Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal.
PLoS Negl Trop Dis. 2012;6(11):e1925. doi: 10.1371/journal.pntd.0001925. Epub 2012 Nov 29.
Buruli ulcer (BU) is a necrotizing disease of the skin, subcutaneous tissue and bone caused by Mycobacterium ulcerans. It has been suggested that the immune response developed during the recommended rifampicin/streptomycin (RS) antibiotherapy is protective, contributing to bacterial clearance. On the other hand, paradoxical reactions have been described during or after antibiotherapy, characterized by pathological inflammatory responses. This exacerbated inflammation could be circumvented by immunosuppressive drugs. Therefore, it is important to clarify if the immune system contributes to bacterial clearance during RS antibiotherapy and if immunosuppression hampers the efficacy of the antibiotic regimen.
METHODOLOGY/PRINCIPAL FINDINGS: We used the M. ulcerans infection footpad mouse model. Corticosteroid-induced immunosuppression was achieved before experimental infection and maintained during combined RS antibiotherapy by the administration of dexamethasone (DEX). Time-lapsed analyses of macroscopic lesions, bacterial burdens, histology and immunohistochemistry were performed in M. ulcerans-infected footpads. We show here that corticosteroid-immunosuppressed mice are more susceptible to M. ulcerans, with higher bacterial burdens and earlier ulceration. Despite this, macroscopic lesions remised during combined antibiotic/DEX treatment and no viable bacteria were detected in the footpads after RS administration. This was observed despite a delayed kinetics in bacterial clearance, associated with a local reduction of T cell and neutrophil numbers, when compared with immunocompetent RS-treated mice. In addition, no relapse was observed following an additional 3 month period of DEX administration.
CONCLUSIONS/SIGNIFICANCE: These findings reveal a major role of the RS bactericidal activity for the resolution of M. ulcerans experimental infections even during immunosuppression, and support clinical investigation on the potential use of corticosteroids or other immunosuppressive/anti-inflammatory drugs for the management of BU patients undergoing paradoxical reactions.
溃疡分枝杆菌（Mycobacterium ulcerans）引起的皮肤、皮下组织和骨骼坏死性疾病即 Buruli 溃疡（BU）。有观点认为，利福平/链霉素（Rifampicin/Streptomycin，RS）推荐抗生素疗法期间产生的免疫应答具有保护性，有助于清除细菌。另一方面，在抗生素治疗期间或之后，已经描述了矛盾反应，其特征是病理性炎症反应。这种加剧的炎症可以通过免疫抑制药物来规避。因此，重要的是要明确在 RS 抗生素治疗期间免疫系统是否有助于清除细菌，以及免疫抑制是否会影响抗生素方案的疗效。
方法/主要发现： 我们使用了 M. ulcerans 感染的脚掌模型。在实验感染前，通过给予地塞米松（Dexamethasone，DEX）实现了皮质类固醇诱导的免疫抑制，并在联合 RS 抗生素治疗期间维持了这种免疫抑制。在 M. ulcerans 感染的脚掌中进行了时间推移分析，以评估宏观病变、细菌负荷、组织学和免疫组织化学。我们在此展示，皮质类固醇免疫抑制的小鼠对 M. ulcerans 更为敏感，具有更高的细菌负荷和更早的溃疡形成。尽管如此，在联合抗生素/DEX 治疗期间，宏观病变仍得到缓解，并且在 RS 给药后，脚掌中未检测到存活的细菌。与免疫功能正常的 RS 治疗小鼠相比，这观察到了细菌清除的延迟动力学，与 T 细胞和中性粒细胞数量的局部减少相关。此外，在 DEX 给药后再额外 3 个月的时间内，未观察到复发。
结论/意义： 这些发现揭示了 RS 杀菌活性在免疫抑制情况下对解决 M. ulcerans 实验感染的主要作用，并支持了对皮质类固醇或其他免疫抑制/抗炎药物用于管理接受矛盾反应的 BU 患者的潜在临床研究。
