O -Acetylation of Capsular Polysialic Acid Enables Escherichia coli K1 Escaping from Siglec-Mediated Innate Immunity and Lysosomal Degradation of E. coli -Containing Vacuoles in Macrophage-Like Cells

Escherichia coli K1 is a leading cause of neonatal meningitis. The mortality and morbidity of this disease remain significantly high despite antibiotic therapy.

Development of a chitosan‐modified PLGA nanoparticle vaccine for protection against Escherichia coli K1 caused meningitis in mice

Background Escherichia coli K1 (E. coli K1) caused neonatal meningitis remains a problem, which rises the urgent need for an effective vaccine. Previously, we rationally designed and produced the recombinant protein OmpAVac (Vo), which elicited protective immunity against E. coli K1 infection. However, Vo has limited stability, which hinders its future industrial application. Method Chitosan-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles were prepared and used as carried for the recombinant Vo. And the safety, stability and immunogenicity of Vo delivered by chitosan-modified PLGA nanoparticles were tested in vitro and in a mouse model of bacteremia. Results We successfully generated chitosan-modified PLGA nanoparticles for the delivery of recombinant Vo (VoNP). In addition, we found that a freeze-drying procedure increases the stability of the VoNPs without changing the shape, size distribution and encapsulation of the Vo protein. Unlike aluminum adjuvant, the nanoparticles that delivered Vo were immunoprotective in mice even after storage for as long as 180 days. Conclusions We identified an effective strategy to improve the stability of Vo to maintain its immunogenicity, which will contribute to the future development of vaccines against E. coli K1.

An ArcA-Modulated Small RNA in Pathogenic Escherichia coli K1

Escherichia coli K1 is the leading cause of meningitis in newborns. Understanding the molecular basis of E. coli K1 pathogenicity will help develop treatment of meningitis and prevent neurological sequelae. E. coli K1 replicates in host blood and forms a high level of bacteremia to cause meningitis in human. However, the mechanisms that E. coli K1 employs to sense niche signals for survival in host blood are poorly understood. We identified one intergenic region in E. coli K1 genome that encodes a novel small RNA, sRNA-17. The expression of sRNA-17 was downregulated by ArcA in microaerophilic blood. The ΔsRNA-17 strain grew better in blood than did the wild-type strain and enhanced invasion frequency in human brain microvascular endothelial cells. Transcriptome analyses revealed that sRNA-17 regulates tens of differentially expressed genes. These data indicate that ArcA downregulates the sRNA-17 expression to benefit bacterial survival in blood and penetration of the blood–brain barrier. Our findings reveal a signaling mechanism in E. coli K1 for host adaptation.

A Probiotic Lactobacillus gasseri Alleviates Escherichia coli-Induced Cognitive Impairment and Depression in Mice by Regulating IL-1β Expression and Gut Microbiota

Excessive expression of interleukin (IL)-1β in the brain causes depression and cognitive dysfunction. Herein, we investigated the effect of Lactobacillus gasseri NK109, which suppressed IL-1β expression in activated macrophages, on Escherichia coli K1-induced cognitive impairment and depression in mice. Germ-free and specific pathogen-free mice with neuropsychiatric disorders were prepared by oral gavage of K1. NK109 alleviated K1-induced cognition-impaired and depressive behaviors, decreased the expression of IL-1β and populations of NF-κB+/Iba1+ and IL-1R+ cells, and increased the K1-suppressed population of BDNF+/NeuN+ cells in the hippocampus. However, its effects were partially attenuated by celiac vagotomy. NK109 treatment mitigated K1-induced colitis and gut dysbiosis. Tyndallized NK109, even if lysed, alleviated cognitive impairment and depression. In conclusion, NK109 alleviated neuropsychiatric disorders and colitis by modulating IL-1β expression, gut microbiota, and vagus nerve-mediated gut–brain signaling.

Antibacterial Effects of Derivatives of Porphyrin, Naphthalene diimide, Aminophenol and Benzodioxane on Methicillin Resistant Staphylococcus aureus and Neuropathogenic Escherichia coli K1

Background: Infectious diseases contribute to substantial mortality and morbidity worldwide despite advances in therapeutic intervention highlighting the need to identify drugs with antimicrobial properties. Methods: Here, we utilised several compounds from the following classes: porphyrin, naphthalene diimide, aminophenol derivatives, and benzodioxane, and evaluated their antibacterial activities. Bactericidal and bacteriostatic activity of these compounds were determined against methicillinresistant Staphylococcus aureus (MRSA) and Escherichia coli K1 with various concentrations of the drugs. Moreover, the ability of the bacteria to bind/associate to host cells was also ascertained in the absence and presence of aforementioned compounds. Results: The results revealed that porphyrin derivative (AYTHPP) had potent effects against MRSA, abolishing viability and blocking binding to the host cells. Importantly, novel AYTHPP exhibited powerful effects against MRSA even though it was not photoactivated. In contrast, other compounds, including naphthalene diimide, acetamol derivatives and benzodioxane, showed no inhibitory effects. Conclusion: The mechanism of action of porphyrin is likely through the production of reactive oxygen species causing oxidative stress, leading to apoptosis and/or necrosis via perturbations in the plasma membrane. Future studies will determine their in vivo efficacy together will associated molecular mode of action.