Innate Immune Response to Influenza Virus Type I Interferons

Ligation of the Toll-like receptors in the endosome of the infected cell triggers an immune response in several ways. The first response is an attempt to protect surrounding cells from subsequent infection with new influenza viruses that will quickly begin to emerge from the infected cell. The infected cell has developed a method of telling its neighbors that it is infected with a "virus" and they need to protect themselves at all costs. Through this signal, the infected cell says "this virus will kill you if you allow it in and allow it to overtake your molecular machinery—raise your defenses, destroy your RNA molecules, and shut-down protein synthesis." This signal is provided in the form of the type I interferons, which include interferon-alpha and Interferon-beta (IFN-a and IFN-ß) (Katze et al., 2002; Proietti et al., 2002).

IFN-ß is encoded by a single gene, whereas there are more than 20 different genes that code for IFN-a in both humans and mice. IFN-a and IFN-ß share a ubiquitously expressed heterodimeric receptor and, thus, share many, if not all, functions. IFN-a/ß binding leads to receptor dimerization, activation of the Janus Activated Kinase (JAK):Signal Transducer and Activators of Transcription (STAT) pathway, and induction of genes containing an IFN-stimulated response element (ISRE) in their regulatory region (Darnell et al., 1994; Barnes et al., 2002). Thus, influenza virus induced IFN-a/ß production drives new gene transcription in the healthy cells immediately surrounding the infected ones.

These interferons induce about 20-30 ISRE-containing genes, several of which have antiviral activities that can protect against virus replication. The first is 2', 5' oligoadenylate synthetase, which activates a ribonuclease that digests double-stranded RNA in the target cell (Hovanessian, 1991). A second gene that is activated is a protein kinase that inhibits the initiation step of protein synthesis (Hovanessian, 1991; Samuel, 1991). Presumably, by destroying all of the double-stranded RNA in a cell and by temporarily shutting down all new gene expression and protein synthesis, replication and subsequent spread of the infecting virus would be blocked. This early virus-induced, IFN activation of cellular transcription constitutes the initial antiviral immune response of the host.

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