Department of Microbial Pathogenesis, University of Maryland-Baltimore, Baltimore, Maryland, USA.
Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
Infect Immun. 2018 Aug 22;86(9). doi: 10.1128/IAI.00406-18. Print 2018 Sep.
Infectious diseases propagated by arthropod vectors, such as tularemia, are commonly initiated via dermal infection of the skin. However, due to the technical difficulties in achieving accurate and reproducible dermal deposition, intradermal models are less commonly used. To overcome these limitations, we used microneedle arrays (MNAs), which are micron-scale polymeric structures, to temporarily disrupt the barrier function of the skin and deliver a bacterial inoculum directly to the dermis of an animal. MNAs increase reliability by eliminating leakage of the inoculum or blood from the injection site, thereby providing a biologically relevant model for arthropod-initiated disease. Here, we validate the use of MNAs as a means to induce intradermal infection using a murine model of tularemia initiated by We demonstrate targeted delivery of the MNA bolus to the dermal layer of the skin, which subsequently led to innate immune cell infiltration. Additionally, -coated MNAs were used to achieve lethality in a dose-dependent manner in C57BL/6 mice. The immune profile of infected mice mirrored that of established infection models, consisting of markedly increased serum levels of interleukin-6 and keratinocyte chemoattractant, splenic T-cell depletion, and an increase in splenic granulocytes, together confirming that MNAs can be used to reproducibly induce tularemia-like pathogenesis in mice. When MNAs were used to immunize mice using an attenuated mutant ( Δ), all immunized mice survived a lethal subcutaneous challenge. Thus, MNAs can be used to effectively deliver viable bacteria and provide a novel avenue to study intradermally induced microbial diseases in animal models.
通过节肢动物媒介传播的传染病，如兔热病，通常通过皮肤的皮肤感染开始。然而，由于实现精确和可重复的皮肤沉积的技术困难，皮内模型的使用较少。为了克服这些限制，我们使用微针阵列（MNAs），这是一种微米级的聚合物结构，暂时破坏皮肤的屏障功能，并将细菌接种物直接递送至动物的真皮。MNAs 通过消除接种物或血液从注射部位泄漏来提高可靠性，从而为节肢动物引发的疾病提供了一种生物学上相关的模型。在这里，我们使用兔热病的小鼠模型验证了 MNAs 作为诱导皮内感染的手段的使用。我们证明了 MNA 团块靶向递送至皮肤的真皮层，随后导致固有免疫细胞浸润。此外，用 涂层 MNAs 以剂量依赖的方式在 C57BL/6 小鼠中实现致死性。感染小鼠的免疫谱与已建立的 感染模型相似，包括白细胞介素-6 和角质形成细胞趋化因子的血清水平显着增加，脾 T 细胞耗竭以及脾粒细胞增加，共同证实 MNAs 可用于在小鼠中重现性地诱导兔热病样发病机制。当使用减毒 突变体（Δ）通过 MNAs 对小鼠进行免疫时，所有免疫的小鼠都能在致命的皮下挑战中存活下来。因此，MNAs 可用于有效递送电活细菌，并为在动物模型中研究皮内诱导的微生物疾病提供了新途径。
