The role of the cytoplasmic tail of the influenza virus M2 protein in viral morphology and replication

The influenza A virus is the causative agent of influenza virus disease - commonly known as 'the flu'. Considerable numbers of people are infected seasonally, with most illness resolving quickly. The social and economic impact can be severe, and presents a significant burden for healthcare systems.

Influenza A is a negative sense, single stranded RNA virus with a host-derived lipid envelope that can form both filamentous and spherical virions. The genome encodes for at least 14 genes from eight RNA segments, the main focus of this report being on the ion channel matrix protein 2 (M2). M2 is primarily responsible for allowing the flow of protons down the concentration gradient in early infection, when the virus is within an acidified endosome. The lowering of the pH within the viral core triggers viral membrane fusion with the endosomal membrane, and facilitates release of the viral RNPs in to the cell cytoplasm.

M2 is also known to interact with many of the other viral and cellular proteins during all stages of viral infection. It binds to both the matrix protein 1, M1, and possibly interacts with the nucleoprotein, NP, as well as interacting with cellular factors such as Annexin A6, and cholesterol. Biophysically, M2 is crucial during viral budding in that it provides the force necessary to induce negative gaussian membrane curvature which enables 'pinching off' of new virions.

Here we show that the cytoplasmic tail (CT) of M2 is able to interact with many cellular proteins and processes, such as autophagy through LC3 binding, the cellular SUMO system through a SUMO interacting motif, SIM, and the cellular intermediate filament Vimentin. We have used a myriad of techniques in an attempt to elucidate and characterise these interactions of the M2 CT, and how mutations in the M2 CT may ultimately affect viral morphology. Further understanding of viral morphology being affected by other viral proteins and has been investigated through the study of live attenuated influenza viruses (LAIVs) used in seasonal vaccinations. Through this, a medically applicable outcome of influenza morphology is also presented for future investigation.