Malaria is a disease with diverse symptoms depending on host immune status and pathogenicity of Plasmodium parasites. The continuous parasite growth within a host suggests mechanisms of immune evasion by the parasite and/or immune inhibition in response to infection. To identify pathways commonly inhibited after malaria infection, we infected C57BL/6 mice with four Plasmodium yoelii strains causing different disease phenotypes and 24 progeny of a genetic cross. mRNAs from mouse spleens day 1 and/or day 4 post infection (p.i.) were hybridized to a mouse microarray to identify activated or inhibited pathways, upstream regulators, and host genes playing an important role in malaria infection. Strong interferon responses were observed after infection with the N67 strain, whereas initial inhibition and later activation of hematopoietic pathways were found after infection with 17XNL parasite, showing unique responses to individual parasite strains. Inhibitions of pathways such as Th1 activation, dendritic cell (DC) maturation, and NFAT immune regulation were observed in mice infected with all the parasite strains day 4 p.i., suggesting universally inhibited immune pathways. As a proof of principle, treatment of N67-infected mice with antibodies against T cell receptors OX40 or CD28 to activate the inhibited pathways enhanced host survival. Controlled activation of these pathways may provide important strategies for better disease management and for developing an effective vaccine.

中文翻译：

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约埃氏疟原虫感染后的宿主途径的检测普遍被抑制以进行免疫干预。

疟疾是一种具有多种症状的疾病，取决于宿主的免疫状况和疟原虫的致病性。宿主体内寄生虫的持续生长表明寄生虫可逃避免疫和/或对感染有免疫抑制作用。为了确定疟疾感染后通常被抑制的途径，我们用四种导致不同疾病表型和24个遗传杂交后代的约氏疟原虫菌株感染了C57BL / 6小鼠。将感染后第1天和/或第4天的小鼠脾脏（pi）的mRNA与小鼠微阵列杂交，以鉴定在疟疾感染中起重要作用的激活或抑制途径，上游调节剂和宿主基因。N67株感染后观察到强烈的干扰素反应，而在感染17XNL寄生虫后发现了对造血途径的初步抑制和后来的激活，显示出对单个寄生虫菌株的独特反应。在感染后第4天感染了所有寄生虫菌株的小鼠中均观察到Th1激活，树突状细胞（DC）成熟和NFAT免疫调节等途径的抑制，表明免疫途径普遍受到抑制。作为原理的证明，用针对T细胞受体OX40或CD28的抗体激活被抑制的途径治疗N67感染的小鼠，可以提高宿主的存活率。这些途径的受控激活可以为更好的疾病管理和开发有效的疫苗提供重要的策略。在感染后第4天感染了所有寄生虫菌株的小鼠中均观察到Th1激活，树突状细胞（DC）成熟和NFAT免疫调节等途径的抑制，表明免疫途径普遍受到抑制。作为原理的证明，用针对T细胞受体OX40或CD28的抗体激活被抑制的途径治疗N67感染的小鼠，可以提高宿主的存活率。这些途径的受控激活可以为更好的疾病管理和开发有效的疫苗提供重要的策略。在感染后第4天感染了所有寄生虫菌株的小鼠中均观察到Th1激活，树突状细胞（DC）成熟和NFAT免疫调节等途径的抑制，表明免疫途径普遍受到抑制。作为原理的证明，用针对T细胞受体OX40或CD28的抗体激活被抑制的途径治疗N67感染的小鼠，可以提高宿主的存活率。这些途径的受控激活可以为更好的疾病管理和开发有效的疫苗提供重要的策略。用抗T细胞受体OX40或CD28的抗体激活N67感染的小鼠激活被抑制的途径，可以提高宿主的存活率。这些途径的受控激活可以为更好的疾病管理和开发有效的疫苗提供重要的策略。用抗T细胞受体OX40或CD28的抗体激活N67感染的小鼠激活被抑制的途径，可以提高宿主的存活率。这些途径的受控激活可以为更好的疾病管理和开发有效的疫苗提供重要的策略。