存在于白蛉唾液中的核苷会诱导免疫抑制并促进感染的建立。
Nucleosides present on phlebotomine saliva induce immunossuppression and promote the infection establishment.
作者信息
Carregaro Vanessa, Ribeiro José M, Valenzuela Jesus G, Souza-Júnior Djalma L, Costa Diego L, Oliveira Carlo J F, Sacramento Laís A, Nascimento Manuela S L, Milanezi Cristiane M, Cunha Fernando Q, Silva João S
机构信息
Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
Section of Vector Biology, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America; Vector Molecular Biology Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
出版信息
PLoS Negl Trop Dis. 2015 Apr 7;9(4):e0003600. doi: 10.1371/journal.pntd.0003600. eCollection 2015 Apr.
BACKGROUND
Sand fly saliva plays a crucial role in establishing Leishmania infection. We identified adenosine (ADO) and adenosine monophosphate (AMP) as active pharmacologic compounds present in Phlebotomus papatasi saliva that inhibit dendritic cell (DC) functions through a PGE2/IL 10-dependent mechanism.
METHODOLOGY/PRINCIPAL FINDINGS: Herein, we prepared a mixture of ADO and AMP in equimolar amounts similar to those present in the salivary-gland extract (SGE) form one pair of salivary glands of P. papatasi and co-injected it with Leishmania amazonensis or L. major into mouse ears. ADO+AMP mimicked exacerbative effects of P. papatasi saliva in leishmaniasis, increasing parasite burden and cutaneous lesions. Enzymatic catabolism of salivary nucleosides reversed the SGE-induced immunosuppressive effect associated with IL-10 enhancement. Immunosuppressive factors COX2 and IL-10 were upregulated and failed to enhance ear lesion and parasite burden in IL 10-/- infected mice. Furthermore, nucleosides increased regulatory T cell (Treg) marker expression on CD4+CD25- cells, suggesting induction of Tregs on effector T cells (T eff). Treg induction (iTreg) was associated with nucleoside-induced tolerogenic dendritic cells (tDCs) expressing higher levels of COX2 and IL-10. In vitro generation of Tregs was more efficient in DCs treated with nucleosides. Suppressive effects of nucleosides during cutaneous leishmaniasis were mediated through an A2AR-dependent mechanism. Using BALB/c mice deficient in A2A ADO receptor (A2AR-/-), we showed that co-inoculated mice controlled infection, displaying lower parasite numbers at infection sites and reduced iTreg generation.
CONCLUSION/SIGNIFICANCE: We have demonstrated that ADO and AMP in P. papatasi saliva mediate exacerbative effects of Leishmania infection by acting preferentially on DCs promoting a tolerogenic profile in DCs and by generating iTregs in inflammatory foci through an A2AR mechanism.
背景
白蛉唾液在利什曼原虫感染的建立过程中起着关键作用。我们鉴定出腺苷（ADO）和单磷酸腺苷（AMP）是巴氏白蛉唾液中存在的活性药理化合物，它们通过一种依赖前列腺素E2/白细胞介素10的机制抑制树突状细胞（DC）的功能。
方法/主要发现：在此，我们制备了一种等摩尔量的ADO和AMP混合物，其含量与来自一对巴氏白蛉唾液腺的唾液腺提取物（SGE）中的含量相似，并将其与亚马逊利什曼原虫或硕大利什曼原虫共同注射到小鼠耳中。ADO + AMP模拟了巴氏白蛉唾液在利什曼病中的加重作用，增加了寄生虫负荷和皮肤病变。唾液核苷的酶促分解代谢逆转了与白细胞介素10增强相关的SGE诱导的免疫抑制作用。免疫抑制因子COX2和白细胞介素10上调，并且在白细胞介素10基因敲除的感染小鼠中未能增强耳部病变和寄生虫负荷。此外，核苷增加了CD4 + CD25-细胞上调节性T细胞（Treg）标志物的表达，表明效应T细胞（Teff）上诱导了Tregs。Treg诱导（iTreg）与核苷诱导的表达更高水平COX2和白细胞介素10的耐受性树突状细胞（tDCs）相关。核苷在体外生成Tregs方面对DC的处理更有效。皮肤利什曼病期间核苷的抑制作用是通过一种依赖A2AR的机制介导的。使用缺乏A2A ADO受体（A2AR-/-）的BALB / c小鼠，我们表明共同接种的小鼠控制了感染，在感染部位显示出较低的寄生虫数量并减少了iTreg的产生。
结论/意义：我们已经证明，巴氏白蛉唾液中的ADO和AMP通过优先作用于DC，促进DC中的耐受性特征，并通过A2AR机制在炎症灶中产生iTregs，从而介导利什曼原虫感染的加重作用。
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