Function of Influenza Virus Neuraminidase

In 1966, Seto and Rott showed that the function of neuraminidase was probably associated with the release of virus from host cells (Seto and Rott, 1966). It was then found that antibody directed specifically against flu neuraminidase, and which abolished the activity of the enzyme for large substrates, did not prevent the infection of susceptible cells, but blocked the release of newly formed virus particles (Webster and Laver, 1967).

The role of neuraminidase in the release of virus particles from infected cells was demonstrated most elegantly by Palese, Compans, and their colleagues in 1974 (Palese et al., 1974a). Electron micrographs were made of surfaces of cells infected with temperature sensitive (ts) neuraminidase mutants of influenza virus at the permissive temperature and at the restrictive temperature (where the virus replicated but where the neuraminidase lacked enzyme activity). These showed virus particles budding normally from the cells and going off to infect other cells at the permissive temperature. However in cells infected with the ts mutants at the restrictive temperature, virus particles budded from the cell in the normal manner, but then remained attached to each other and to the surface of the infected cells, forming great clumps of virus particles. These were clearly not going anywhere, and the infection was effectively terminated (Figure 17.8).

It is believed, therefore, that the function of flu virus neuraminidase is to remove sialic acid receptors for the virus from the host cells, and also, perhaps more importantly, from the

Figure 17.8. Electron micrographs of the surface regions of MDCK cells infected with temperature sensitive (ts) neuraminidase mutants of influenza virus after inoculation and incubation for 12.5 hr at the permissive temperature of 330C ((a) left) and at the restrictive temperature of 39.50C ((b) right). The aggregates of virus particles which accumulated at the restrictive temperature could be dispersed by incubation with bacterial neuraminidase. Staining experiments showed that the aggregated virus particles formed at the restrictive temperature were covered in sialic acid residues, while this was absent on those well-dispersed particles formed at the permissive temperature. Magnification approximately X30,000. (Reprinted from Palese etal. [1974a] with permission from Elsevier.)

Figure 17.8. Electron micrographs of the surface regions of MDCK cells infected with temperature sensitive (ts) neuraminidase mutants of influenza virus after inoculation and incubation for 12.5 hr at the permissive temperature of 330C ((a) left) and at the restrictive temperature of 39.50C ((b) right). The aggregates of virus particles which accumulated at the restrictive temperature could be dispersed by incubation with bacterial neuraminidase. Staining experiments showed that the aggregated virus particles formed at the restrictive temperature were covered in sialic acid residues, while this was absent on those well-dispersed particles formed at the permissive temperature. Magnification approximately X30,000. (Reprinted from Palese etal. [1974a] with permission from Elsevier.)

newly formed virus particles themselves. The two surface antigens on the influenza virus particle, the hemagglutinin and the neuraminidase, are themselves glycoproteins and possess carbohydrate side chains with terminal sialic acid receptors for other virus particles. The main function of the neuraminidase therefore might be to remove receptors for influenza virus from newly formed virus particles so allowing these to be released and spread the infection (Palese et al., 1974a). Another function of flu virus neuraminidase might be to destroy sialic acid containing inhibitors for the virus in the mucous secretions of the respiratory tract, so enabling the virus to more easily infect cells, and there may be other functions as yet undiscovered.

Chickens vaccinated with pure neuraminidase "heads" were protected from death by lethal avian influenza viruses. But whether this protection was due to inhibition of neu-raminidase activity or to enhanced clearance of the virus by the immune system was not established (Webster et al., 1988).

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