Laboratory of Mucosal Pathogens and Cellular Immunology, Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20903, USA.
Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT 59480, USA.
Microbes Infect. 2016 Dec;18(12):758-767. doi: 10.1016/j.micinf.2016.07.003. Epub 2016 Jul 27.
Our laboratory has employed in vitro and in vivo mouse models based on Francisella tularensis Live Vaccine Strain (LVS)-induced protection to elucidate immune correlates for intracellular bacteria. Among the effectors found was GM-CSF, a pleiotropic cytokine that is integral to the development and proliferation of myeloid cells, including alveolar macrophages. GM-CSF has roles in resistance to primary murine infection with several intracellular pathogens, but its role during Francisella infection is unknown. Francisella is an intracellular pathogen that infects lungs after inhalation, primarily invading alveolar macrophages. Here we show that GM-CSF has route-dependent roles during primary infection of mice with LVS. GM-CSF deficient (GM-CSF KO) mice were slightly more susceptible than wild type to intradermal infection, but had increased resistance to intranasal infection. Similarly, these mice had increased resistance to pulmonary infection with virulent F. tularensis (SchuS4). LVS-vaccinated GM-CSF KO mice had normal adaptive immune responses, as measured by T cell activities after LVS intradermal or intranasal vaccination, and survived lethal secondary LVS challenge. GM-CSF KO mice also had robust humoral responses, producing elevated levels of serum antibodies following LVS vaccination compared to wild type mice. Taken together, our data demonstrates that the absence of GM-CSF improves resistance to pulmonary, but not intradermal, infection with Francisella.
我们的实验室已经使用基于弗朗西斯氏菌活疫苗株（LVS）诱导保护的体内和体外小鼠模型，来阐明与细胞内细菌相关的免疫相关性。在发现的效应物中，有一种是 GM-CSF，它是一种多效细胞因子，对于髓样细胞（包括肺泡巨噬细胞）的发育和增殖至关重要。GM-CSF 在抵抗几种细胞内病原体对小鼠的初次感染中具有作用，但在弗朗西斯菌感染中的作用尚不清楚。弗朗西斯菌是一种细胞内病原体，吸入后感染肺部，主要侵犯肺泡巨噬细胞。在这里，我们表明 GM-CSF 在 LVS 对小鼠的初次感染中具有依赖途径的作用。GM-CSF 缺陷（GM-CSF KO）小鼠比野生型对皮内感染的敏感性略高，但对鼻内感染的抵抗力增强。同样，这些小鼠对毒力弗朗西斯菌（SchuS4）的肺部感染也具有更强的抵抗力。用 LVS 接种的 GM-CSF KO 小鼠具有正常的适应性免疫反应，如 LVS 皮内或鼻内接种后 T 细胞活性的测量所示，并且在致命的二次 LVS 挑战中存活。GM-CSF KO 小鼠也具有强大的体液反应，与野生型小鼠相比，在 LVS 接种后产生更高水平的血清抗体。总之，我们的数据表明，GM-CSF 的缺失可改善对肺部但不是皮内感染的抵抗力。弗朗西斯菌。
