Wozniak Karen L, Hole Camaron R, Yano Junko, Fidel Paul L, Wormley Floyd L
The South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX, USA.
Department of Biology, The University of Texas at San Antonio, San Antonio, TX, USA.
Microbiology (Reading). 2014 Jul;160(Pt 7):1440-1452. doi: 10.1099/mic.0.073445-0. Epub 2014 Apr 23.
Cryptococcus neoformans is a significant cause of fungal meningitis in patients with impaired T cell-mediated immunity (CMI). Experimental pulmonary infection with a C. neoformans strain engineered to produce IFN-γ, H99γ, results in the induction of Th1-type CMI, resolution of the acute infection, and protection against challenge with WT Cryptococcus. Given that individuals with suppressed CMI are highly susceptible to pulmonary C. neoformans infection, we sought to determine whether antimicrobial peptides were produced in mice inoculated with H99γ. Thus, we measured levels of antimicrobial peptides lipocalin-2, S100A8, S100A9, calprotectin (S100A8/A9 heterodimer), serum amyloid A-3 (SAA3), and their putative receptors Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE) in mice during primary and recall responses against C. neoformans infection. Results showed increased levels of IL-17A and IL-22, cytokines known to modulate antimicrobial peptide production. We also observed increased levels of lipocalin-2, S100A8, S100A9 and SAA3 as well as TLR4(+) and RAGE(+) macrophages and dendritic cells in mice inoculated with H99γ compared with WT H99. Similar results were observed in the lungs of H99γ-immunized, compared with heat-killed C. neoformans-immunized, mice following challenge with WT yeast. However, IL-22-deficient mice inoculated with H99γ demonstrated antimicrobial peptide production and no change in survival rates compared with WT mice. These studies demonstrate that protection against cryptococcosis is associated with increased production of antimicrobial peptides in the lungs of protected mice that are not solely in response to IL-17A and IL-22 production and may be coincidental rather than functional.
新型隐球菌是T细胞介导的免疫（CMI）受损患者真菌性脑膜炎的重要病因。用经基因工程改造以产生IFN-γ的新型隐球菌菌株H99γ进行实验性肺部感染，可诱导Th1型CMI，解决急性感染，并预防野生型新型隐球菌的攻击。鉴于CMI受抑制的个体对肺部新型隐球菌感染高度易感，我们试图确定接种H99γ的小鼠是否产生抗菌肽。因此，我们在小鼠针对新型隐球菌感染的初次和再次应答过程中，测量了抗菌肽lipocalin-2、S100A8、S100A9、钙卫蛋白（S100A8/A9异二聚体）、血清淀粉样蛋白A-3（SAA3）及其假定受体Toll样受体4（TLR4）和晚期糖基化终产物受体（RAGE）的水平。结果显示，已知可调节抗菌肽产生的细胞因子IL-17A和IL-22水平升高。我们还观察到，与野生型H99相比，接种H99γ的小鼠中lipocalin-2、S100A8、S100A9和SAA3以及TLR4(+)和RAGE(+)巨噬细胞和树突状细胞的水平升高。在用野生型酵母攻击后，与热灭活的新型隐球菌免疫的小鼠相比，H99γ免疫的小鼠肺部也观察到类似结果。然而，接种H99γ的IL-22缺陷小鼠显示出抗菌肽产生，与野生型小鼠相比存活率没有变化。这些研究表明，对隐球菌病的保护与受保护小鼠肺部抗菌肽产量增加有关，这并不完全是对IL-17A和IL-22产生的反应，可能是巧合而非功能性的。
