Safety and immunogenicity of an adjuvanted
            <i>Escherichia coli</i>
            adhesin vaccine in healthy women with and without histories of recurrent urinary tract infections: results from a first-in-human phase 1 study

Eldridge, Gary R.; Hughey, Heidi; Rosenberger, Lois B.; Martin, Steven M.; Shapiro, Andrew Marc; D’Antonio, Elizabeth; Krejci, Kent G.; Shore, Neal D.; Peterson, James T.; Lukes, Andrea S.; Starks, Courtney M.

doi:10.1080/21645515.2020.1834807

Cited by 37 publications

(26 citation statements)

References 39 publications

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“…Given how pathogenic bacteria can circumvent the host immune response by generating protected niches ( Grant and Hung, 2013 ) and due to the constantly growing presence of multidrug-resistant strains ( Boucher et al, 2009 ), treatment of persistent or recurring infections is increasingly challenging. Although vaccination approaches against FimH ( Eldridge et al, 2021 ) or non-conventional treatments, such as small mannosides ( Schönemann et al, 2019 ; Mydock-McGrane et al, 2016 ), showed promising results, treatments of infections caused by type 1 piliated pathogens remains difficult. Our findings underscore the importance of the mannose-binding domain, and several conserved amino acid residues in this domain, in the interaction between FimH and CD14.…”

Section: Discussionmentioning

confidence: 99%

Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14

Tomasek

Leithner

Glatzova

et al. 2022

eLife

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A key attribute of persistent or recurring bacterial infections is the ability of the pathogen to evade the host's immune response. Many Enterobacteriaceae express type 1 pili, a pre-adapted virulence trait, to invade host epithelial cells and establish persistent infections. However, the molecular mechanisms and strategies by which bacteria actively circumvent the immune response of the host remain poorly understood. Here, we identified CD14, the major co-receptor for lipopolysaccharide detection, on mouse dendritic cells as a binding partner of FimH, the protein located at the tip of the type 1 pilus of Escherichia coli. The FimH amino acids involved in CD14 binding are highly conserved across pathogenic and non-pathogenic strains. Binding of the pathogenic strain CFT073 to CD14 reduced dendritic cell migration by overactivation of integrins and blunted expression of co-stimulatory molecules by overactivating the NFAT pathway, both rate-limiting factors of T cell activation. This response was binary at the single cell level, but averaged in larger populations exposed to both piliated and non-piliated pathogens, presumably via the exchange of immunomodulatory cytokines. While defining an active molecular mechanism of immune evasion by pathogens, the interaction between FimH and CD14 represents a potential target to interfere with persistent and recurrent infections, such as urinary tract infections or Crohn's disease.

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Section: Discussionmentioning

confidence: 99%

Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14

Tomasek

Leithner

Glatzova

et al. 2022

eLife

View full text Add to dashboard Cite

show abstract

“…Given how pathogenic bacteria circumvent the host immune response by generating protected niches (Grant & Hung, 2013) and the constantly growing presence of multi-drug resistant strains (Boucher et al, 2009), treatment of persistent or recurring infections is increasingly challenging. Although vaccination approaches against FimH (Eldridge et al, 2020) or non-conventional treatments, such as small mannosides (Schönemann et al, 2019;Mydock-McGrane et al, 2016), showed promising results, treatments of infections caused by type 1 piliated pathogens remains difficult. Our findings underscore the importance of the mannose-binding domain, and several conserved amino acid residues in this domain, in the interaction between FimH and CD14.…”

Section: Discussionmentioning

confidence: 99%

Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14

Tomasek

Leithner

Glatzova

et al. 2021

Preprint

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A key attribute of persistent or recurring bacterial infections is the ability of the pathogen to evade the host’s immune response. Many Enterobacteriaceae express type 1 pili, a pre-adapted virulence trait, to invade host epithelial cells and establish persistent infections. However, the molecular mechanisms and strategies by which bacteria actively circumvent the immune response of the host remain poorly understood. Here, we identified CD14, the major co-receptor for lipopolysaccharide detection, on dendritic cells as a previously undescribed binding partner of FimH, the protein located at the tip of the type 1 pilus of Escherichia coli. The FimH amino acids involved in CD14 binding are highly conserved across pathogenic and non-pathogenic strains. Binding of pathogenic bacteria to CD14 lead to reduced dendritic cell migration and blunted expression of co-stimulatory molecules, both rate-limiting factors of T cell activation. While defining an active molecular mechanism of immune evasion by pathogens, the interaction between FimH and CD14 represents a potential target to interfere with persistent and recurrent infections, such as urinary tract infections or Crohn’s disease.

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“…In an open-label, dose-escalation phase I trial, 67 women with or without history of recurrent UTIs received intramuscular injections of FimH adhesin on four occasions. The drug was well tolerated with no serious adverse events reported and women with a history of UTIs had a 150-fold increase in FimH antibodies 254 . These preliminary positive data have led to FDA permission for compassionate use of the vaccine in patients with UTIs caused by multi drug-resistant E. coli 6 ; however, no data on therapeutic efficacy have been disclosed.…”

Section: Vaccination Strategiesmentioning

confidence: 98%

Immunomodulation therapy offers new molecular strategies to treat UTI

et al. 2022

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Innovative solutions are needed for the treatment of bacterial infections, and a range of antibacterial molecules have been explored as alternatives to antibiotics. A different approach is to investigate the immune system of the host for new ways of making the antibacterial defence more efficient. However, the immune system has a dual role as protector and cause of disease: in addition to being protective, increasing evidence shows that innate immune responses can become excessive and cause acute symptoms and tissue pathology during infection. This role of innate immunity in disease suggests that the immune system should be targeted therapeutically, to inhibit over-reactivity. The ultimate goal is to develop therapies that selectively attenuate destructive immune response cascades, while augmenting the protective antimicrobial defence but such treatment options have remained underexplored, owing to the molecular proximity of the protective and destructive effects of the immune response. The concept of innate immunomodulation therapy has been developed successfully in urinary tract infections, based on detailed studies of innate immune activation and disease pathogenesis. Effective, disease-specific, immunomodulatory strategies have been developed by targeting specific immune response regulators including key transcription factors. In acute pyelonephritis, targeting interferon regulatory factor 7 using small interfering RNA or treatment with antimicrobial peptide cathelicidin was protective and, in acute cystitis, targeting overactive effector molecules such as IL-1β, MMP7, COX2, cAMP and the pain-sensing receptor NK1R has been successful in vivo. Furthermore, other UTI treatment strategies, such as inhibiting bacterial adhesion and vaccination, have also shown promise.

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Safety and immunogenicity of an adjuvanted Escherichia coli adhesin vaccine in healthy women with and without histories of recurrent urinary tract infections: results from a first-in-human phase 1 study

Cited by 37 publications

References 39 publications

Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14

Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14

Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14

Immunomodulation therapy offers new molecular strategies to treat UTI

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