Role of the IKK/NF-κB pathway in the regulation of apoptosis during influenza virus infection

The influenza virus represents one of the most important viral pathogens causing respiratory illness in humans and in animals. New influenza virus strains are constantly produced by protein mutation (antigenic drift) or genome reassortment (antigenic shift) and this high variability determines a resistance to antiviral drugs. In the recent years, the emergence of new avian and swine influenza A virus strains able to infect humans represents a serious threat to global human health. Given the high mutation rate of the viral proteins, a more innovative approach to anti-influenza therapy is the search for selected cellular targets essential for viral replication. In particular, the study of virus-regulated signal transduction pathways leading to metabolic changes in the host cell may lead to the discovery of novel drug targets. On this basis, one of the objectives of this work was to investigate the effects of influenza virus infection on the modulation of pathways involved in the control of cell survival and in particular on the IKKNF-κB pathway. Altogether, the results obtained indicate the existence of a complex network of pro- and anti -apoptotic signals induced by influenza virus, including activation of JNK and Akt kinases, and suggest that the balancing of various factors can determine the fate of infected cells. In particular, the activation of the IKK/NF-κB pathway, which is dependent on the viral strain and the cell type, appears to play an important role in host cell survival regulation, leading to expression of several anti-apoptotic proteins. In addition, in view of the emergence of highly pathogenic avian influenza strains able to infect humans, in the second part of this work we have utilized the H5N9-A/Ck/It/9097/97 strain to set up an in vitro model of avian influenza virus for the study of novel antiviral molecules. We have shown that A/Ck virus replicates efficiently in MDCK cells, causing a rapid shut-off of cell protein synthesis, massive disassembly of the host microtubular network, and sustained production of viral progeny particles in the supernatant of infected cells. Using this model, we have shown that cyclopentenone prostanoids (CyPG) potently inhibits A/Ck virus replication, causing dysregulation of viral protein synthesis, associated with cytoprotective HSP70 expression, and inhibition of virus-induced NF-κB activity. These results indicate that CyPG possess antiviral activity against avian influenza virus acting at a level different from the currently available anti-influenza drugs, suggesting a possible therapeutic use of cyclopentenone prostanoids or prostanoids-derived molecules during clinical complications of avian influenza-virus infection.