Research Report 2010 2011 - Helmholtz-Zentrum für ...

SCIENTIFIC REPORTS | Infection and Immunity | Strategies for Prevention and Therapy
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04 Strategies for Prevention and Therapy
TOPIC SPEAKER | Prof. Carlos A. Guzmán, MD, PhD | Department of Vaccinology and Applied Microbiology |
cag@helmholtz-hzi.de
One third of all deaths occurring each year worldwide are directly caused by infectious agents. Microorganisms are also responsible
for at least 15% of new cancers, and they are involved in the pathogenesis of many chronic non-infectious diseases. Furthermore,
a recent report suggested that the incidence of lung cancer is signifi cantly increased in case of chronic tuberculosis. In addition,
the major public health problem represented by infections is rendered even more dramatic by the global emergence of multiple
drug-resistant strains. It is, therefore, critical to establish new approaches to fi ght microbial pathogens. Thus, the main objective
of this topic is to develop innovative tools and strategies for the prevention, management and control of infections and infectionassociated
diseases. This is achieved by identifying novel intervention targets and bioactive molecules, designing new immune
interventions, and establishing novel diagnostics and biomarkers.
In the project “Molecular Mechanisms of Hepatitis C Virus Infection and Replication” virus-host interactions crucial for hepatitis C
virus (HCV) replication are investigated. These efforts should help to both defi ne new drug targets conferring inhibition of HCV
replication and implement screening assays for the identifi cation of molecules preventing interactions crucially involved in HCV
replication. To this end, cell based assays are exploited to identify cellular co-factors that HCV usurps for its propagation. Cellbased
high-throughput screening systems are also being developed to identify HCV-specifi c inhibitors using HZI natural compound
libraries. In this context, a novel luciferase-based screening system to monitor HCV replication was developed which was adapted
to 384-well format in collaboration with the Department of Chemical Biology. This allowed the screening of large compound
libraries for small molecules that may interfere with HCV replication. At the same time, the direct infl uence of immunosuppressive
drugs on HCV propagation was assessed. This is of interest, because chronic HCV infection is one of the key indicators for liver
transplantation, and immunosuppression is mandatory after transplantation to prevent graft rejection. Thus, these studies can
help to eventually improve the management of HCV patients post transplantation. A particular focus of the work lays in the
characterization of determinants defi ning the narrow species-tropism of HCV which should support the development of immunocompetent
small animal models for this virus.
In the project “Senescence Surveillance in Chronic Hepatitis and Hepatocellular Carcinome” innovative mouse models are
developed to study the role of the cellular senescence programme for immune surveillance during chronic liver infl ammation and
liver cancer. This is linked with studies addressing the oncogenic potential of HBV and HCV structural proteins in hepatocarcinogenesis.
Beyond this, functional genomics driven approaches are exploited to study the molecular mechanisms of liver damage,
liver regeneration and liver cancer. To this end, microRNA based shRNA technology enabling stable or reversible RNAi-mediated
inhibition of endogenous genes in cultured cells or in experimental mouse models is used. Genome-scale retro- and lentiviral
shRNA libraries targeting the murine and the human genome are harnessed to identify new therapeutic targets in liver cancer and
liver regeneration.
The project “Immune Aging and Chronic Infection” aims to defi ne the effects of persistent infections in immune homeostasis and
immune senescence. In this context, there is a consensus that the adaptive immune response to emerging infections is compromised
in the elderly. Aging results in a loss of both naïve T-cells and T-cell clonal diversity, thereby increasing the susceptibility to
novel infections and decreasing the ability to generate protective immunity upon vaccination. However, the underlying mechanism