[Tetanus - still a reality in Sweden]. / Stelkramp ännu en realitet i Sverige.

Tetanus (lockjaw) is a potentially life-threatening disease caused by a neurotoxin produced by the spore forming bacterium Clostridium tetani. The incidence has decreased substantially the last decades in most high-income countries, much due to well established vaccination programs. However, although uncommon, tetanus still remains a reality in Sweden. The condition is diagnosed based on clinical parameters and is hard to distinguish from many other more common differential diagnoses. Lack of vaccine induced antibodies is the most important risk factor for developing tetanus. Here we present a patient who developed tetanus two weeks following a puncture wound, but who was initially misdiagnosed with wake-up stroke. The case illustrates the importance of reviewing a patient's tetanus vaccine history, which determines what prophylactic measures are adequate to take, especially following potentially contaminated wounds.

Molecular Basis of Acute Cystitis Reveals Susceptibility Genes and Immunotherapeutic Targets.

Tissue damage is usually regarded as a necessary price to pay for successful elimination of pathogens by the innate immune defense. Yet, it is possible to distinguish protective from destructive effects of innate immune activation and selectively attenuate molecular nodes that create pathology. Here, we identify acute cystitis as an Interleukin-1 beta (IL-1ß)-driven, hyper-inflammatory condition of the infected urinary bladder and IL-1 receptor blockade as a novel therapeutic strategy. Disease severity was controlled by the mechanism of IL-1ß processing and mice with intact inflammasome function developed a moderate, self-limiting form of cystitis. The most severe form of acute cystitis was detected in mice lacking the inflammasome constituents ASC or NLRP-3. IL-1ß processing was hyperactive in these mice, due to a new, non-canonical mechanism involving the matrix metalloproteinase 7- (MMP-7). ASC and NLRP-3 served as transcriptional repressors of MMP7 and as a result, Mmp7 was markedly overexpressed in the bladder epithelium of Asc-/- and Nlrp3-/- mice. The resulting IL-1ß hyper-activation loop included a large number of IL-1ß-dependent pro-inflammatory genes and the IL-1 receptor antagonist Anakinra inhibited their expression and rescued susceptible Asc-/- mice from bladder pathology. An MMP inhibitor had a similar therapeutic effect. Finally, elevated levels of IL-1ß and MMP-7 were detected in patients with acute cystitis, suggesting a potential role as biomarkers and immunotherapeutic targets. The results reproduce important aspects of human acute cystitis in the murine model and provide a comprehensive molecular framework for the pathogenesis and immunotherapy of acute cystitis, one of the most common infections in man. TRIAL REGISTRATION: The clinical studies were approved by the Human Ethics Committee at Lund University (approval numbers LU106-02, LU236-99 and Clinical Trial Registration RTP-A2003, International Committee of Medical Journal Editors, www.clinicaltrials.gov).

The Genetics of Urinary Tract Infections and the Innate Defense of the Kidney and Urinary tract.

The urinary tract is a sterile organ system. Urinary tract infections (UTIs) are common and often serious infections. Research has focused on uropathogen, environment, and host factors leading to UTI pathogenesis. A growing body of evidence exists implicating genetic factors that can contribute to UTI risks. In this review, we highlight genetic variations in aspects of the innate immune system critical to the host response to uropathogens. This overview includes genetic variations in pattern recognition receptor molecules, chemokines/cytokines, and neutrophil activation. We also comprehensively cover murine knockout models of UTI, genetic variations involved in renal scarring as a result of ascending UTIs, and asymptomatic bacteriuria.

IRF7 inhibition prevents destructive innate immunity-A target for nonantibiotic therapy of bacterial infections.

Boosting innate immunity represents an important therapeutic alternative to antibiotics. However, the molecular selectivity of this approach is a major concern because innate immune responses often cause collateral tissue damage. We identify the transcription factor interferon regulatory factor 7 (IRF-7), a heterodimer partner of IRF-3, as a target for non-antibiotics-based therapy of bacterial infections. We found that the efficient and self-limiting innate immune response to bacterial infection relies on a tight balance between IRF-3 and IRF-7. Deletion of Irf3 resulted in overexpression of Irf7 and led to an IRF-7-driven hyperinflammatory phenotype, which was entirely prevented if Irf7 was deleted. We then identified a network of strongly up-regulated, IRF-7-dependent genes in Irf3(-/-) mice with kidney pathology, which was absent in Irf7(-/-) mice. IRF-3 and IRF-7 from infected kidney cell nuclear extracts were shown to bind OAS1, CCL5, and IFNB1 promoter oligonucleotides. These data are consistent in children with low IRF7 expression in the blood: attenuating IRF7 promoter polymorphisms (rs3758650-T and rs10902179-G) negatively associated with recurrent pyelonephritis. Finally, we identified IRF-7 as a target for immunomodulatory therapy. Administering liposomal Irf7 siRNA to Irf3(-/-) mice suppressed mucosal IRF-7 expression, and the mice were protected against infection and renal tissue damage. These findings offer a response to the classical but unresolved question of "good versus bad inflammation" and identify IRF7 as a therapeutic target for protection against bacterial infection.

Urinary Tract Infection Molecular Mechanisms and Clinical Translation.

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.

Bacterial control of host gene expression through RNA polymerase II.

The normal flora furnishes the host with ecological barriers that prevent pathogen attack while maintaining tissue homeostasis. Urinary tract infections (UTIs) constitute a highly relevant model of microbial adaptation in which some patients infected with Escherichia coli develop acute pyelonephritis, while other patients with bacteriuria exhibit an asymptomatic carrier state similar to bacterial commensalism. It remains unclear if the lack of destructive inflammation merely reflects low virulence or if carrier strains actively inhibit disease-associated responses in the host. Here, we identify a new mechanism of bacterial adaptation through broad suppression of RNA polymerase II­dependent (Pol II­dependent) host gene expression. Over 60% of all genes were suppressed 24 hours after human inoculation with the prototype asymptomatic bacteriuria (ABU) strain E. coli 83972, and inhibition was verified by infection of human cells. Specific repressors and activators of Pol II­dependent transcription were modified, Pol II phosphorylation was inhibited, and pathogen-specific signaling was suppressed in cell lines and inoculated patients. An increased frequency of strains inhibiting Pol II was epidemiologically verified in ABU and fecal strains compared with acute pyelonephritis, and a Pol II antagonist suppressed the disease-associated host response. These results suggest that by manipulating host gene expression, ABU strains promote tissue integrity while inhibiting pathology. Such bacterial modulation of host gene expression may be essential to sustain asymptomatic bacterial carriage by ensuring that potentially destructive immune activation will not occur.