Understanding host protease gene involvement during influenza virus replication as a potential disease intervention strategy

Abstract

Influenza A virus causes seasonal epidemics and periodic pandemics threatening the health of millions of people each year. Vaccination is an effective strategy for reducing morbidity and mortality, and in the absence of drug resistance, the efficacy of chemoprophylaxis is comparable to that of vaccines. However, the rapid emergence of drug resistance has emphasized the need for new drug targets. Knowledge of the host cell components required for influenza replication has been an area targeted for disease intervention. We screened human protease genes for those involved in influenza virus replication, and validated five human protease genes using RNA interference approaches. Pathway analysis determined three global cellular pathways governing inflammation, cAMP/calcium signaling, and apoptosis, in which the five protease genes were involved. Analyses of host microRNAs predicted to govern expression of these genes showed that eight miRNAs regulated gene expression during virus replication. We also investigated the role of the protease gene, TMPRSS2, known to cleave and activate influenza hemagglutinin in influenza cell-to-cell spread. Together, these findings identify unique host genes and microRNAs important for influenza replication providing potential new targets for disease intervention strategies.