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Myxovirus resistance (Mx) proteins are dynamin-like GTPases that are inducible by interferons (IFNs) following virus infections. Most studies investigating Mx proteins have focused on their activity against influenza A viruses (IAV), although emerging evidence suggests that some Mx proteins may exhibit broader antiviral activity. Herein, we demonstrate that in addition to IAV, overexpression of mouse Mx1 (mMx1), but not mMx2, resulted in potent inhibition of growth of the human alphaherpesviruses herpes simplex virus 1 (HSV-1) and HSV-2, whereas neither inhibited the mouse betaherpesvirus murine cytomegalovirus (MCMV) in vitro. IFN induction of a functional endogenous mMx1 in primary mouse fibroblasts ex vivo was also associated with inhibition of HSV-1 growth. Using an in vitro overexpression approach, we demonstrate that mutations that result in redistribution of mMx1 from the nucleus to the cytoplasm or in loss of its combined GTP binding and GTPase activity also abrogated its ability to inhibit HSV-1 growth. Overexpressed mMx1 did not inhibit early HSV-1 gene expression but was shown to inhibit both replication of the HSV-1 genome as well as subsequent late gene expression. In a mouse model of cutaneous HSV-1 infection, mice expressing a functional endogenous mMx1 showed significant reductions in the severity of skin lesions as well as reduced HSV-1 titers in both the skin and dorsal root ganglia (DRG). Together, these data demonstrate that mMx1 mediates potent antiviral activity against human alphaherpesviruses by blocking replication of the viral genome and subsequent steps in virus replication. Moreover, endogenous mMx1 potently inhibited pathogenesis in the zosteriform mouse model of HSV-1 infection. IMPORTANCE While a number of studies have demonstrated that human Mx proteins can inhibit particular herpesviruses in vitro, we are the first to report the antiviral activity of mouse Mx1 (mMx1) against alphaherpesviruses both in vitro and in vivo. We demonstrate that both overexpressed mMx1 and endogenous mMx1 potently restrict HSV-1 growth in vitro. mMx1-mediated inhibition of HSV-1 was not associated with inhibition of virus entry and/or import of the viral genome into the nucleus, but rather with inhibition of HSV-1 genomic replication as well as subsequent late gene expression. Therefore, inhibition of human alphaherpesviruses by mMx1 occurs by a mechanism that is distinct from that reported for human Mx proteins against herpesviruses. Importantly, we also provide evidence that expression of a functional endogenous mMx1 can limit HSV-1 pathogenesis in a mouse model of infection. [ABSTRACT FROM AUTHOR]

It iswell-established that influenza virus infections predispose individuals to secondary bacterial infections (SBIs), which may result in a range of clinical outcomes from relatively mild (e.g. sinusitis and otitis media) to severe (e.g. pneumonia and septicaemia). The most common bacterial pathogen associated with SBI following influenza virus infections is Streptococcus pneumoniae (SPN). Of circulating human seasonal influenza viruses, influenza A viruses (IAV) of both the A(H1N1)pdm09 and A(H3N2) subtypes are associated with severe disease but have differing hospitalisation and complication rates. To study the interplay of these two IAV subtypes with SBI, we used a ferret model of influenza infection followed by secondary challenge with a clinical strain of SPN to determine the severity and the period of susceptibility for SBI. Ferrets challenged with SPN 5 days after infectionwith A(H3N2) or A(H1N1)pdm09 viruses developed severe disease that required euthanasia. When the time between viral infection and bacterial challengewas extended, A/H1N1pdm09-infected animals remained susceptible to SBI- for up to 10 days after the viral infection. For A(H3N2)- but not A(H1N1)pdm09-infected ferrets, susceptibility to SBI-associated disease could be extended out to 16 days postviral infection. While caution should be taken when extrapolating animal models to human infections, the differences between A(H3N2) and A(H1N1)pdm09 strains in duration of susceptibility to SBI observed in the ferret model, may provide some insight regarding the higher rates of SBI-associated disease associated with some strains of A(H3N2) viruses in humans. [ABSTRACT FROM AUTHOR]