TY  - EJOU
AU  - Liao, Xuechun 
AU  - Chen, Xiaoxiao 
AU  - Wei, Shulan 
AU  - Li, Qiong 
AU  - Zhao, Yanqin 
AU  - Xiao, Yuying 
AU  - Zhou, Qi 
AU  - Chen, Jianping 
AU  - He, Jinlei 

TI  - PD-1 Blockade Reduces Parasite Load and Restores Anti-Parasitic Immunity in Murine Visceral Leishmaniasis
T2  - BIOCELL

PY  - 
VL  - 
IS  - 
SN  - 1667-5746

AB  - <b>Objective:</b> Immune checkpoint blockade holds therapeutic potential in visceral leishmaniasis; its underlying mechanism remains unclear. This study aimed to investigate the therapeutic potential and underlying immune mechanisms of Programmed cell death protein 1 (PD-1) blockade in experimental visceral leishmaniasis. <b>Methods:</b> BALB/c mice infected with <i>Leishmania donovani</i> received anti-PD-1 antibody at 35–44 days post-infection. Parasite burden in target organs, serum antibodies, hepatopathology, and transcriptome of the liver were analyzed. T cell exhaustion, activation, apoptosis, and inflammation genes were quantified in target organs. <b>Results:</b> PD-1 blockade reduced splenic parasite load (reduction rate = 82.6%, ***<i>p</i> < 0.001), enhanced hepatic granulomatous maturation, and elevated anti-<i>Leishmania</i> IgG/IgG1/IgG2a levels. qPCR analysis revealed that the expressions of exhaustion marker genes Programmed cell death 1 (<i>Pdcd1</i>) and B and T lymphocyte attenuator (<i>Btla</i>) were upregulated in the liver and spleen following <i>Leishmania</i> infection, indicating an exhausted state. After PD-1 blockade, the expression of pro-inflammatory cytokine genes Tumor necrosis factor alpha (<i>Tnfa</i>), Interferon gamma (<i>Ifng</i>), and Nitric Oxide Synthase 2 (<i>Nos2</i>) was upregulated in the spleen, while the expression of anti-inflammatory cytokine genes Interleukin 4 (<i>Il4</i>) and Interleukin 10 (<i>Il10</i>) was downregulated in the liver. Transcriptome suggested that antigen processing & presentation, Natural Killer cell-mediated cytotoxicity, and neutrophil extracellular trap formation pathways were restored after blockade. Six hub genes associated with immune restoration were identified, of which Activating transcription factor 3 (<i>Atf3</i>) was chosen to be overexpressed in RAW 264.7 and manifested a reduced infection rate and average <i>Leishmania</i> at 12 h post-infection. <b>Conclusion:</b> This study demonstrated PD-1 blockade reinvigorated anti-parasitic immunity through multimodal mechanisms and illuminated both the potential and intricate dynamics of immune checkpoint modulation in leishmaniasis, where treatment success hinges on coordinated immune activation.
KW  - Visceral leishmaniasis; programmed cell death protein 1; immune checkpoint blockade; T cell exhaustion; RNA-sequencing

DO  - 10.32604/biocell.2026.077240