O-antigen modulates infection-induced pain states.
O-antigen modulates infection-induced pain states.
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DOI：
10.1371/journal.pone.0041273
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Klumpp DJ
中科院分区：
文献类型：
--
作者：
Rudick CN;Jiang M;Yaggie RE;Pavlov VI;Done J;Heckman CJ;Whitfield C;Schaeffer AJ;Klumpp DJ
感染相关疼痛的分子引发剂尚不清楚。我们最近发现尿路致病性大肠杆菌 (UPEC) 会在小鼠尿路感染 (UTI) 中引起急性盆腔疼痛。尿路感染疼痛是由大肠杆菌脂多糖 (LPS) 及其受体 TLR4 引起的，但疼痛与炎症无关。已知 LPS 通过酰化脂质 A 成分和 TLR4 之间的相互作用来驱动炎症，但 O 抗原多糖在宿主反应中的功能尚不清楚。在这里，我们使用皮肤过敏（异常性疼痛）来量化骨盆疼痛行为，并使用骶脊髓兴奋性来量化小鼠尿路感染中的中枢神经系统表现，研究了 O 抗原在疼痛中的作用。 O-抗原生物合成缺陷的 UPEC 突变体引起慢性异常性疼痛，在短暂感染清除后持续很长时间，但野生型 UPEC 只引起急性疼痛。缺乏 O 抗原基因簇的大肠杆菌菌株具有慢性疼痛表型，并且表达克隆的 O 抗原基因簇以可预测的方式改变疼痛表型。 TLR4 缺陷小鼠的慢性异常性疼痛被消除，但野生型小鼠的炎症反应在跨越多种疼痛表型的大肠杆菌菌株中相似，表明 O 抗原独立于炎症调节疼痛。患有慢性异常性疼痛的小鼠的脊髓表现出自发放电增加和短期抑制受损，这与集中性疼痛一致。总而言之，这些发现表明 O 抗原作为变阻器发挥作用，调节 LPS 相关的疼痛。这些观察结果对慢性疼痛的传染性病因学和病原体的进化修饰以改变宿主行为具有影响。
The molecular initiators of infection-associated pain are not understood. We recently found that uropathogenic E. coli (UPEC) elicited acute pelvic pain in murine urinary tract infection (UTI). UTI pain was due to E. coli lipopolysaccharide (LPS) and its receptor, TLR4, but pain was not correlated with inflammation. LPS is known to drive inflammation by interactions between the acylated lipid A component and TLR4, but the function of the O-antigen polysaccharide in host responses is unknown. Here, we examined the role of O-antigen in pain using cutaneous hypersensitivity (allodynia) to quantify pelvic pain behavior and using sacral spinal cord excitability to quantify central nervous system manifestations in murine UTI. A UPEC mutant defective for O-antigen biosynthesis induced chronic allodynia that persisted long after clearance of transient infections, but wild type UPEC evoked only acute pain. E. coli strains lacking O-antigen gene clusters had a chronic pain phenotype, and expressing cloned O-antigen gene clusters altered the pain phenotype in a predictable manner. Chronic allodynia was abrogated in TLR4-deficient mice, but inflammatory responses in wild type mice were similar among E. coli strains spanning a wide range of pain phenotypes, suggesting that O-antigen modulates pain independent of inflammation. Spinal cords of mice with chronic allodynia exhibited increased spontaneous firing and compromised short-term depression, consistent with centralized pain. Taken together, these findings suggest that O-antigen functions as a rheostat to modulate LPS-associated pain. These observations have implications for an infectious etiology of chronic pain and evolutionary modification of pathogens to alter host behaviors.
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影响因子：
3.1
作者：
Billips, Benjamin K.;Schaeffer, Anthony J.;Klumpp, David J.
通讯作者：
Klumpp, David J.
影响因子：
4.4
作者：
Foureau, David M.;Mielcarz, Daniel W.;Buzoni-Gatel, Dominique
通讯作者：
Buzoni-Gatel, Dominique
影响因子：
3.2
作者：
BATCHELOR, RA;HARAGUCHI, GE;HULL, SI
通讯作者：
HULL, SI
影响因子：
3.1
作者：
Amor, K;Heinrichs, DE;Whitfield, C
通讯作者：
Whitfield, C
影响因子：
4.4
作者：
Minns, Laurie A.;Menard, Laurence C.;Kasper, Lloyd H.
通讯作者：
Kasper, Lloyd H.