| 3 | Bicarbonate Effects on Antibacterial Immunity and Mucus Glycobiology in the Cystic Fibrosis Lung:A Review With Selected Experimental Observations显示文摘The primary defect in cystic fibrosis(CF)is abnormal chloride and bicarbonate transport in the CF transmembrane conductance regulator epithelial ion channel.The apical surface of the respiratory tract is lined by an airway surface liquid(ASL)layer composed of mucin comprising mainly MUC5A and MUC5B glycoproteins.ASL homeostasis depends on sodium bicarbonate secretion into the airways and secretion deficits alter mucus properties leading to airway obstruction,inflammation and infections.Downstream effects of abnormal ion transport in the lungs include altered intrinsic immune defenses.We observed that neutrophils killed Pseudomonas aeruginosa more efficiently when it had been exposed to sodium bicarbonate,and formation of neutrophil extracellular traps by neutrophils was augmented in the presence of increasing bicarbonate concentrations.Physiological levels of bicarbonate sensitized P.aeruginosa to the antimicrobial peptide cathelicidin LL-37,which is present in both lung ASL and neutrophil extracellular traps.Sodium bicarbonate has various uses in clinical medicine and in the care of CF patients and could be further explored as a therapeutic adjunct against Pseudomonas infections. | Ruth Siew Tzung-Lin Ou Samira Dahesh Kathryn Akong Victor Nizet | 2022 | Infectious Microbes & Diseases2022，4，3： | 0 |
| 4 | Site-Specific Conjugation of Cell Wall Polyrhamnose to Protein SpyAD Envisioning a Safe Universal Group A Streptococcal Vaccine显示文摘Development of an effective vaccine against the leading human bacterial pathogen group A Streptococcus(GAS)is a public health priority.The species defining group A cell wall carbohydrate(GAC,Lancefield antigen)can be engineered to remove its immunodominant N-acetylglucosamine(GlcNAc)side chain,implicated in provoking autoimmune cross-reactivity in rheumatic heart disease,leaving its polyrhamnose core(GACPR).Here we generate a novel protein conjugate of the GACPR and test the utility of this conjugate antigen in active immunization.Instead of conjugation to a standard carrier protein,we selected SpyAD,a highly conserved GAS surface protein containing both B-cell and T-cell epitopes relevant to the bacterium that itself shows promise as a vaccine antigen.SpyAD was synthesized using the XpressTM cell-free protein expression system,incorporating a non-natural amino acid to which GACpr was conjugated by site-specific click chemistry to yield high molecular mass SpyAD-GACPR conjugates and avoid disruption of important T-cell and B-cell immunological epitopes.The conjugated SpyAD-GACPR elicited antibodies that bound the surface of multiple GAS strains of diverse M types and promoted opsonophagocytic killing by human neutrophils.Active immunization of mice with a multivalent vaccine consisting of SpyAD-GACPR,together with candidate vaccine antigens streptolysin O and C5a peptidase,protected against GAS challenge in a systemic infection model and localized skin infection model,without evidence of cross reactivity to human heart or brain tissue epitopes.This general approach may allow GAC to be safely and effectively included in future GAS subunit vaccine formulations with the goal of broad protection without autoreactivity. | Nina J.Gao Satoshi Uchiyama Lucy Pill Samira Dahesh Joshua Olson Leslie Bautista Shilpa Maroju Aym Berges Janet ZLiu Raymond HZurich Nina Mvan Sorge Jeff Fairman Neeraj Kapoor Victor Nizet | 2021 | Infectious Microbes & Diseases2021，3，2： | 0 |
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