Urinary Tract Infections and the Mucosal Immune System

Godaly, Gabriela; Bergsten, Göran; Fischer, Hans; Irjala, Heikki; Lundstedt, Ann-Charlotte; Samuelsson, Patrik; Svensson, Majlis; Svanborg, Catharina

doi:10.1016/b978-0-12-415847-4.00106-3

Cited by 4 publications

(5 citation statements)

References 240 publications

(266 reference statements)

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“…Surrounding cells and recruited inflammatory cells then take the decisions about the quality and quantity of the mucosal response, leading to disease or protection [ 16 ]. The epithelial cells are thus important players in the mucosal immune system; acting both as docking sites for the bacteria and as sensors of microbial attack [ 17 ].…”

Section: Critical Signaling Pathways That Define Symptoms and Pathmentioning

confidence: 99%

“…A change from P- to Type 1 fimbrial expression shifts the host response to the MyD88 and TIRAP dependent arm of the TLR4 signaling pathway, leading to NFkB dependent transcription and inflammasome activation [ 20 ]. For comprehensive updates on the innate immune response to UTI, please see Godaly et al [ 16 ] and Ambite et al [ 17 ].…”

Section: Critical Signaling Pathways That Define Symptoms and Pathmentioning

confidence: 99%

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Urinary Tract Infection Molecular Mechanisms and Clinical Translation

et al. 2016

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Rapid developments in infection biology create new and exciting options for individualized diagnostics and therapy. Such new practices are needed to improve patient survival and reduce morbidity. Molecular determinants of host resistance to infection are being characterized, making it possible to identify susceptible individuals and to predict their risk for future morbidity. Immunotherapy is emerging as a new strategy to treat infections worldwide and controlled boosting of the host immune defense represents an important therapeutic alternative to antibiotics. In proof of concept studies, we have demonstrated that this approach is feasible. The long-term goal is not just to remove the pathogens but to also develop technologies that restore resistance to infection in disease-prone patients and devise personalized therapeutic interventions. Here, we discuss some approaches to reaching these goals, in patients with urinary tract infection (UTI). We describe critical host signaling pathways that define symptoms and pathology and the genetic control of innate immune responses that balance protection against tissue damage. For some of these genes, human relevance has been documented in clinical studies, identifying them as potential targets for immune-modulatory therapies, as a complement to antibiotics.

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Section: Critical Signaling Pathways That Define Symptoms and Pathmentioning

confidence: 99%

Section: Critical Signaling Pathways That Define Symptoms and Pathmentioning

confidence: 99%

Urinary Tract Infection Molecular Mechanisms and Clinical Translation

et al. 2016

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“…UPEC alter the expression of more than 1000 genes in human kidney cells, and in genetically competent mice, kidney or bladder infection modifies the expression of at least 500 genes, depending on the bacterial strain. These include well known responses such as chemokines and receptors for inflammatory cells, and cytokines [ 18 , 19 ], inflammasome and acute phase response genes, type I interferon (IFN), growth factors and antibacterial peptides [ 20 ▪ , 21 ]. In addition, UTIs modify a large number of genes that have not yet been identified as determinants of resistance against infection, predicting that there are new categories of cellular and tissue responses to be explored.…”

Section: Innate Immunity and Molecular Mechanismsmentioning

confidence: 99%

Innate immunity and genetic determinants of urinary tract infection susceptibility

Godaly

Ambite²,

Svanborg³

2015

Current Opinion in Infectious Diseases

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Purpose of reviewUrinary tract infections (UTIs) are common, dangerous and interesting. Susceptible individuals experience multiple, often clustered episodes, and in a subset of patients, infections progress to acute pyelonephritis (APN), sometimes accompanied by uro-sepsis. Others develop asymptomatic bacteriuria (ABU). Here, we review the molecular basis for these differences, with the intention to distinguish exaggerated host responses that drive disease from attenuated responses that favour protection and to highlight the genetic basis for these extremes, based on knock-out mice and clinical studies.Recent findingsThe susceptibility to UTI is controlled by specific innate immune signalling and by promoter polymorphisms and transcription factors that modulate the expression of genes controlling these pathways. Gene deletions that disturb innate immune activation either favour asymptomatic bacteriuria or create acute morbidity and disease. Promoter polymorphisms and transcription factor variants affecting those genes are associated with susceptibility in UTI-prone patients.SummaryIt is time to start using genetics in UTI-prone patients, to improve diagnosis and to assess the risk for chronic sequels such as renal malfunction, hypertension, spontaneous abortions, dialysis and transplantation. Furthermore, the majority of UTI patients do not need follow-up, but for lack of molecular markers, they are unnecessarily investigated.

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“…In the human inoculation IP: 44.224.250. 200 On: Fri, 02 Oct 2020 10:31:34 model, P fimbriae act as independent virulence factors, fulfilling the molecular Koch postulates (67,68). PapGmediated adherence enables the host to sense the attacking uro-pathogens and to activate the innate mucosal response (Fig.…”

Section: Tlr4 and Adaptor-protein Signalingmentioning

confidence: 99%

Susceptibility to Urinary Tract Infection: Benefits and Hazards of the Antibacterial Host Response

Ambite

Nagy²,

Godaly

et al. 2016

Microbiol Spectr

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A paradigm shift is needed to improve and personalize the diagnosis of infectious disease and to select appropriate therapies. For many years, only the most severe and complicated bacterial infections received more detailed diagnostic and therapeutic attention as the efficiency of antibiotic therapy has guaranteed efficient treatment of patients suffering from the most common infections. Indeed, treatability almost became a rationale not to analyze bacterial and host parameters in these larger patient groups. Due to the rapid spread of antibiotic resistance, common infections like respiratory tractor urinary-tract infections (UTIs) now pose new and significant therapeutic challenges. It is fortunate and timely that infectious disease research can offer such a wealth of new molecular information that is ready to use for the identification of susceptible patients and design of new suitable therapies. Paradoxically, the threat of antibiotic resistance may become a window of opportunity, by encouraging the implementation of new diagnostic and therapeutic approaches. The frequency of antibiotic resistance is rising rapidly in uropathogenic organisms and the molecular and genetic understanding of UTI susceptibility is quite advanced. More bold translation of the new molecular diagnostic and therapeutic tools would not just be possible but of great potential benefit in this patient group. This chapter reviews the molecular basis for susceptibility to UTI, including recent advances in genetics, and discusses the consequences for diagnosis and therapy. By dissecting the increasingly well-defined molecular interactions between bacteria and host and the molecular features of excessive bacterial virulence or host-response malfunction, it is becoming possible to isolate the defensive from the damaging aspects of the host response. Distinguishing "good" from "bad" inflammation has been a long-term quest of biomedical science and in UTI, patients need the "good" aspects of the inflammatory response to resist infection while avoiding the "bad" aspects, causing chronicity and tissue damage.

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Urinary Tract Infections and the Mucosal Immune System

Cited by 4 publications

References 240 publications

Urinary Tract Infection Molecular Mechanisms and Clinical Translation

Urinary Tract Infection Molecular Mechanisms and Clinical Translation

Innate immunity and genetic determinants of urinary tract infection susceptibility

Susceptibility to Urinary Tract Infection: Benefits and Hazards of the Antibacterial Host Response

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