolution and carcinogenesis is characterized The role of pattern recognition receptors of the innate immune system (in particular Toll-like receptor 5) in Helicobacter infections, chronic inflammation and associated malignancies is investigated. Modes of interaction of Helicobacter with the ubiquitin-proteasome system in innate immunity are being characterized The impact of the H. pylori cag pathogenicity island and other bacterial virulence factors in malignancies caused by the infection is studied in the gerbil animal model KSHV/HHV8 group, Institute of Virology, Hannover Medical School (Group of Prof Thomas Schulz) Kaposi Sarcoma herpesvirus (KSHV/HHV8) is the infectious cause of Kaposi Sarcoma and two B-cell lymphomas, primary effusion lymphoma and the plasma cell variant of multicentric Castleman.s Disease. These tumours play a role in immunosuppressed patients, in particular HIV-infected individuals and transplant recipients. Owing to the wide distribution of KSHV and HIV in subsaharan Africa, AIDS-associated Kaposi Sarcoma is now the commonest tumour in subsaharan Africa. Under INCA, we want to investigate: the molecular basis of latent persistence of KSHV in infected cells, in particular the role of brd proteins in latent replication (see G. Platt et al., J. Virol. 73: 9789 . 9795, 1999; Mattson et al., J Gen Virol.83:179-188, 2002; Viejo-Borbolla et al. J. Virol. 77: 7093-100, 2003 ; Viejo-Borbolla et al., J. Virol. 79: 13618-13629, 2005; Ottinger et al., J. Virol. 80: 10772-86, 2006). the contribution of individual KSHV proteins to the KSHV-induced alterations of the cellular transcriptome, using a combination of reverse genetics to delete individual viral genes from the viral genome and transcriptome analysis of cells infected with these mutants to correlate the biological phenotype of these mutants with their impact on the cellular transcriptome (see Brinkmann et al., J. Virol., 77: 9346-58,2003; Brinkmann et al., J. Virol., 81: 42-58,2007). potential therapeutic targets by screening for chemical inhibitors of KSHV persistence and reactivation and identifying their mode of action. the interaction of KSHV with the cellular ubiquitin-proteasome system. These topics will be investigated in close collaboration with other members of the INCA consortium who will pursue similar goals or approaches with their own pathogens.

Suerbaum S, Michetti P. Helicobacter pylori infection. N. Engl. J. Med. 2002; 347:1175-86 (review). Falush D, Wirth T, …, Achtman M, Suerbaum S. Traces of human migrations in Helicobacter pylori populations. Science 2003; 299:1582-5. Suerbaum S, Josenhans C, …, Fox JG. The complete genome sequence of the carcinogenic bacterium Helicobacter hepaticus. Proc Natl Acad Sci USA 2003; 100:7901-6. Niehus E, …, Suerbaum S, Josenhans C. Genome-wide analysis of transcriptional hierarchy and feedback regulation in the flagellar system of Helicobacter pylori. Mol Microbiol 2004; 52: 947-61. Schmausser B, ....., Josenhans C, Müller-Hermelink HK, Eck M. Expression and subcellular distribution of toll-like receptors TLR4, TLR5 and TLR9 on the gastric epithelium in Helicobacter pylori infection. Clin Exp Immunol 2004, 136:521-6. Lee SK, Josenhans C. Helicobacter pylori and the innate immune system. Int J Med Microbiol 2005; 295(5):325-34. (review) Luppi M, Barozzi P, Schulz TF, Setti G, Staskus K, Trovato R, Narni F, Donelli A, Maiorana A, Marasca R, Sandrini S, Torelli G, Sheldon J (2000) Bone Marrow failure associated with Human Herpesvirus 8 infection after transplantation N Engl J Med 343: 1378-1385 Viejo-Borbolla, A., Kati, E., Sheldon, J., Nathan, K., Mattsson, K., Szekely, L., Schulz, T.F. (2003) A domain in the C-terminal region of latency – associated nuclear antigen (LANA-1) of KSHV affects transcriptional activation and binding to nuclear heterochromatin. J Virol. 77: 7093-100. Brinkmann MM, Glenn M, Rainbow L, Kieser A, Henke-Gendo C, Schulz TF. (2003) Activation of mitogen-activated protein kinase and NF-kappaB pathways by a Kaposi's sarcoma-associated herpesvirus K15 membrane protein. J Virol. 77: 9346-58 Barozzi P, Luppi M, Facchetti F, Mecucci C, Alu M, Sarid R, Rasini V, Ravazzini L, Rossi E, Festa S, Crescenzi B, Wolf DG, Schulz TF, Torelli G. (2003) Post-transplant Kaposi sarcoma originates from the seeding of donor-derived progenitors. Nature Medicine 9: 554-61. Dedicoat M, Newton R, Alkharsah K.R, Sheldon J, Szabados I, Ndlovu B, Page T, Casabonne D, Gilks CF, Cassol SA, Whitby D, Schulz T.F. (2004) Mother to child transmission of human herpesvirus 8 in South Africa. J. Inf. Dis. 190:1068-75 Henke-Gendo C, Mengel M, Hoeper MM, Alkharsah K, Schulz TF. (2005) Absence of Kaposi's Sarcoma-associated Herpesvirus in Patients with Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 172:1581-5 Viejo-Borbolla A, Ottinger M, Bruning E, Burger A, Konig R, Kati E, Sheldon JA, Schulz TF. (2005) Brd2/RING3 interacts with a chromatin-binding domain in the Kaposi's Sarcoma-associated herpesvirus latency-associated nuclear antigen 1 (LANA-1) that is required for multiple functions of LANA-1. J Virol. 79:13618-29. Ottinger, M., Christalla, T., Nathan, K., Brinkmann, M., Viejo-Borbolla, A., Schulz, T.F. (2006) The Kaposi’s Sarcoma-Associated Herpesvirus LANA-1 interacts with the short variant of BRD4 and releases cells from a BRD4- and BRD2/RING3- induced G1 cell cycle arrest J. Virol. 80: 10772-86 Brinkmann, M., Pietrek, M., Dittrich-Breiholz, O., Kracht, M., Schulz, T.F. (2007) Modulation of host gene expression by the K15 protein of Kaposi’s sarcoma-associated herpesvirus J. Virol. 81: 42-58.Alkharsah, K. R., Dedicoat, M., Blasczyk, R., Newton, R., Schulz, T.F. (2007) Influence of HLA Alleles on Shedding of Kaposi’s Sarcoma Herpesvirus in Saliva in an African Population. J. Inf. Dis. in press