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Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening disease caused by a novel bunyavirus (SFTSV), mainly transmitted by ticks. With no effective therapies or vaccines available, understanding the disease's mechanisms is crucial. Recent studies found increased expression of programmed cell death-1 (PD-1) on dysfunctional T cells in SFTS patients. However, the role of the PD-1/programmed cell death-ligand 1 (PD-L1) pathway in SFTS progression remains unclear. We investigated PD-1 blockade as a potential therapeutic strategy against SFTSV replication. Our study analyzed clinical samples and performed in vitro experiments, revealing elevated PD-1/PD-L1 expression in various immune cells following SFTSV infection. An anti-PD-1 nanobody, NbP45, effectively inhibited SFTSV infection in peripheral blood mononuclear cells (PBMCs), potentially achieved through the mitigation of apoptosis and the augmentation of T lymphocyte proliferation. Intriguingly, subcutaneous administration of NbP45 showed superior efficacy compared to a licensed anti-PD-1 antibody in an SFTSV-infected humanized mouse model. These findings highlight the involvement of the PD-1/PD-L1 pathway during acute SFTSV infection and suggest its potential as a host target for immunotherapy interventions against SFTSV infection. Synopsis: Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening disease caused by infection with a novel bunyavirus (SFTSV). However, the existence of multiple SFTSV genotypes presents a significant challenge for developing therapeutic antibodies targeting SFTSV. 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. During SFTSV infection, the expression of PD-1/PD-L1 in immune cells was significantly upregulated. Subcutaneous NbP45, a new nanobody developed by us, exhibited better protective efficacy than the anti-PD1 antibody drug with traditional format of whole IgG. PD-1/PD-L1 could serve as the conserved host targets for developing potential immunotherapy interventions to broadly treat SFTSV infection. Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening disease caused by infection with a novel bunyavirus (SFTSV). However, the existence of multiple SFTSV genotypes presents a significant challenge for developing therapeutic antibodies targeting SFTSV. 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. [ABSTRACT FROM AUTHOR]

Abstract Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening disease caused by a novel bunyavirus (SFTSV), mainly transmitted by ticks. With no effective therapies or vaccines available, understanding the disease’s mechanisms is crucial. Recent studies found increased expression of programmed cell death-1 (PD-1) on dysfunctional T cells in SFTS patients. However, the role of the PD-1/programmed cell death-ligand 1 (PD-L1) pathway in SFTS progression remains unclear. We investigated PD-1 blockade as a potential therapeutic strategy against SFTSV replication. Our study analyzed clinical samples and performed in vitro experiments, revealing elevated PD-1/PD-L1 expression in various immune cells following SFTSV infection. An anti-PD-1 nanobody, NbP45, effectively inhibited SFTSV infection in peripheral blood mononuclear cells (PBMCs), potentially achieved through the mitigation of apoptosis and the augmentation of T lymphocyte proliferation. Intriguingly, subcutaneous administration of NbP45 showed superior efficacy compared to a licensed anti-PD-1 antibody in an SFTSV-infected humanized mouse model. These findings highlight the involvement of the PD-1/PD-L1 pathway during acute SFTSV infection and suggest its potential as a host target for immunotherapy interventions against SFTSV infection.