How important is influenza as a human pathogen?

MxA

Pretty damn important.

How do we know? Because humans have a gene encoding a protein which seems to be dedicated to preventing influenza virus infection. Interferon-inducible dynamin-like myxovirus resistance protein (MxA) is found in membranes of the smooth endoplasmic reticulum–Golgi intermediate compartment. On influenza virus infection of the cell, it redistributes to sites of virus replication and promotes missorting of the myxovirus nucleocapsid (N) protein into membrane-associated, large perinuclear complexes. By preventing the N protein entering the nucleus, influenza virus replication is disrupted.

Influenza A viruses of avian or swine origin sporadically enter the human population but do not readily transmit between individuals. In rare cases, however, they establish a new virus lineage in humans. The mechanisms by which invading viruses overcome the species barrier are not well understood, but multiple adaptations to the new host are required. Surprisingly little is known about adaptive mutations that overcome restriction factors of the intrinsic and innate host defense system.

A recent paper in PLOS Pathogens identifies adaptive mutations in pandemic strains of influenza that confer resistance to the interferon-induced antiviral factor MxA. The resistance-enhancing mutations changed several amino acids in the viral nucleoprotein which is the main nucleocapsid component. These mutations were sufficient to increase the pathogenicity of an avian influenza virus strain in a Mx-positive mouse model. Interestingly, the resistance-associated amino acids are counter-selected in circulating avian influenza strains, because they compromise general viral replication fitness. Innate immunity factor MxA provides a barrier against zoonotic introduction of influenza A viruses and adaptive mutations in the influenza N protein should be carefully monitored.

Why should you care about this? -> H7N9

 

Pandemic Influenza A Viruses Escape from Restriction by Human MxA through Adaptive Mutations in the Nucleoprotein. (2013) PLoS Pathog 9(3): e1003279. doi:10.1371/journal.ppat.1003279
The interferon-induced dynamin-like MxA GTPase restricts the replication of influenza A viruses. We identified adaptive mutations in the nucleoprotein (NP) of pandemic strains A/Brevig Mission/1/1918 (1918) and A/Hamburg/4/2009 (pH1N1) that confer MxA resistance. These resistance-associated amino acids in NP differ between the two strains but form a similar discrete surface-exposed cluster in the body domain of NP, indicating that MxA resistance evolved independently. The 1918 cluster was conserved in all descendent strains of seasonal influenza viruses. Introduction of this cluster into the NP of the MxA-sensitive influenza virus A/Thailand/1(KAN-1)/04 (H5N1) resulted in a gain of MxA resistance coupled with a decrease in viral replication fitness. Conversely, introduction of MxA-sensitive amino acids into pH1N1 NP enhanced viral growth in Mx-negative cells. We conclude that human MxA represents a barrier against zoonotic introduction of avian influenza viruses and that adaptive mutations in the viral NP should be carefully monitored.

 

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