Acute respiratory tract infections are important causes of morbidity and mortality worldwide, particularly in infants and the elderly. Influenza A virus (IAV), human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are major causes of viral respiratory disease. Respiratory viruses infect airway epithelial cells, resulting in virus amplification and spread. Viruses such as IAV and RSV also infect cells of the immune system, such as airway macrophages (AMΦ), however virus replication is generally blocked in these cells.
Recent studies in our laboratory used RNA-seq to investigate differences in expression of host factors between AMΦ and airway epithelial cells, in the presence or absence of IAV infection, in an attempt to identify putative restriction factors that may block virus infection. Based on these results we have focused on particular gene families where certain members were expressed at high levels in AMΦ, but not in epithelial cells. We have used overexpression and/or knockdown approaches to screen families of membrane-associated RING-CH (MARCH) ubiquitin ligases, interferon-inducible transmembrane (IFITM)-family proteins and T-cell immunoglobulin and mucin (TIM)-domain family proteins for antiviral activity against IAV, RSV and HMPV. Preliminary data indicates that overexpression of MARCH8 (but not other MARCH-family proteins) does not alter IAV entry, but does inhibit virus release from infected cells. Moreover, MARCH8 expression also inhibited replication of other respiratory viruses such as RSV. Current studies in the laboratory aim to define the mechanisms underlying the antiviral activity of MARCH8, as well as defining the role of endogenous MARCH8 in limiting respiratory virus infection.