Many invertebrates coopt their coagulation cascade to resist microbial infection; however, it has been unclear whether mammals use an equivalent system. In Science, Shayakhmetov and colleagues demonstrate that the human blood-coagulation factor FX is important for the recognition of and immune response to adenovirus. After infection, FX rapidly coats the adenoviral hexon and engages Toll-like receptor 4 (TLR4) on tissue macrophages. FX therefore seems to facilitate binding in a way analogous to the well-known TLR4 coreceptor MD2. Engagement of TLR4 by FX-coated adenovirus triggers a host of inflammatory cytokines via a classic signaling pathway dependent on the adaptor MyD88 and transcription factor NF-κB, whereas mutant virus unable to bind FX does not trigger TLR4 signaling. This mechanism of FX-mediated release of inflammatory cytokines might underlie some of the adverse immunological reactions that have hampered adenoviral gene-therapy approaches.

Science 338, 795–798 (2012)