Allan S. Lau, Davy CW Lee.
Department of Paediatrics, Queen Mary Hospital, The University of Hong
Kong
Host defense mechanisms are activated, following infection by pathogens
including bacteria and viruses. Viruses have developed many ways to evade
immunity including cytokine activities and even take advantage of the immune
response to enhance their replication.
Cytokines, including interferon (IFN) and tumor necrosis factor (TNF),
are potent pleiotropic proteins that act as local and/or systemic intercellular
regulatory factors to activate different branches of the immune system. They play critical roles in many
biological processes including inflammation, immunity and hematopoiesis.
IFNs are produced primarily by
macrophages, fibroblasts, B and dendritic cells. The biological actions of IFNs are mediated by multiple
pathways including degradation of mRNA by ribonuclease L and inhibition of translation
by PKR, a double-stranded RNA (dsRNA)-dependent protein kinase.
We postulate that suppression of PKR activity may result in the
downregulation of cytokine expression during pathogen invasion of the
host. This may be one of the
mechanisms for pathogens, especially viruses, to evade the immune system. In
this presentation, we will review the role of PKR in mediating antiviral and
antiproliferative effects of IFN and TNF. Previous reports including ours have
demonstrated that PKR functions as a tumor suppressor and inducer of apoptosis
via the activation of anti-oncogene p53. We have shown that suppression of PKR
activity resulted in the generation of persistently infected cell lines with a
highly cytopathic encephalomyocarditis virus, associated with delayed
virus-induced apoptosis (Yeung and Lau; JBC 1998, PNAS 1999). We will also
review the role of PKR in regulating transcription and signal transduction
pathways that are essential to cellular defense against infections.
In addition to cytokine suppression,
we will discuss other mechanisms adopted by different viruses to enhance its
survival and replication in their battle against host immune defense. These include hindrance of antigen
presentation to T cells, perturbation of dendritic cell functions, and
suppression of hematopoietic stem cells.
Thus, the outcome of a successful infection by an invading virus
requires the orchestration of specific virus-induced proteins directly or
indirectly implicated in suppressing immune response of the host.