Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
Public Health Research Institute Tuberculosis Center, New Jersey Medical School-Rutgers University, Newark, New Jersey, USA.
mBio. 2018 Mar 13;9(2):e00297-18. doi: 10.1128/mBio.00297-18.
Carbapenem-resistant is a problem worldwide. A carbapenem-resistant lineage classified as multilocus sequence type 258 (ST258) is prominent in the health care setting in many regions of the world, including the United States. ST258 strains can be resistant to virtually all clinically useful antibiotics; treatment of infections caused by these organisms is difficult, and mortality is high. As a step toward promoting development of new therapeutics for ST258 infections, we tested the ability of rabbit antibodies specific for ST258 capsule polysaccharide to enhance human serum bactericidal activity and promote phagocytosis and killing of these bacteria by human neutrophils. We first demonstrated that an isogenic deletion strain is significantly more susceptible to killing by human heparinized blood, serum, and neutrophils than a wild-type ST258 strain. Consistent with the importance of capsule as an immune evasion molecule, rabbit immune serum and purified IgG specific for ST258 capsule polysaccharide type 2 (CPS2) enhanced killing by human blood and serum Moreover, antibodies specific for CPS2 promoted phagocytosis and killing of ST258 by human neutrophils. Collectively, our findings suggest that ST258 CPS2 is a viable target for immunoprophylactics and/or therapeutics. Infections caused by carbapenem-resistant are difficult to treat, and mortality is high. New prophylactic approaches and/or therapeutic measures are needed to prevent or treat infections caused by these multidrug-resistant bacteria. A strain of carbapenem-resistant , classified by multilocus sequence typing as ST258, is present in many regions of the world and is the most prominent carbapenem-resistant lineage in the United States. Here we show that rabbit antibodies specific for capsule polysaccharide of ST258 significantly enhance human serum bactericidal activity and promote phagocytosis and killing of this pathogen by human neutrophils. These studies have provided strong support for the idea that development of an immunotherapy (vaccine) for carbapenem-resistant infections is feasible and has merit.
耐碳青霉烯肠杆菌是一个全球性的问题。在世界许多地区，包括美国在内，一种被归类为多位点序列型 258（ST258）的耐碳青霉烯肠杆菌谱系在医疗保健环境中非常突出。ST258 菌株几乎可以对所有临床上有用的抗生素产生耐药性；这些生物体引起的感染的治疗很困难，死亡率很高。作为促进开发针对 ST258 感染的新疗法的一步，我们测试了针对 ST258 荚膜多糖的兔抗体增强人血清杀菌活性以及促进人中性粒细胞吞噬和杀死这些细菌的能力。我们首先证明，与野生型 ST258 菌株相比，同源缺失菌株对人肝素化血液、血清和中性粒细胞的杀伤作用明显更敏感。与荚膜作为免疫逃避分子的重要性一致，兔免疫血清和针对 ST258 荚膜多糖型 2（CPS2）的纯化 IgG 特异性增强了人血液和血清的杀伤作用。此外，针对 CPS2 的抗体促进了 ST258 被人中性粒细胞吞噬和杀死。总的来说，我们的发现表明 ST258 CPS2 是免疫预防和/或治疗的可行靶标。耐碳青霉烯肠杆菌引起的感染难以治疗，死亡率很高。需要新的预防方法和/或治疗措施来预防或治疗这些耐多药细菌引起的感染。一种被多位点序列分型归类为 ST258 的耐碳青霉烯肠杆菌菌株存在于世界许多地区，并且是美国最突出的耐碳青霉烯肠杆菌谱系。在这里，我们表明针对 ST258 荚膜多糖的兔抗体显著增强了人血清杀菌活性，并促进了人中性粒细胞对这种病原体的吞噬和杀伤。这些研究为开发针对耐碳青霉烯肠杆菌感染的免疫疗法（疫苗）是可行的且有价值的这一观点提供了有力支持。
