Macroparasites at peripheral sites of infection are major and dynamic modifiers of systemic antimicrobial pattern recognition responses
Macroparasites at peripheral sites of infection are major and dynamic modifiers of systemic antimicrobial pattern recognition responses
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DOI：
10.1111/mec.12212
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发表时间：
2013-05-01
影响因子：
4.9
通讯作者：
Bradley, J. E.
中科院分区：
文献类型：
--
作者：
Friberg, I. M.;Little, S.;Bradley, J. E.
面对致病性和共生微生物暴露时的免疫防御和免疫稳态的维持是由先天抗菌模式识别受体（PRR）（例如 Toll 样受体（TLR））引导的。虽然 PRR 介导的反应程序是涉及微生物的长期宿主-病原体或宿主共生共同进化动力学的结果，但另一种可能性是大型寄生共同感染可能是这种相互作用的重要调节剂。我们通过实验证明，感染周围部位的大型寄生虫（胃肠道线虫模型，Heligmosomoides）会在系统水平（培养的脾细胞）引起 TLR 表达和功能的实质性改变，在蠕虫负荷较高时主要上调 TLR2、TLR4 和 TLR9 介导的细胞因子反应。我们在 BALB/c 和 C57BL/6 小鼠中在单脉冲和滴流暴露于 Heligmosomoides 幼虫下以及在 SWR 和 CBA 小鼠中在单脉冲暴露下一致观察到这种效应。对野生林鼠 (Apodemus sylvaticus) 中 TLR2 介导的肿瘤坏死因子-α 反应的补充长期调查与大型寄生虫在某些环境条件下的实质性影响一致。然而，一般模式是大型寄生虫与 TLR 功能的关联是时间动态的和环境依赖性的：随着现场和实验室感染暴露的不同条件以及实验室中宿主遗传菌株的不同而变化。这些结果是令人信服的证据，表明大型寄生虫是自然存在的哺乳动物中系统先天抗菌反应性的主要和动态调节剂，因此可能对微生物暴露与免疫系统之间的相互作用产生重要影响。
Immune defences and the maintenance of immunological homeostasis in the face of pathogenic and commensal microbial exposures are channelled by innate antimicrobial pattern recognition receptors (PRRs) such as toll-like receptors (TLRs). Whilst PRR-mediated response programmes are the result of long-term host-pathogen or hostcommensal co-evolutionary dynamics involving microbes, an additional possibility is that macroparasitic co-infections may be a significant modifier of such interactions. We demonstrate experimentally that macroparasites (the model gastrointestinal nematode, Heligmosomoides) at peripheral sites of infection cause substantial alteration of the expression and function of TLRs at a systemic level (in cultured splenocytes), predominantly up-regulating TLR2, TLR4 and TLR9-mediated cytokine responses at times of high standing worm burdens. We consistently observed such effects in BALB/c and C57BL/6 mice under single-pulse and trickle exposures to Heligmosomoides larvae and in SWR and CBA mice under single-pulse exposures. A complementary long-term survey of TLR2-mediated tumour necrosis factor-alpha responses in wild wood mice (Apodemus sylvaticus) was consistent with substantial effects of macroparasites under some environmental conditions. A general pattern, though, was for the associations of macroparasites with TLR function to be temporally dynamic and context-dependent: varying with different conditions of infection exposure in the field and laboratory and with host genetic strain in the laboratory. These results are compelling evidence that macroparasites are a major and dynamic modifier of systemic innate antimicrobial responsiveness in naturally occurring mammals and thus likely to be an important influence on the interaction between microbial exposures and the immune system.