Inhibition of SFTSV replication in humanized mice by a subcutaneously administered anti-PD1 nanobody

EMBO Mol Med. 2024 Mar;16(3):575-595. doi: 10.1038/s44321-024-00026-0. Epub 2024 Feb 16.

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.

Keywords: Nanobody; NbP45; PD-1 Blockade; SFTSV; Subcutaneous Injection.

MeSH terms

  • Animals
  • B7-H1 Antigen
  • Bunyaviridae Infections* / drug therapy
  • Humans
  • Leukocytes, Mononuclear
  • Mice
  • Phlebovirus* / physiology
  • Programmed Cell Death 1 Receptor
  • Severe Fever with Thrombocytopenia Syndrome*

Substances

  • B7-H1 Antigen
  • Programmed Cell Death 1 Receptor