J. immune system prospects to their inhibition (Physique 2 and Physique 3) [48], whereas a combination of immune pressure in the human population and the high mutation rate of the influenza A computer virus leads to the generation of new computer virus strains that escape the existing adaptive humoral and cellular immune responses (Physique 1 and Physique 5). 4.1. Escape from Innate Immunity Influenza A viruses have adopted numerous strategies to evade the antiviral nature of the innate immune system. In particular, the NS1 protein contributes to antagonizing the antiviral innate immune response. Cells infected with genetically altered influenza viruses with a non-functional NS1 gene displayed stronger IFN responses than cells infected with wild type computer virus. Viruses with a NS1 defect also display reduced virulence after contamination of mice and pigs [218,219,220,221,222,223,224]. NS1 inhibits RIG-I receptor signaling by numerous means. The NS1 protein blocks the acknowledgement of 5′-phosphorylated viral ssRNA by the RIG-I receptor [42]. More downstream of the RIG-I signaling pathway, NS1 prevents oligomerization of TRIM25 by interacting with the coiled coil domain, and so inhibits TRIM25-mediated RIG-I CARD ubiquitination which is essential for downstream signaling [225]. Finally, activation and nuclear translocation of IRF-3, NF-B and ATF-2/c-Jun is also prevented by NS1 [226,227,228,229]. Hereby NS1 limits RIG-I mediated transcriptional activation of the IFN- promoter [230,231]. NS1 also alters host cell gene expression by binding to CPSF30 (cleavage and polyadenylation specificity factor); it prevents polyadenylation of the 3′ A 922500 end of host pre-mRNA [232,233,234]. Furthermore, NS1 limits gene expression in general, interfering with the mRNA export machinery [235,236]. NS1 is not the only viral protein that restrains the innate immune system. Both influenza PB2 (especially variants made up of an aspartic acid at position 9) and PB1-F2 (only variants made up of a serine at position 66) limit the production of IFN- through association with MAVS [237,238,239,240,241]. Viral proteins PB2, PB1 and EPHB4 PA form the influenza polymerase complex, the main function of which is usually viral A 922500 RNA and mRNA synthesis. In addition, it is also involved in cap-snatching of host mRNAs and thereby reduces host cell gene expression including that of IFN- [242,243,244,245,246]. The recently discovered PA-X viral protein is able to repress cellular gene expression, especially those genes involved in regulating the initiation of the cellular immune response [4]. As explained above, influenza A computer virus infection leads to the production of antiviral PKR (Table 1). In order for PKR to limit viral replication, it first needs to be activated by viral dsRNA. PKR activation is usually under tight regulation of the cellular A 922500 p58IPK protein which inhibits PKR activity, but is usually inactive when it forms a complex with heatshock protein 40 (hsp40) [247,248]. Binding of NP to the p58IPK-hsp40 complex releases p58IPK, and thereby NP inhibits the effects of PKR [249]. In contrast, the influenza M2 protein, which also binds the p58IPK-hsp40 complex, inhibits p58IPK release and thereby limits protein synthesis which eventually prospects to host cell apoptosis, possibly enhancing viral particle release [250]. By encapsidating influenza A viral RNA, the NP protein is likely to reduce the formation of dsRNA, which could normally lead to activation of RIG-I signaling. Since most PRRs are located inside the cytoplasm, the nuclear replication strategy of the influenza A computer virus also prevents the acknowledgement of viral RNA by cytosolic PRR. In addition to limiting the production of type I IFNs, influenza A computer virus also disturbs type I IFN receptor signaling. Influenza A computer virus contamination induces the expression of SOCS (suppressor of cytokine signaling) proteins which inhibit IFN / receptor signaling on the level of JAK/STAT activation [251,252]. Besides interfering with innate signaling, influenza A viruses are also able to counteract cells of the innate immune system. For example, influenza computer virus contamination of monocytes impairs their ability to differentiate into mature DCs [253]. Furthermore, it was shown that NS1 can inhibit DC maturation, and so indirectly limit the induction of virus-specific CD8+ T cell responses [254]. The NK response elicited during an infection is also evaded by the influenza A computer virus [255]. The progressive mutation of glycosylation sites of influenza computer virus HA proteins prospects to reduced NK recognition of the HA on virus-infected cells [256]. Downregulation of the chain of NKp46 receptors by free HA proteins results in impaired signaling and thereby decreased.