Cope R B, Stang B, Valentine B A, Bermudez L E
Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR, USA.
Photodermatol Photoimmunol Photomed. 2004 Feb;20(1):14-20. doi: 10.1111/j.1600-0781.2004.00073.x.
Ultraviolet radiation (UVR) pre-exposure enhances Mycobacterium ulcerans infection in the Crl:IAF(HA)-hrBR hairless guinea-pig, possibly via a photoimmunosuppressive mechanism. The trans-cis photoisomerization of epidermal urocanic acid is an important initiator of the web of events leading to photoimmunosuppression. Thus, the hypothesis tested in this paper was that topical pre-exposure to UVR-irradiated urocanic acid mixture containing cis-urocanic acid (UVR-UCA) enhances the ulcerative form of M. ulcerans infection in the Crl:IAF(HA)-hrBR hairless guinea-pig model of human Buruli ulcer disease.
Groups of six animals were subjected to daily topical treatment with either 0 (vehicle only), 0.1, 0.5 or 1 mg of trans (tUCA) or UVR-UCA (contained a cis : trans urocanic acid isomer ratio of 1 : 9) for three consecutive days. A sham treatment group was also included in the experiment. Three days following their final treatment, the guinea-pigs were intradermally infected in the right dorsal flank with 1.5 x 107 CFU of M. ulcerans in 0.1 ml of phosphate-buffered saline (PBS) and sham infected with 0.1 ml of PBS in the left dorsal flank. The resultant skin lesions were then measured over the next 21 days. At day 21 postinfection, the animals were tested for delayed-type hypersensitivity (DTH) reactivity to M. ulcerans cell fragment antigens (MCF).
Distinct, well-demarcated, dermally situated skin nodules were present at infected, but not sham-infected, skin sites by day 3 postinfection, and the lesions progressed to frank ulcers by day 5. Between days 5 and 21, the mean lesion diameters of the UVR-UCA-treated animals were significantly (P<0.001) greater than those of the sham, vehicle only or tUCA-treated groups. UVR-UCA-treated guinea-pigs also had significantly (P<0.001) suppressed DTH responses to MCF compared with the other treatment groups. There were no significant (P>0.4) differences between the lesion sizes and DTH responses of the tUCA, vehicle only or sham treatment groups. These results demonstrate that topical exposure to UVR-UCA promotes M. ulcerans infection and suppresses DTH responses to M. uclerans antigens in infected animals. These results lend credence to the hypothesis that UVR-mediated enhancement of Buruli ulcer disease in the Crl:IAF(HA)-hrBR hairless guinea-pig model occurs via modulation of cis-urocanic acid-susceptible immune pathways.
紫外线辐射（UVR）预暴露可增强溃疡分枝杆菌在Crl:IAF(HA)-hrBR无毛豚鼠中的感染，可能是通过光免疫抑制机制。表皮尿刊酸的反式-顺式光异构化是导致光免疫抑制一系列事件的重要起始因素。因此，本文所验证的假设是，局部预暴露于含有顺式尿刊酸的UVR照射尿刊酸混合物（UVR-UCA）可增强Crl:IAF(HA)-hrBR无毛豚鼠人类布鲁里溃疡病模型中溃疡分枝杆菌感染的溃疡性表现。
将每组6只动物连续3天每天进行局部治疗，分别给予0（仅赋形剂）、0.1、0.5或1 mg的反式（tUCA）或UVR-UCA（顺式:反式尿刊酸异构体比例为1:9）。实验中还包括一个假治疗组。在最后一次治疗3天后，将豚鼠右背部皮内注射0.1 ml磷酸盐缓冲盐水（PBS）中含1.5×107 CFU的溃疡分枝杆菌，左背部皮内注射0.1 ml PBS进行假感染。然后在接下来的21天内测量所产生的皮肤病变。在感染后第21天，检测动物对溃疡分枝杆菌细胞片段抗原（MCF）的迟发型超敏反应（DTH）反应性。
在感染后第3天，感染部位出现明显的、界限清楚的位于真皮层的皮肤结节，而假感染部位未出现，到第5天病变发展为明显的溃疡。在第5天至第21天之间，UVR-UCA处理组动物的平均病变直径显著（P<0.001）大于假治疗组、仅赋形剂处理组或tUCA处理组。与其他治疗组相比，UVR-UCA处理的豚鼠对MCF的DTH反应也显著（P<0.001）受到抑制。tUCA处理组、仅赋形剂处理组或假治疗组的病变大小和DTH反应之间无显著（P>0.4）差异。这些结果表明，局部暴露于UVR-UCA可促进溃疡分枝杆菌感染，并抑制感染动物对溃疡分枝杆菌抗原的DTH反应。这些结果支持了以下假设：在Crl:IAF(HA)-hrBR无毛豚鼠模型中，UVR介导的布鲁里溃疡病增强是通过调节对顺式尿刊酸敏感的免疫途径发生。
