Human MxA protein protects mice lacking a functional alpha beta interferonsystem against La Crosse virus and other lethal viral infections

The human MxA protein is part of the antiviral state induced by alpha/beta interferon (IFN-alpha/beta). MxA inhibits the multiplication of several RNA viruses in cell culture. However, its antiviral potential in vivo has not yet been fully explored. We have generated MxA-transgenic mice that lack a functional IFN system by crossing MxA-transgenic mice constitutively expres sing MxA with genetically targeted (knockout) mice lacking the beta subunit of the IFN-alpha/beta receptor (IFNAR-1(-/-) mice). These mice are an idea l animal model to investigate the unique antiviral activity of human MxA in vivo, because they are unable to express other IFN-induced proteins. Here, we show that MxA confers resistance to Thogoto virus, La Crosse virus, and Semliki Forest virus. No Thogoto virus progeny was detectable in MxA-trans genic mice, indicating an efficient block of virus replication at the prima ry site of infection, In the case of La Crosse virus, MxA restricted invasi on of the central nervous system. In contrast, Semliki Forest virus multipl ication in the brain was detectable in both MxA-expressing and nonexpressin g IFNAR-1(-/-) mice. However, viral titers were clearly reduced in MxA-tran sgenic mice. Our results demonstrate that MxA does not need the help of oth er IFN-induced proteins fur activity but is a powerful antiviral agent on i ts own, Moreover, the results suggest that MxA may protect humans from pote ntial fatal infections by La Crosse virus and other viral pathogens.