PD-1 Blockade Reduces Parasite Load and Restores Anti-Parasitic Immunity in Murine Visceral LeishmaniasisOA
Objective: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.Methods:BALB/c mice infected with Leishmania donovani 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.Results:PD-1blockade reduced splenic parasite load(reduction rate=82.6%,***p<0.001),enhanced hepatic granulomatous maturation,and elevated anti-Leishmania IgG/IgG1/IgG2a levels.qPCR analysis revealed that the expressions of exhaustion marker genes Programmed cell death 1(Pdcd1)and B and T lymphocyte attenuator(Btla)were upregulated in the liver and spleen following Leishmania infection,indicating an exhausted state.After PD-1 blockade,the expression of pro-inflammatory cytokine genes Tumor necrosis factor alpha(Tnfa),Interferon gamma(Ifng),and Nitric Oxide Synthase 2(Nos2)was upregulated in the spleen,while the expression of anti-inflammatory cytokine genes Interleukin 4(Il4)and Interleukin 10(Il10)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(Atf3)was chosen to be overexpressed in RAW 264.7 and manifested a reduced infection rate and average Leishmania at 12 h post-infection.Conclusion: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.
Xuechun Liao;Xiaoxiao Chen;Shulan Wei;Qiong Li;Yanqin Zhao;Yuying Xiao;Qi Zhou;Jianping Chen;Jinlei He
Department of Pathogenic Biology,West China School of Basic Medical Sciences and Forensic Medicine,Sichuan University,Chengdu,ChinaDepartment of Pharmaceutics,School of Pharmacy,Chengdu Medical College,Chengdu,ChinaDepartment of Pathogenic Biology,West China School of Basic Medical Sciences and Forensic Medicine,Sichuan University,Chengdu,ChinaDepartment of Pathogenic Biology,West China School of Basic Medical Sciences and Forensic Medicine,Sichuan University,Chengdu,ChinaDepartment of Pathogenic Biology,West China School of Basic Medical Sciences and Forensic Medicine,Sichuan University,Chengdu,ChinaDepartment of Pathogenic Biology,West China School of Basic Medical Sciences and Forensic Medicine,Sichuan University,Chengdu,ChinaDepartment of Pathogenic Biology,West China School of Basic Medical Sciences and Forensic Medicine,Sichuan University,Chengdu,ChinaDepartment of Pathogenic Biology,West China School of Basic Medical Sciences and Forensic Medicine,Sichuan University,Chengdu,ChinaDepartment of Pathogenic Biology,West China School of Basic Medical Sciences and Forensic Medicine,Sichuan University,Chengdu,China
医药卫生
Visceral leishmaniasisprogrammed cell death protein 1immune checkpoint blockadeT cell exhaustionRNA-sequencing
《BIOCELL》 2026 (5)
P.216-238,23
supported by the National Natural Science Foundation of China to Jinlei He[Grant number:82102425]the Sichuan Science and Technology Program to Jinlei He[Grant number:2024NSFSC1756].
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