Hahn Mark M, Gunn John S
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
Infectious Diseases Institute, The Ohio State University, Columbus, OH 43210, USA.
Microorganisms. 2020 Feb 13;8(2):253. doi: 10.3390/microorganisms8020253.
serovar Typhi causes 14.3 million acute cases of typhoid fever that are responsible for 136,000 deaths each year. Chronic infections occur in 3%-5% of those infected and Typhi persists primarily in the gallbladder by forming biofilms on cholesterol gallstones, but how these bacterial communities evade host immunity is not known. biofilms produce several extracellular polymeric substances (EPSs) during chronic infection, which are hypothesized to prevent pathogen clearance either by protecting biofilm-associated bacteria from direct humoral attack or by modulating innate phagocyte interaction with biofilms. Using wild-type and EPS-deficient planktonic and biofilm the direct attack hypothesis was tested by challenging biofilms with human serum and antimicrobial peptides. Biofilms were found to be tolerant to these molecules, but these phenotypes were independent of the tested EPSs. By examining macrophage and neutrophil responses, new roles for biofilm-associated capsular polysaccharides and slime polysaccharides were identified. The Typhi Vi antigen was found to modulate innate immunity by reducing macrophage nitric oxide production and neutrophil reactive oxygen species (ROS) production. The slime polysaccharides colanic acid and cellulose were found to be immune-stimulating and represent a key difference between non-typhoidal serovars and typhoidal serovars, which do not express colanic acid. Furthermore, biofilm tolerance to the exogenously-supplied ROS intermediates hydrogen peroxide (HO) and hypochlorite (ClO) indicated an additional role of the capsular polysaccharides for both serovars in recalcitrance to HO but not ClO, providing new understanding of the stalemate that arises during chronic infections and offering new directions for mechanistic and clinical studies.
伤寒杆菌每年引发1430万例急性伤寒热病例，导致13.6万人死亡。3%-5%的感染者会出现慢性感染，伤寒杆菌主要通过在胆固醇胆结石上形成生物膜而在胆囊中持续存在，但这些细菌群落如何逃避宿主免疫尚不清楚。在慢性感染期间，生物膜会产生几种细胞外聚合物（EPSs），据推测，这些聚合物要么通过保护与生物膜相关的细菌免受直接体液攻击，要么通过调节先天吞噬细胞与生物膜的相互作用来阻止病原体清除。使用野生型和缺乏EPS的浮游菌和生物膜，通过用人血清和抗菌肽挑战生物膜来检验直接攻击假说。发现生物膜对这些分子具有耐受性，但这些表型与测试的EPSs无关。通过检查巨噬细胞和中性粒细胞的反应，确定了与生物膜相关的荚膜多糖和黏液多糖的新作用。发现伤寒杆菌Vi抗原通过减少巨噬细胞一氧化氮的产生和中性粒细胞活性氧（ROS）的产生来调节先天免疫。发现黏液多糖柯氏酸和纤维素具有免疫刺激作用，这代表了非伤寒血清型和伤寒血清型之间的关键区别，伤寒血清型不表达柯氏酸。此外，生物膜对外源供应的ROS中间体过氧化氢（HO）和次氯酸盐（ClO）的耐受性表明，两种血清型的荚膜多糖在对HO而非ClO的抗性中具有额外作用，这为慢性感染期间出现的僵局提供了新的理解，并为机制和临床研究提供了新的方向。
