Fusion protein is the main determinant of metapneumovirus host tropism

Abstract

Human metapneumovirus (HMPV) and avian metapneumovirus subgroup C (AMPV-C) infect humans and birds, respectively. This study confirmed the difference in host range in turkey poults, and analysed the contribution of the individual metapneumovirus genes to host range in an in vitro cell-culture model. Mammalian Vero-118 cells supported replication of both HMPV and AMPV-C in contrast to avian quail fibroblast (QT6) cells in which only AMPV-C replicated to high titres. Inoculation of Vero-118 and QT6 cells with recombinant HMPV in which genes were exchanged with those of AMPV-C revealed that the metapneumovirus fusion (F) protein is the main determinant for host tropism. Chimeric viruses in which polymerase complex proteins were exchanged between HMPV and AMPV-C replicated less efficiently compared with HMPV in QT6 cells. Using mini-genome systems, it was shown that exchanging these polymerase proteins resulted in reduced replication and transcription efficiency in QT6 cells. Examination of infected Vero-118 and QT6 cells revealed that viruses containing the F protein of AMPV-C yielded larger syncytia compared with viruses containing the HMPV F protein. Cell-content mixing assays revealed that the F protein of AMPV-C was more fusogenic compared with the F protein of HMPV, and that the F2 region is responsible for the difference observed between AMPV-C and HMPV Fpromoted fusion in QT6 and Vero-118 cells. This study provides insight into the determinants of host tropism and membrane fusion of metapneumoviruses.

Breaking In: Human Metapneumovirus Fusion and Entry

“…In cell culture, HMPV expressing only F (HMPVΔGΔSH) binds to the cell surface with the same efficiency as wild type virus [61]. Moreover, HMPV F confers species specificity of infection, as F was found to be primarily responsible for the difference in the ability of AMPV-C and HMPV to infect quail fibroblast (QT6) cells [62]. Further, the F2 subunit (and not the G protein) of both hRSV [38] and HMPV [62] has been shown to confer species-specific infection of cells.…”

“…Moreover, HMPV F confers species specificity of infection, as F was found to be primarily responsible for the difference in the ability of AMPV-C and HMPV to infect quail fibroblast (QT6) cells [62]. Further, the F2 subunit (and not the G protein) of both hRSV [38] and HMPV [62] has been shown to confer species-specific infection of cells. This evidence strongly indicated that HMPV F interacts with cell surface receptors, and both protein and carbohydrate receptors for HMPV F have been discovered.…”

Human Metapneumovirus: Lessons Learned over the First Decade

“…As for most paramyxoviruses, the trigger that leads to the membrane fusion event remains unknown, although it is tempting to speculate that binding to integrin ␣v␤1 may provide such a trigger (47). By generating chimeric viruses between HMPV and AMPV, it has been shown that the F protein is an important determinant of metapneumovirus host range (57).…”

A Live Attenuated Human Metapneumovirus Vaccine Strain Provides Complete Protection against Homologous Viral Infection and Cross-Protection against Heterologous Viral Infection in BALB/c Mice

“…F protein is synthesized as a precursor, and its activation requires cleavage by host cell protease (37,38). Vector-expressed or mammalian cell-expressed F protein can induce high levels of neutralizing antibodies and produce moderate resistance to the replication of intranasally administered challenge virus, suggesting that F protein is one of the major antigens that induce protection against hMPV infection (4,11,12).…”