Airway macrophages (MΦ) are an important component of the innate host-defence against influenza A virus (IAV), initiating local inflammatory responses and priming subsequent adaptive responses. Historically, MΦ have also been considered to play a critical role in controlling the severity of seasonal IAV infection by limiting virus release through “abortive replication” such that infectious virus particles are not released from infected cells. Previously, we compared murine MΦ and epithelial cells for their ability to support genomic replication and transcription, synthesis of viral proteins, assembly of virions and release of infectious progeny following exposure to genetically defined seasonal IAV strains. We observed restriction late in the virus life cycle in seasonal IAV-infected MΦ, where virus assembly is defective and newly synthesized virions are not released. Our recent data suggests a similar late-stage block also exists in human alveolar MΦ.
In contrast, some highly pathogenic avian IAV (HPAI) H5N1 strains have been reported to replicate productively in MΦ. We used reverse genetics (RG) H5N1 viruses containing 6 genes from seasonal IAV plus HA/NA genes from HPAI H5N1 to identify strains that productively or abortively replicate in murine and human MΦ. At 24 hours post-infection, intracellular expression of viral proteins (M1, NP, HA, M2) and vRNPs was detected during both abortive and productive replication in MΦ. However, plasma membrane localisation of M2 viral protein was significantly reduced during abortive replication. These data indicate that abortive replication of IAV in MΦ may be associated with impaired plasma membrane trafficking of at least one viral protein to the surface infected cells. Current studies are focused on (i) identifying cellular factors responsible for limiting productive replication in MΦ by seasonal IAV and (ii) investigating the viral determinants that enable highly pathogenic IAV strains to evade the host MΦ response and replicate productively in these cells.