We provided compelling evidence for the involvement of the PD-1/PD-L1 pathway in the acute infection caused by SFTSV, while demonstrating the potent inhibitory effect of our novel anti-PD1 nanobody, NbP45, against SFTSV infection in vitro and in SFTSV-infected NCG-HuPBL mouse model. Here, HMGN5 is linked to infection.