Dr. Whittaker's group is studying the cell biology of influenza and coronavirus, major pathogens of humans and a variety of animal species. The work covers three main areas:
Entry of influenza into cells
Influenza enters cells by receptor-mediated endocytosis, and is triggered for fusion and uncoating by the low pH environment of the endosome. They are studying the entry process in cells expressing dominant-negative forms of various cellular proteins, including dynamin and Rab GTPases and protein kinase C. In dynamin mutant cells, virus entry was arrested in long tubular extensions of the plasma membrane. They are also studying novel inhibitors of virus entry that may affect events needed for endocytosis and investigating differences in the route of entry between clinical and lab-adapted strains of the virus.
Nuclear transport of influenza virus
Influenza virus replicates in the cell nucleus, and so its genome (vRNP) must enter and exit the nucleus during replication. They have previously shown that the virus matrix protein (M1) is a key regulator of vRNP nuclear transport. They have recently established a permeabilized cell system to study vRNP nuclear transport. vRNPs are prevented from entering the nucleus by addition of wheat germ agglutinin, which blocks the nuclear pore. Nuclear export of the virus genome is blocked by the drug leptomycin B and they are currently characterizing the export block in terms of sub-nuclear localization and biochemical interactions.
Entry of Coronaviruses
Coronaviruses are major cause of disease in several animal species and with the recent emergence of the SARS virus have become increasingly important as human pathogens. Dr.Whittaker's laboratory uses infectious bronchitis virus of chickens as a model to examine how coronaviruses in general enter cells--specifically what factors control receptor binding and envelope fusion.
Endocytosis
Influenza virus, as well as other enveloped viruses such as SFV and VSV are excellent systems to study basic endocytic processes in cells. In concert with the work focussed on the pathogenesis of influenza the group is examining the regulation of lysosome-targeted endocytic traffic. They have recently found that specific isoforms of protein kinase C (PKC) prevent degradation of epidermal growth factor (EGF), with possible implications for cancer biology.
Endocytic trafficking of EGF
Upon ligand stimulation of its receptor at the cell surface, EGF is taken up into cells by receptor-mediated endocytosis, and is targeted to the late endosome/lysome for degradation and signal attenuation. They have been studying the entry process in cells expressing dominant-negative forms of protein kinase C betaII. In mutant cells, EGF was not degraded and was trapped in the late endosome. The group is currently studying the implications of PKC action on the ability of EGF to undergo sustained signalling within the endosome.
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