The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner

Uptake of bacteria by phagocytes is a crucial step in innate immune defence. Members of the disintegrin and metalloproteinase (ADAM) family critically control the immune response by limited proteolysis of surface expressed mediator molecules. Here, we investigated the significance of ADAM17 and its regulatory adapter molecule iRhom2 for bacterial uptake by phagocytes. Inhibition of metalloproteinase activity led to increased phagocytosis of pHrodo labelled Gram-negative and -positive bacteria (E. coli and S. aureus, respectively) by human and murine monocytic cell lines or primary phagocytes. Bone marrow-derived macrophages showed enhanced uptake of heat-inactivated and living E. coli when they lacked either ADAM17 or iRhom2 but not upon ADAM10-deficiency. In monocytic THP-1 cells, corresponding short hairpin RNA (shRNA)-mediated knockdown confirmed that ADAM17, but not ADAM10, promoted phagocytosis of E. coli. The augmented bacterial uptake occurred in a cell autonomous manner and was accompanied by increased release of the chemokine CXCL8, less TNFα release and only minimal changes in the surface expression of the receptors TNFR1, TLR6 and CD36. Inhibition experiments indicated that the enhanced bacterial phagocytosis after ADAM17 knockdown was partially dependent on TNFα-activity but not on CXCL8. This novel role of ADAM17 in bacterial uptake needs to be considered in the development of ADAM17 inhibitors as therapeutics

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

A Promoter Mutation Causes Differential Nitrate Reductase Activity of Mycobacterium tuberculosis and Mycobacterium bovis

The recent publication of the genome sequence of Mycobacterium bovis showed >99.95% identity to M. tuberculosis. No genes unique to M. bovis were found. Instead numerous single-nucleotide polymorphisms (SNPs) were identified. This has led to the hypothesis that differential gene expression due to SNPs might explain the differences between the human and bovine tubercle bacilli. One phenotypic distinction between M. tuberculosis and M. bovis is nitrate reduction, which not only is an essential diagnostic tool but also contributes to mycobacterial pathogenesis. We previously showed that narGHJI encodes a nitrate reductase in both M. tuberculosis and M. bovis and that NarGHJI-mediated nitrate reductase activity was substantially higher in the human tubercle bacillus. In the present study we used a genetic approach to demonstrate that an SNP within the promoter of the nitrate reductase gene cluster narGHJI is responsible for the different nitrate reductase activity of M. tuberculosis and M. bovis. This is the first example of an SNP that leads to differential gene expression between the human and bovine tubercle bacilli

Use of UV-C Light for Surface Desinfection: Results from a Portable Sanitizing Device

Albrecht U-V, Vonberg R-P, Woltemate S, Sedlacek L. Use of UV-C Light for Surface Desinfection: Results from a Portable Sanitizing Device. In: 63. Jahrestagung der Deutschen Gesellschaft für Hygiene und Mikrobiologie (DGHM) e. V. International Journal of Medical Microbiology. Vol 301. Elsevier; 2011

Portable UV light as an alternative for decontamination

Petersson LP, Albrecht U-V, Sedlacek L, Gemein S, Gebel J, Vonberg R-P. Portable UV light as an alternative for decontamination. American Journal of Infection Control. 2014;42(12):1334-1336.We evaluated the capability of a commercially available hand-held device that emits ultraviolet (UV) light to disinfect plain surfaces. Eight bacterial species were tested, including Clostridium difficile ribotype 027 and 3 other spore-forming species. Even bacterial spores could be successfully inactivated within a few seconds of irradiation. UV light may provide an alternative for the decontamination of medical products, such as mobile phones or tablet computers, that cannot be treated otherwise

Standardized, App-Based Disinfection of iPads in a Clinical and Nonclinical Setting: Comparative Analysis

Albrecht U-V, von Jan U, Sedlacek L, Groos S, Suerbaum S, Vonberg R-P. Standardized, App-Based Disinfection of iPads in a Clinical and Nonclinical Setting: Comparative Analysis. Journal of Medical Internet Research. 2013;15(8): e176

Towards individualized diagnostics of biofilm-associated infections: a case study

Biofilm resistance: Moving toward individualized testing A procedure for individualized testing of biofilms might yield more reliable data on antibiotic susceptibility in clinical conditions. Researchers in Germany, led by Mathias Müsken at the Helmholtz Centre for Infection Research, developed a method to analyze the antibiotic resistance of patients’ biofilm samples, using microscopy and cell staining. They studied Pseudomonas aeruginosa biofilms gathered from people with cystic fibrosis. The procedure revealed differences in antibiotic susceptibility between bacteria growing in biofilms and in the free-living state. The findings cast doubt on the general utility of antibiotic resistance profiles derived from standard laboratory studies. The clinical advantages of using the procedure to study the antibiotic susceptibility of patients’ unique biofilms should be investigated further. The researchers suggest individualized testing might increase the effectiveness of treatment for chronically infected patients

Multidrug-resistant Mycobacterium tuberculosis: a report of cosmopolitan microbial migration and an analysis of best management practices

Background!#!Tuberculosis (TB) control is a primary global health priority but the goal to eliminate TB is being threatened by the increase in incidence of multidrug-resistant tuberculosis (MDR-TB). With this series of seven MDR-TB cases in migrant patients with identical Mycobacterium tuberculosis strains we aim to illustrate the challenges encountered during therapy and follow-up: language barriers, access to care for migrant patients, depression due to isolation, adverse reactions to the treatment, management of pediatric TB, further contact tracing. We also discuss best practices for the management of complex MDR-TB cases in settings with low overall TB incidence focusing on modern diagnostic assays and an individualized and an interdisciplinary therapeutic approach.!##!Methods!#!We describe a case series of seven consecutively diagnosed MDR-TB patients, six of them treated at our tertiary care hospital between May 2018 and March 2020. Epidemiologic data was gained by semi-structured patient interviews and reconstruction of the migration route. The origin of the cluster was confirmed by genotyping of the TB-strains.!##!Results!#!Six related patients were diagnosed with pulmonary MDR-TB between May and August 2018. All had a positive Interferon-Gamma-Release Assay (IGRA), in five patients sputum microscopy was positive for acid-fast bacilli (AFB). The genetic and phenotypical drug susceptibility test did not match with MDR-TB strains from an East-African origin. The index patient was identified through genetical fingerprinting. By changing the therapy to a modern MDR-TB regime and using an interdisciplinary and culture-sensitive approach, all patients improved clinically and radiologically.!##!Conclusion!#!Human migration plays an important role for the global spread of MDR-TB in low incidence countries. Early case detection and adequate treatment are key to prevention of outbreaks. Especially language barriers and complex migration routes make genotyping of TB-strains a crucial tool to identify cases clusters, the potential index patient and transmission dynamics. We are fortunate enough to experience times in which new TB-antibiotics were made available and in which molecular assays revolutionized TB-diagnostics. We need to take advantage of that and develop personalized therapies for patients suffering from drug resistant TB