Cell defence against viral/bacterial infections: closer mechanism than anticipated?

The ability of the host to detect invasion by a pathogen-ic intruder and to activate the defence mechanism to elim-inate the infection is essential for survival. The hostdefence system against the invading pathogen is composedfrom the innate and adaptive immunity. While the adaptiveresponse is based on the recognition of antigen-specificlymphocytes and their clonal selection, the innate immuneresponse is not pathogen-specific and provides rapidresponse that is not long-lasting; however, this response isessential for the generation of the adaptive immunity. Aninnate immune response has developed as a rapid and reg-ulated defence mechanism in which the recognition of aninvading pathogenic organism can occur upon binding tospecific viral receptors, where many of these are signallingmolecules or Toll-like receptors (TLRs) that can recognizethe conserved patterns of proteins, lipoproteins, dsRNA, orunmethylated CpG DNA (Kopp and Medzhitov, 1999;Akira et al., 2001; Underhill and Ozinsky, 2002). Whileoriginally discovered by their ability to recognize bacteri-al and parasite invasion, it has been shown recently thatmammalian TLRs can also recognize the patterns on thesurface of virions such as the respiratory syncial virus-encoded F fusion protein (Kurt-Jones et al., 2000) andviral RNA or DNA. Altogether, the broad array of cellularresponses to invading pathogens can include phagocytosis,induction of inflammatory cytokines, chemokines and co-stimulatory molecules. Among the inflammatorycytokines, type I interferons (IFNs) play a unique role inthe antiviral innate immune response, since they have notonly the ability to directly inhibit viral replication, but alsoinduce differentiation of dendritic cells, activation of nat-ural killer (NK) cells and macrophages. However, aberrantexpression of IFNα genes has been shown to be associat-ed with several chronic viral infections and autoimmunediseases (Neighbor et al., 1981; Preble et al., 1982;Rhodes-Feuillette et al., 1983; Arvin and Miller, 1984;Fitzgerald-Bocarsly et al., 1991; Kunzi et al., 1995). Thereis also accumulating evidence that inappropriate or dereg-ulated expression of chemokines or their receptors canplay a role in the autoimmune response (Karpus et al.,1995) and rheumatoid arthritis (Nanki et al., 2000). Thus,the identification of factors that regulate the inducible andtimely expression of these inflammatory proteins is of pri-mary importance.The interactions of pathogens with cellular receptorsinduce multiple signalling pathways leading to the activa-tion of transcription factors that control the expression ofa diverse set of genes coordinating the immune respons-es. Although cascades of multiple kinases mediate activa-tion of these transcription factors, their functionaldiversity is modulated by interaction with other transcrip-tion factors and co-factors. Indeed, these regulatory net-works are critical components of the host defence againstinvading pathogens, including viruses.Two families of cellular factors play a critical role inthe transcriptional activation of the early inflammatorygenes. One is the well-characterized family of NFκB fac-tors (Lenardo and Baltimore, 1989); the other is a newlyemerging family of interferon response factors (IRFs)(Nguyen et al., 1977). The IRFs have been first identifiedby their role in the virus-mediated induction of type I IFNgenes, but later were shown to also participate in theinduction of chemokines (e.g. Rantes and MIP-1),cytokines (e.g. IL-12 and IL-15), genes involved directlyin the antiviral response (PKR, 2,i5iOAS), antibacterialresponse (iNOS and gp91