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

SCIENTIFIC REPORTS | Infection and Immunity | Strategies for Prevention and Therapy 103
04.2 Interaction between Innate and Adaptive Immunity
PROJECT LEADER | Prof. Dr. Ulrich Kalinke | Research Group Experimental Infection Research | Twincore |
ulrich.kalinke@twincore.de
PROJECT MEMBERS | Dr. Claudia Detje | Dr. Theresa Frenz | Elena Grabski | Sabrina Heindorf | Julia Heinrich |
Christian Mers | Claudia Soldner
Following viral infection, type I interferon responses that
secure the initial survival of the host are usually induced
within hours. It is approximately a week later that adaptive
immunity is activated to an extent that it is able to eradicate
the infecting pathogen. In earlier studies we showed that
upon viral infection a small number of highly specialised
immune cells, also addressed as plasmacytoid dendritic cells
(pDC), produce large quantities of protective type I interferon.
Practically all viruses examined more closely developed
countermeasures that inhibit the induction or the function
of such type I interferon responses. We are investigating how
different viruses induce type I interferon responses, which
strategies they have developed to undermine these responses
and how interferons secure the survival of the host.
Mechanisms of type I interferon induction and its protective
function The molecular mechanism of type I interferon
induction may vary depending on the inducing agent and the
analysed tissue of cell type. We study in the mouse model
how the entry of the vesicular stomatitis virus (VSV) into the
central nervous system via the olfactory system is inhibited
interferon-dependently (see also Figure 1). Furthermore, we
analyse the influence type I interferon responses have on
immune cell functions. In this context, we have found that a
vaccinia virus-derived attenuated pathogen variant, modified
vaccinia virus (MVA), which triggers strong type I interferon
responses, also induces a type I interferon-dependent expansion
of virus-specific T cells. In this context type I interferon
stimulation of both the antigen-presenting dendritic cells as
well as T cells plays a central role. Furthermore, we investigate
the influence type I interferon has on the induction of
long-lasting antibody responses. This work plays an important
role for the development of new vaccination strategies.
Virus-mediated activation of human pDC Some patients
with chronic hepatitis C virus (HCV) infection can be successfully
treated with an interferon-alpha/ribavirin combination
therapy. However, so far little is known about whether
the body’s own interferon system is sufficiently activated
in HCV infection. We investigate which HCV and/or host
encoded factors influence the strength and composition of
HCV-induced cytokine response of human pDC. This work is
carried out in vitro with primary human pDC isolated from
blood samples from healthy donors. In the future also experiments
with pDC from chronically HCV infected patients will
be carried out.
Perspective An improved understanding of the multiple
functions of type I interferon can help to optimize type I
interferon-based therapies of tumors, autoimmune diseases
and viral infections. Furthermore deeper knowledge of viral
mechanisms of immune stimulation and evasion will provide
new approaches for vaccine development.
After intranasal infection of mice, VSV infects olfactory nerves,
travels over the axons to the olfactory bulb and is arrested in
peripheral areas of the olfactory bulb by a type I interferon
dependent mechanism. The image shows the histological analysis
of the olfactory bulb of a mouse that was infected with
an eGFP-expressing VSV (upper panel). It is clearly visible that
the virus is stopped in the glomerular layer of the olfactory
bulb (lower panel). Photos: Twincore
Frenz, T., Waibler, Z., Hofmann, J., Hamdorf, M., Lantermann, M., Reizis, B., Tovey, M,G.,
Aichele, P., Sutter, G., & Kalinke, U. (2010) Concomitant IFNAR-triggering of T cells and
of DC is required to promote maximal MVA-induced T-Cell expansion. European Journal
of Immunology 40, 2769-2777.
Waibler, Z., Anzaghe, M., Frenz, T., Schwantes, A., Pöhlmann, C., Ludwig, H., Palomo-
Otero, M., Alcamí, A., Sutter, G., & Kalinke, U. (2009) Vaccinia virus-mediated inhibition
of type I interferon responses is a multifactorial process involving the soluble type I
interferon receptor B18 and intracellular components. Journal of Virology 83, 1563-1571.
Detje, C.N., Meyer, T., Schmidt, H., Kreuz, D., Rose, J.K., Bechmann, I., Prinz, M., & Kalinke,
U. (2009) Local type I IFN receptor signaling protects against virus spread within
the central nervous system. Journal of Immunology 182, 2297-2304.