Data from: Macroparasites at peripheral sites of infection are major and dynamic modifiers of systemic anti-microbial pattern recognition responses

Immune defences and the maintenance of immunological homeostasis in the face of pathogenic and commensal microbial exposures are channelled by innate anti-microbial pattern recognition receptors (PRRs) such as toll-like receptors (TLRs). Whilst PRR-mediated response programmes are the result of long-term host-pathogen or host-commensal 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 TNF-α responses in wild 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.

当机体暴露于病原微生物与共生微生物时，其免疫防御功能与免疫稳态维持均由固有抗菌模式识别受体（pattern recognition receptors, PRRs）介导，例如toll样受体（Toll-like receptors, TLRs）。PRR介导的应答程序是宿主与病原微生物、共生微生物长期共进化动态过程的产物，而另有假说认为，大型寄生虫共感染可能会对这类宿主-微生物互作产生显著调控作用。本研究通过实验证实，感染外周部位的大型寄生虫（本研究选用的模式生物为胃肠道线虫贺曼线虫属（Heligmosomoides））可在全身层面（于培养的脾细胞中）显著改变TLRs的表达与功能；在蠕虫负荷较高的时期，主要上调TLR2、TLR4及TLR9介导的细胞因子应答。我们在接受单次脉冲感染或点滴感染贺曼线虫幼虫的BALB/c、C57BL/6小鼠，以及接受单次脉冲感染的SWR、CBA小鼠中，均一致观测到此类效应。针对野生林姬鼠（Apodemus sylvaticus）中TLR2介导的肿瘤坏死因子α（Tumor Necrosis Factor-α, TNF-α）应答开展的补充长期调查，也证实大型寄生虫在部分环境条件下可产生显著调控效应。不过整体呈现出的普遍规律是，大型寄生虫与TLR功能之间的关联具有时间动态性与情境依赖性：在野外与实验室环境中，其效应随感染暴露条件的不同而变化；在实验室环境中，其效应也随宿主遗传品系的差异而有所不同。上述结果提供了强有力的证据，证明大型寄生虫是自然生存哺乳动物全身固有抗菌免疫应答的重要且动态的调控因子，因此极有可能对微生物暴露与免疫系统之间的互作产生重要影响。