Influenza Neuraminidase : Novel mechanisms of influenza NA that enable adaptation and promote diversification

Sammanfattning: Influenza A viruses (IAVs) are one of the most common human respiratory pathogens and are largely responsible for the seasonal influenza epidemics that cause mild to severe disease. The two IAV glycoproteins, hemagglutinin (HA or H) and neuraminidase (NA or N), serve as the major surface antigens and also are the main determinants of infectivity, pathogenicity and transmissibility. Due to the high abundance in the IAV envelope and its defined functions of mediating cell binding and viral entry, current influenza vaccines have primarily been developed based on HA. The less abundant NA is a receptor-destroying enzyme that facilitates virion release from the infected cell and the escape from decoy receptors during the entry process. Despite these important roles for infection, NA has been largely neglected in vaccines because of its low abundance and labile properties.The work in this thesis involves several studies that have primarily focused on establishing a general overview of NA maturation and providing a biochemical assessment of the enzymatic properties in the NAs from circulating H1N1 IAVs. The results from these studies show that the membrane integration of a class of NAs is dependent on the synthesis of its long C-terminus, NA tetramerization is coordinated by its N-terminal transmembrane domain (TMD) and the distal enzymatic head domain, NA stability changes are related to intrinsic and extrinsic determinants, and that the N-linked glycosylation sites on the NA head domain contribute to viral incorporation. In addition, we demonstrated that NA oligomeric structure possesses sufficient plasticity to allow the formation of heterotetramers, which increases the tolerance for suboptimal substitutions and contributes to the diversification of its enzymatic properties.Together, these results provide new insights into the NA maturation process and the biochemical mechanisms that are responsible for the NA property differences that are observed in circulating H1N1 IAVs.