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Andy Mehle
The transmission of influenza from avian to human populations
is a significant public health concern and has the potential to
establish new pandemics. Many viral and host factors contribute
to the ability of influenza to cross species from birds to humans
and influence virus replication and pathogenicity. We have
studied the role the influenza RNA polymerase, the virus's
replication machinery, plays in controlling species tropism.
Avian viruses generally replicate poorly in humans, but a single
mutation in the polymerase from these viruses significantly
enhances replication and pathogenicity in mammalian systems.
Our work shows that an inhibitory factor or activity present
in human cells blocks the activity of the replication machinery
from avian viruses. The single mutation in the avian polymerases
allows these viruses to now avoid inhibition. Thus, as influenza
jumps from birds to people, it must overcome an inhibitor that
specifically targets its polymerase. Importantly, almost all
circulating strains of human influenza contain this mutation
which permits them to replicate efficiently. These findings
provide insight into virus-host interactions and factors
influencing the infectivity and relative pathogenicity of viruses
newly transferred into humans. They also provide another avenue
to explore in preventing the transmission of influenza from
birds to humans. We are actively pursuing several experimental
strategies to better understand how the structure and function of
the influenza RNA polymerase influences virus-host interactions
Selected Publications
Mehle, A. and Doudna, J.A. (2008)
An inhibitory activity in human cells restricts the function of an avian-like influenza virus polymerase.
Cell Host Microbe 4, 111-122.
(1.3MB .pdf)
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