Muñoz-Durango Natalia, Gómez Alexander, García-Valencia Natalia, Roldán Miguel, Ochoa Marcela, Bautista-Erazo David E, Ramírez-Pineda José R
Grupo Inmunomodulación (GIM), Instituto de Investigaciones Médicas, Facultad de Medicina, Corporación Académica para el Estudio de Patologías Tropicales (CAEPT), Universidad de Antioquia, Medellín, Colombia.
Instituto de Patología, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.
Front Microbiol. 2022 Jun 13;13:907631. doi: 10.3389/fmicb.2022.907631. eCollection 2022.
A mouse model of cutaneous leishmaniasis (CL) by that reproduces the characteristics of the human disease remains elusive. Here we report the development of a CL model that uses a mouse-adapted isolate to reproducibly induce a dermal disease with a remarkable similarity to human CL. BALB/c mice infected intradermally in the ear with 10 stationary UA-946 promastigotes develop a progressive cutaneous disease that exhibits the typical ulcerated lesions with indurated borders observed in CL patients. Although most of parasites in the inoculum die within the first week of infection, the survivors vigorously multiply at the infection site during the following weeks, paralleling disease appearance and aggravation. Regional lymphadenopathy as well as lymphatic dissemination of parasites to draining lymph nodes (dLN) was evidenced early after infection. Viable parasites were also isolated from spleen at later timepoints indicating systemic parasitic dissemination, but, strikingly, no signs of systemic disease were observed. Increasing numbers of myeloid cells and T lymphocytes producing IFNγ and IL-4 were observed in the dLN as disease progressed. A mixed adaptive -specific T cell-mediated response was induced, since recall experiments using dLN cells and splenocytes revealed the production of type 1 (IFNγ, IL-2), type 2 (IL-4, IL-13), regulatory (IL-10), and inflammatory (GM-CSF, IL-3) cytokines. Humoral adaptive response was characterized by early production of IgG1- followed by IgG2a-type of -specific antibodies. IFNγ/IL-4 and IgG2a/IgG1 ratios indicated that the initial non-protective Th2 response was redirected toward a protective Th1 response. studies revealed a profuse recruitment of myeloid cells and of IFNγ- and IL-4-producing T lymphocytes to the site of infection, and the typical histopathological changes induced by dermotropic species. Evidence that this model is suitable to investigate pharmacological and immunomodulatory interventions, as well as for antigen discovery and vaccine development, is also presented. Altogether, these results support the validity and utility of this novel mouse model to study the pathogenesis, immunity, and therapeutics of infections.
一种能够再现人类皮肤利什曼病（CL）特征的小鼠模型仍然难以捉摸。在此，我们报告了一种CL模型的建立，该模型使用一种适应小鼠的分离株，可重复性地诱导出一种与人类CL极为相似的皮肤疾病。用10个静止期的UA - 946前鞭毛体皮内注射感染耳部的BALB/c小鼠会发展出一种进行性皮肤疾病，表现出CL患者中观察到的典型的有硬结边缘的溃疡病变。尽管接种物中的大多数寄生虫在感染的第一周内死亡，但存活的寄生虫在接下来的几周内在感染部位大量繁殖，与疾病的出现和加重情况平行。感染后早期就证实了局部淋巴结病以及寄生虫向引流淋巴结（dLN）的淋巴扩散。在后期时间点，也从脾脏中分离出了活的寄生虫，表明存在全身寄生虫扩散，但令人惊讶的是，未观察到全身疾病的迹象。随着疾病进展，在dLN中观察到产生IFNγ和IL - 4的髓样细胞和T淋巴细胞数量增加。诱导了一种混合的适应性特异性T细胞介导的反应，因为使用dLN细胞和脾细胞的回忆实验显示产生了1型（IFNγ、IL - 2）、2型（IL - 4、IL - 13）、调节性（IL - 10）和炎性（GM - CSF、IL - 3）细胞因子。体液适应性反应的特征是早期产生IgG1，随后产生IgG2a型特异性抗体。IFNγ/IL - 4和IgG2a/IgG1比率表明最初的非保护性Th2反应转向了保护性Th1反应。研究揭示了髓样细胞以及产生IFNγ和IL - 4的T淋巴细胞大量募集到感染部位，以及嗜皮肤性物种诱导的典型组织病理学变化。还提供了证据表明该模型适用于研究药理和免疫调节干预措施，以及用于抗原发现和疫苗开发。总之，这些结果支持了这种新型小鼠模型在研究CL感染的发病机制、免疫和治疗方面的有效性和实用性。
