PDF(Pubmed)
Abstract：
The interplay between host nutritional immune mechanisms and bacterial nutrient uptake systems has a major impact on the disease outcome. The host immune factor calprotectin (CP) limits the availability of essential transition metals, such as manganese (Mn) and zinc (Zn), to control the growth of invading pathogens. We previously demonstrated that the competition between CP and the human pathogen group A streptococcus (GAS) for Zn impacts GAS pathogenesis. However, the contribution of Mn sequestration by CP in GAS infection control and the role of GAS Mn acquisition systems in overcoming host-imposed Mn limitation remain unknown. Using a combination of in vitro and in vivo studies, we show that GAS-encoded mtsABC is a Mn uptake system that aids bacterial evasion of CP-imposed Mn scarcity and promotes GAS virulence. Mn deficiency caused by either the inactivation of mtsC or CP also impaired the protective function of GAS-encoded Mn-dependent superoxide dismutase. Our ex vivo studies using human saliva show that saliva is a Mn-scant body fluid, and Mn acquisition by MtsABC is critical for GAS survival in human saliva. Finally, animal infection studies using wild-type (WT) and CP-/- mice showed that MtsABC is critical for GAS virulence in WT mice but dispensable in mice lacking CP, indicating the direct interplay between MtsABC and CP in vivo. Together, our studies elucidate the role of the Mn import system in GAS evasion of host-imposed metal sequestration and underscore the translational potential of MtsABC as a therapeutic or prophylactic target.
摘要：
宿主营养免疫机制和细菌营养摄取系统之间的相互作用对疾病结果具有重大影响。宿主免疫因子钙卫蛋白（CP）限制了必需过渡金属的可用性，如锰(Mn)和锌(Zn)，控制入侵病原体的生长。我们先前证明了CP与人类病原体A组链球菌（GAS）之间对Zn的竞争会影响GAS的发病机理。然而,CP隔离Mn在GAS感染控制中的贡献以及GASMn采集系统在克服宿主施加的Mn限制中的作用仍然未知。使用体外和体内研究的组合，我们表明，GAS编码的mtsABC是一种Mn摄取系统，可帮助细菌逃避CP施加的Mn稀缺性并促进GAS毒力。由mtsC或CP失活引起的Mn缺乏也损害了GAS编码的Mn依赖性超氧化物歧化酶的保护功能。我们使用人类唾液的离体研究表明，唾液是一种锰含量低的体液，通过MtsABC获得Mn对于人唾液中的GAS存活至关重要。最后,使用野生型（WT）和CP-/-小鼠的动物感染研究表明，MtsABC对WT小鼠的GAS毒力至关重要，但在缺乏CP的小鼠中可有可无，表明MtsABC和CP在体内的直接相互作用。一起,我们的研究阐明了Mn导入系统在GAS逃避宿主施加的金属隔离中的作用,并强调了MtsABC作为治疗或预防靶标的翻译潜力.
