APICAL M2 PROTEIN IS REQUIRED FOR EFFICIENT INFLUENZA A VIRUS REPLICATION

influenza;matrix protein 2;attenuation;not listed

Wohlgemuth, NicholasMachamer, Carolyn E. ;

Johns Hopkins University

关键词: influenza;    matrix protein 2;    attenuation;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/59141/Thesis%20draft%20final.docx?sequence=2&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Influenza virus infections are a major public health burden around the world. This dissertation examines the influenza A virus M2 protein and how it can contribute to a better understanding of influenza virus biology and improve vaccination strategies. M2 is a member of the viroporin class of virus proteins characterized by their predicted ion channel activity. While traditionally studied only for their ion channel activities, viroporins frequently contain long cytoplasmic tails that play important roles in virus replication and disruption of cellular function. The currently licensed live, attenuated influenza vaccine (LAIV) contains a mutation in the M segment coding sequence of the backbone virus which confers a missense mutation (alanine to serine) in the M2 gene at amino acid position 86. Previously discounted for not showing a phenotype in immortalized cell lines, this mutation contributes to both the attenuation and temperature sensitivity phenotypes of LAIV in primary human nasal epithelial cells. Furthermore, viruses encoding serine at M2 position 86 induced greater IFN-λ responses at early times post infection. Reversing mutations such as this, and otherwise altering LAIV’s ability to replicate in vivo, could result in an improved LAIV development strategy. Influenza viruses infect at and egress from the apical plasma membrane of airway epithelial cells. Accordingly, the virus transmembrane proteins, HA, NA, and M2, are all targeted to the apical plasma membrane and contribute to egress. When M2 is targeted away from the apical plasma membrane, virus replication and budding are significantly diminished. Consequently, viruses encoding M2 targeted away from the apical plasma membrane could be developed as vaccine candidates or used to improve systemic influenza virus models. Together these studies demonstrate that non-immunodominant viral proteins, like M2, can be modified and used to drastically affect virus replication and function while potentially leading to new therapeutics and prophylactics.