Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, Brazil.
Faculdade de Medicina Nilton Lins, Universidade Nilton Lins, Manaus, Brazil.
PLoS Negl Trop Dis. 2023 Jun 5;17(6):e0011416. doi: 10.1371/journal.pntd.0011416. eCollection 2023 Jun.
Nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein family (NLR) are intracellular pathogen recognition receptors mediating innate immunity, releasing proinflammatory cytokines IL-1β and IL-18, and promoting pyroptotic cell death, upon sensing pathogenic or endogenous danger signals. In animal models, NLRP3 inflammasome has a dual role, pathogenic or protective in Leishmania-infection, depending on the Leishmania species and mice strain. Caspase recruitment containing domain 8 (CARD8) is a negative regulator of NLRP3 inflammasome and also an inhibitor of transcription factor NFĸB, a major transcription factor of proinflammatory cytokines. We investigated whether single nucleotide variants in CARD8 may partially explain why only a proportion of individuals coming from the same area of endemicity of leishmaniasis develop cutaneous leishmaniasis caused by Leishmania guyanensis. We genotyped four single nucleotide variants of the CARD8 gene by direct nucleotide sequencing in 1741 individuals from an endemic area of leishmaniasis, constituting 850 patients with CL and 891 healthy controls. The frequencies of the genotypes of the variants rs2288877 T>C, rs73944113 C>T, and rs2043211 A>T are similar among the patients with CL and HC, while the variant rs2288876 A>G) reveals an excess of the genotype AA among the patients with CL (44%) compared to 37% in the HC group. Allele A of the variant rs2288876 A>G) is associated with susceptibility to CL (OR = 1.2 [95%CI 1.03-1.4]; P = 0.01). Haplotype analysis showed that individuals harboring the haplotype CCAA have 280% odds of developing CL caused by L. guyanensis (OR = 3.8 [95% CI 2.0-7.7]; p = 0.00004). The variants rs2288877 T>C and rs2288876 A>G correlate with the plasma level of IL-8. Spearman correlation showed a significant positive correlation between the rs2288876 A>G allele A and the level of IL-8 (ρ = 0.22; p = 0.0002). CARD8 may partially contribute to the development of CL caused by L. guyanensis.
核苷酸结合寡聚化结构域、富含亮氨酸重复序列的蛋白家族（NLR）是细胞内病原体识别受体，介导先天免疫，在感知病原体或内源性危险信号时，释放促炎细胞因子 IL-1β 和 IL-18，并促进细胞焦亡性死亡。在动物模型中，NLRP3 炎性体在利什曼原虫感染中具有双重作用，是致病性的或保护性的，这取决于利什曼原虫的种类和小鼠品系。Caspase recruitment containing domain 8 (CARD8) 是 NLRP3 炎性体的负调节剂，也是转录因子 NFκB 的抑制剂，NFκB 是促炎细胞因子的主要转录因子。我们研究了 CARD8 中的单核苷酸变异是否可以部分解释为什么来自利什曼病流行地区的同一人群中只有一部分人会发展为由利什曼原虫 guyanensis 引起的皮肤利什曼病。我们通过直接核苷酸测序在来自利什曼病流行地区的 1741 个人中对 CARD8 基因的四个单核苷酸变异进行了基因分型，其中包括 850 名 CL 患者和 891 名健康对照者。CL 患者和 HC 之间的变异 rs2288877 T>C、rs73944113 C>T 和 rs2043211 A>T 基因型的频率相似，而变异 rs2288876 A>G) 显示 CL 患者中的基因型 AA 过多（44%），而 HC 组中的基因型 AA 为 37%。变异 rs2288876 A>G) 的等位基因 A 与 CL 的易感性相关（OR = 1.2 [95%CI 1.03-1.4]；P = 0.01）。单体型分析表明，携带 CCAA 单体型的个体患由 L. guyanensis 引起的 CL 的可能性增加 280%（OR = 3.8 [95%CI 2.0-7.7]；p = 0.00004）。rs2288877 T>C 和 rs2288876 A>G 与 IL-8 的血浆水平相关。Spearman 相关性分析显示，rs2288876 A>G 等位基因 A 与 IL-8 水平呈显著正相关（ρ = 0.22；p = 0.0002）。CARD8 可能部分导致由 L. guyanensis 引起的 CL 的发生。
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