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Sören Verstraete, Sascha C Verbruggen, José A Hordijk, Ilse Vanhorebeek, Karolijn Dulfer, Fabian Güiza, Esther van Puffelen, An Jacobs, Sandra Leys, Astrid Durt, Hanna Van Cleemput, Renate D Eveleens, Gonzalo Garcia Guerra, Pieter J Wouters, Koen F Joosten, Greet Van den Berghe
Withholding early parenteral nutrition for 1 week in the PICU did not negatively affect survival, anthropometrics, health status, and neurocognitive development, and improved inhibitory control 2 years after PICU admission.
Bartholomew, T. L., Kidd, T. J., Sa Pessoa, J., Conde Alvarez, R., Bengoechea, J. A.
Acinetobacter baumannii causes a wide range of nosocomial infections. This pathogen is considered a threat to human health due to the increasing isolation of multidrug resistant strains. There is a major gap in knowledge on the infection biology of A. baumannii, and only few virulence factors have been characterized including the lipopolysaccharide. The lipid A expressed by A. baumannii is hepta-acylated and contains 2-hydroxylaurate. The late acyltransferases controlling the acylation of the lipid A have been already characterized. Here we report the characterization of A. baumannii LpxO, which encodes the enzyme responsible for the 2-hydroxylation of the lipid A. By genetic methods and mass spectrometry, we demonstrate that LpxO catalyses the 2-hydroxylation of the laurate transferred by A. baumannii LpxL. LpxO-dependent lipid A 2-hydroxylation protects A. baumannii from polymyxin B, colistin, and human β-defensin 3. LpxO contributes to survival of A. baumannii in human whole blood, and is required for pathogen survival in the waxmoth Galleria mellonella. LpxO also protects Acinetobacter from G. mellonella antimicrobial peptides and limits the expression of them. Further demonstrating the importance of LpxO-dependent modification in immune evasion, 2-hydroxylation of the lipid A limits the activation of MAPK JNK to attenuate inflammatory responses. In addition, LpxO-controlled lipid A modification mediates the production of the anti-inflammatory cytokine IL-10 via the activation of the transcriptional factor CREB. IL-10, in turn, limits the production of inflammatory cytokines following A. baumannii infection. Altogether, our studies suggest that LpxO is a candidate to develop anti A. baumannii drugs.
Soentjens P, De Koninck K, Tsoumanis A, et al.
AbstractBACKGROUNDEffective and safe single-visit rabies vaccination for pre- and post-exposure prophylaxis (PrEP and PEP) could substantially simplify rabies prevention and therefore increase compliance.METHODSIn a comparative trial, 303 healthy adults received a primary vaccination consisting of two intradermal (ID) doses of 0.1mL of the purified chicken embryo cell vaccine (PCEV) during a single visit. One year later, subjects were randomly assigned to receive either four or two ID PEP booster doses of 0.1mL of PCEV during a single visit.The primary endpoint for immunogenicity was the percentage of subjects with an adequate antibody level (>0.5 IU/mL) seven days after the booster doses. The safety endpoint was the proportion of participants developing adverse events (AE) following primary and/or booster vaccination.RESULTSll subjects, except one (99.3%) in each study group, had a rabies antibody titer >0.5 IU/mL on day 7 following the booster schedules.Subjects exposed to the four-dose PEP schedule had a geometric mean titer of 20 IU/mL versus 14 IU/mL for the two-dose PEP schedule (p=0.0228).Local reactions at the injection site following PrEP and PEP were mild and transient and only seen in 14.9% and 49.6 to 53% of the participants respectively. No serious AE were reported.CONCLUSIONIn healthy adults, a two-dose (2x 0.1mL) single-visit intradermal post-exposure prophylaxis schedule was as immunologically adequate and safe as a four-dose (4x 0.1mL) single-visit PEP schedule, seven to twenty-eight months following a two-dose (2x 0.1mL) single-visit intradermal pre-exposure prophylaxis.
Heidar Ali Panahi, Azam Bolhassani, Gholamreza Javadi, Zahra Noormohammadi
by Heidar Ali Panahi, Azam Bolhassani, Gholamreza Javadi, Zahra Noormohammadi
Human papillomaviruses (HPVs) are a group of circular double-stranded DNA viruses, showing severe tropism to mucosal tissues. A subset of HPVs, especially HPV16 and 18, are the primary etiological cause for several epithelial cell malignancies, causing about 5.2% of all cancers worldwide. Due to the high prevalence and mortality, HPV-associated cancers have remained as a significant health problem in human society, making an urgent need to develop an effective therapeutic vaccine against them. Achieving this goal is primarily dependent on the identification of efficient tumor-associated epitopes, inducing a robust cell-mediated immune response. Previous information has shown that E5, E6, and E7 early proteins are responsible for the induction and maintenance of HPV-associated cancers. Therefore, the prediction of major histocompatibility complex (MHC) class I T cell epitopes of HPV16, 18, 31 and 45 oncoproteins was targeted in this study. For this purpose, a two-step plan was designed to identify the most probable CD8+ T cell epitopes. In the first step, MHC-I and II binding, MHC-I processing, MHC-I population coverage and MHC-I immunogenicity prediction analyses, and in the second step, MHC-I and II protein-peptide docking, epitope conservation, and cross-reactivity with host antigens’ analyses were carried out successively by different tools. Finally, we introduced five probable CD8+ T cell epitopes for each oncoprotein of the HPV genotypes (60 epitopes in total), which obtained better scores by an integrated approach. These predicted epitopes are valuable candidates for in vitro or in vivo therapeutic vaccine studies against the HPV-associated cancers. Additionally, this two-step plan that each step includes several analyses to find appropriate epitopes provides a rational basis for DNA- or peptide-based vaccine development.
Sally Peprah, Constance Tenge, Isaiah O. Genga, Mediatrix Mumia, Pamela A. Were, Robert T. Kuremu, Walter N. Wekesa, Peter O. Sumba, Tobias Kinyera, Isaac Otim, Ismail D. Legason, Joshua Biddle, Steven J. Reynolds, Ambrose O. Talisuna, Robert J. Biggar, Kishor Bhatia, James J. Goedert, Ruth M. Pfeiffer and Sam M. Mbulaiteye
The burden of Plasmodium falciparum (Pf) malaria in Kenya is decreasing; however, it is still one of the top 10 causes of morbidity, particularly in regions of western Kenya. Between April 2015 and June 2016, we enrolled 965 apparently healthy children aged 0–15 years in former Nyanza and Western Provinces in Kenya to characterize the demographic, geographic, and household risk factors of asymptomatic malaria as part of an epidemiologic study to investigate the risk factors for endemic Burkitt lymphoma. The children were sampled using a stratified, multistage cluster sampling survey design. Malaria was assessed by rapid diagnostic test (RDT) and thick-film microscopy (TFM). Primary analyses of Pf malaria prevalence (pfPR) are based on RDT. Associations between weighted pfPR and potential risk factors were evaluated using logistic regression, accounting for the survey design. Plasmodium falciparum malaria prevalence was 36.0% (27.5%, 44.5%) by RDT and 22.3% (16.0%, 28.6%) by TFM. Plasmodium falciparum malaria prevalence was positively associated with living in the lake-endemic area (adjusted odds ratio [aOR] 3.46; 95% confidence interval [95% CI] 1.63, 7.37), paternal occupation as peasant farmer (aOR 1.87; 1.08, 3.26) or manual laborer (aOR 1.83; 1.00, 3.37), and keeping dogs (aOR 1.62; 0.98–2.69) or cows (aOR 1.52; 0.96–2.40) inside or near the household. Plasmodium falciparum malaria prevalence was inversely associated with indoor residual insecticide spraying (IRS) (aOR 0.44; 0.19, 1.01), having a household connected to electricity (aOR 0.47; 0.22, 0.98), and a household with two (aOR 0.45; 0.22, 0.93) or ≥ three rooms (aOR 0.41; 0.18, 0.93). We report high but geographically heterogeneous pfPR in children in western Kenya and significant associations with IRS and household-level socioeconomic factors.
Konze, S. A., Abraham, W.-R., Goethe, E., Surges, E., Kuypers, M. M. M., Hoeltig, D., Meens, J., Vogel, C., Stiesch, M., Valentin-Weigand, P., Gerlach, G.-F., Buettner, F. F. R.
Actinobacillus pleuropneumoniae is a capnophilic pathogen of the porcine respiratory tract lacking enzymes of the oxidative branch of the tricarboxylic acid (TCA) cycle. We previously claimed that A. pleuropneumoniae instead uses the reductive branch in order to generate energy and metabolites. Here we show that bicarbonate and oxaloacetate supported anaerobic growth of A. pleuropneumoniae. Isotope mass spectrometry revealed heterotrophic fixation of carbon from stable isotope labeled bicarbonate by A. pleuropneumoniae which was confirmed by nano-scale secondary ion mass spectrometry at a single cell level. By gas chromatography-combustion-isotope ratio mass spectrometry we could further show that the labeled carbon atom is mainly incorporated into the amino acids aspartate and lysine, which are derived from the TCA metabolite oxaloacetate. We therefore suggest that carbon fixation occurs at the interface of glycolysis and the reductive branch of the TCA cycle. The heme precursor -aminolevulinic acid supported growth of A. pleuropneumoniae similar to bicarbonate implying that anaplerotic carbon fixation is needed for heme synthesis. However, deletion of potential carbon fixing enzymes including PEP-carboxylase (PEPC), PEP-carboxykinase (PEPCK), malic enzyme and oxaloacetate decarboxylase as well as various combinations thereof did not affect carbon fixation. Interestingly, generation of a deletion mutant lacking all four enzymes was not possible suggesting that carbon fixation in A. pleuropneumoniae is an essential metabolic pathway controlled by a redundant set of enzymes. A double deletion mutant lacking PEPC and PEPCK was not impaired in carbon fixation in vitro, but showed reduction of virulence in a pig infection model.
Lauren Zebertavage, Shelly Bambina, Jessica Shugart, Alejandro Alice, Kyra D. Zens, Peter Lauer, Bill Hanson, Michael J. Gough, Marka R. Crittenden, Keith S. Bahjat
by Lauren Zebertavage, Shelly Bambina, Jessica Shugart, Alejandro Alice, Kyra D. Zens, Peter Lauer, Bill Hanson, Michael J. Gough, Marka R. Crittenden, Keith S. Bahjat
Dysregulated signaling via the epidermal growth factor receptor (EGFR)-family is believed to contribute to the progression of a diverse array of cancers. The most common variant of EGFR is EGFRvIII, which results from a consistent and tumor-specific in-frame deletion of exons 2–7 of the EGFR gene. This deletion generates a novel glycine at the junction and leads to constitutive ligand-independent activity. This junction forms a novel shared tumor neo-antigen with demonstrated immunogenicity in both mice and humans. A 21-amino acid peptide spanning the junctional region was selected, and then one or five copies of this 21-AA neo-peptide were incorporated into live-attenuated Listeria monocytogenes-based vaccine vector. These vaccine candidates demonstrated efficient secretion of the recombinant protein and potent induction of EGFRvIII-specific CD8+ T cells, which prevented growth of an EGFRvIII-expressing squamous cell carcinoma. These data demonstrate the potency of a novel cancer-specific vaccine candidate that can elicit EGFRvIII-specific cellular immunity, for the purpose of targeting EGFRvIII positive cancers that are resistant to conventional therapies.
Daniel Grinnan, Laszlo Farkas
American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 12, Page 1460-1461, June 15, 2019.
Hsu C, Chang I, Hsieh P, et al.
AbstractKlebsiella pneumoniae is an important human pathogen causing hospital-acquired and community-acquired infections. Systemic K. pneumoniae infections may be preceded by gastrointestinal colonization, but the basis of this bacterium’s interaction with the intestinal epithelium remains unclear. Here, we report that the K. pneumoniae Sap (sensitivity to antimicrobial peptides) transporter contributes to bacterial–host cell interactions and in vivo virulence. Gene deletion showed that sapA is required for the adherence of a K. pneumoniae blood isolate to intestinal epithelial, lung epithelial, urinary bladder epithelial, and liver cells. The ΔsapA mutant was deficient for translocation across intestinal epithelial monolayers, macrophage interactions, and induction of proinflammatory cytokines. In a mouse gastrointestinal infection model, ΔsapA yielded significantly decreased bacterial loads in liver, spleen and intestine, reduced liver abscess generation, and decreased mortality. These findings offer new insights into the pathogenic interaction of K. pneumoniae with the host gastrointestinal tract to cause systemic infection.
Ortega, Sterling B.; Pandiyan, Poornima; Windsor, Jana; Torres, Vanessa O.; Selvaraj, Uma M.; Lee, Amy; Morriss, Michael; Tian, Fenghua; Raman, Lakshmi; Stowe, Ann M.
Extracorporeal membrane oxygenation provides short-term cardiopulmonary life support, but is associated with peripheral innate inflammation, disruptions in cerebral autoregulation, and acquired brain injury. We tested the hypothesis that extracorporeal membrane oxygenation also induces CNS-directed adaptive immune responses which may exacerbate extracorporeal membrane oxygenation-associated brain injury.
A single center prospective observational study.
Pediatric and cardiac ICUs at a single tertiary care, academic center.
Twenty pediatric extracorporeal membrane oxygenation patients (0–14 yr; 13 females, 7 males) and five nonextracorporeal membrane oxygenation Pediatric Logistic Organ Dysfunction score matched patients
Measurements and Main Results:
Venous blood samples were collected from the extracorporeal membrane oxygenation circuit at day 1 (10–23 hr), day 3, and day 7 of extracorporeal membrane oxygenation. Flow cytometry quantified circulating innate and adaptive immune cells, and CNS-directed autoreactivity was detected using an in vitro recall response assay. Disruption of cerebral autoregulation was determined using continuous bedside near-infrared spectroscopy and acquired brain injury confirmed by MRI. Extracorporeal membrane oxygenation patients with acquired brain injury (n = 9) presented with a 10-fold increase in interleukin-8 over extracorporeal membrane oxygenation patients without brain injury (p < 0.01). Furthermore, brain injury within extracorporeal membrane oxygenation patients potentiated an inflammatory phenotype in adaptive immune cells and selective autoreactivity to brain peptides in circulating B cell and cytotoxic T cell populations. Correlation analysis revealed a significant relationship between adaptive immune responses of extracorporeal membrane oxygenation patients with acquired brain injury and loss of cerebral autoregulation.
We show that pediatric extracorporeal membrane oxygenation patients with acquired brain injury exhibit an induction of pro-inflammatory cell signaling, a robust activation of adaptive immune cells, and CNS-targeting adaptive immune responses. As these patients experience developmental delays for years after extracorporeal membrane oxygenation, it is critical to identify and characterize adaptive immune cell mechanisms that target the developing CNS.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Drs. Ortega, Pandiyan, Raman, and Stowe contributed equally.
Drs. Ortega and Pandiyan designed, performed, and analyzed the immunology-based assays and co-wrote the article. Dr. Pandiyan performed and analyzed the immunology-based assays as well as recruited patients and co-wrote the article. Ms. Windsor and Dr. Lee recruited patients and Ms. Windsor, Ms. Torres, Ms. Selvaraj, and Dr. Stowe processed samples. Dr. Tian quantified autoregulation disruption based on wavelength transform coherence. Dr. Morriss scored all neuroimaging. Drs. Raman and Stowe designed and supervised the study and co-wrote the article. All authors read, edited, and approved of the article.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).
Drs. Tian and Raman were supported, in part by, American Heart Association (AHA) Beginning-Grant-in Aid (15BGIA25860045). Drs. Pandiyan and Raman were funded by Extracorporeal Life Support Organization research grant and UT Southwestern Center for Translational Medicine award. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001105. Dr. Stowe was supported from the AHA (14SDG 18410020), National Institutes of Health/National Institute of Neurological Disorders and Stroke (NS088555), Dr. Ortega (14POST20480373) and Ms. Selvaraj (17PRE33660147) from the AHA.
Drs. Ortega’s, Pandiyan’s, Windsor’s, and Stowe’s institutions received funding from Extracorporeal Life Support Organization and National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under award number UL1TR001105. Drs. Ortega, Pandiyan, Windsor, Torres, Raman, and Stowe received support for article research from the NIH. Dr. Tian’s institution received funding from the American Heart Association, and he disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest.
Address requests for reprints to: Ann M. Stowe, PhD, Department of Neurology, University of Kentucky College of Medicine, 741 S. Limestone St., BBSRB 363, Lexington, KY, 40536. E-mail: Ann.Stowe@uky.edu
Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Colin N Chao,
Isaiah O. Genga,
Pamela A. Were,
Ismail D. Legason,
Robert J. Biggar,
James J. Goedert,
Ruth M. Pfeiffer,
Sam M. Mbulaiteye
Tanzania experiences significant malaria‐related morbidity and mortality, but accurate data are scarce. We update the data on patterns of low‐grade Plasmodium falciparum malaria infection among children in northern Tanzania.
P. falciparum malaria prevalence (pfPR) was assessed in a representative sample of 819 children enrolled in 94 villages in northern Tanzania between October 2015 and August 2016, using a complex survey design. Individual‐ and household‐level risk‐factors for pfPR were elicited using structured questionnaires. pfPR was assessed using rapid diagnostic tests (RDTs) and thick film microscopy (TFM). Associations with pfPR, based on RDT, were assessed using adjusted odds ratios (aOR) and confidence intervals (CI) from weighted survey logistic regression models.
pfPR was 39.5% (95% CI: 31.5, 47.5) by RDT and 33.4% (26.0, 40.6) by TFM. pfPR by RDT was inversely associated with higher‐education parents, especially mothers (5‐7 years of education: aOR 0.55; 95% CI: 0.31, 0.96, senior secondary education: aOR 0.10; 95% CI: 0.02, 0.55), living in a house near the main road (aOR 0.34; 95% CI: 0.15, 0.76), in a larger household (2 rooms: aOR 0.40; 95% CI: 0.21, 0.79, more than 2 rooms OR 0.35; 95% CI: 0.20, 0.62). Keeping a dog near or inside the house was positively associated with pfPR (aOR 2.01; 95% CI: 1.26, 3.21). pfPR was not associated with bed‐net use or indoor residual spraying.
Nearly 40% of children in northern Tanzania had low‐grade malaria antigenemia. Higher parental education and household metrics but not mosquito bed‐net use, were inversely associated with pfPR.
This article is protected by copyright. All rights reserved.
Dubé M, Chan E, Lake J, et al.
AbstractBackgroundDipeptidyl peptidase-4 (DPP-4) inhibitors have pleotropic anti-inflammatory and immune regulatory effects in addition to their glucoregulatory actions. We evaluated inflammation and immune markers in suppressed HIV infection during treatment with the DPP-4 inhibitor sitagliptin.MethodsVirologically suppressed adults with HIV without diabetes mellitus on stable ART with ≥100/mm 3 CD4 cells were randomized to 16 weeks of sitagliptin 100 mg/d vs. placebo in a multicenter trial. The primary endpoint was the change in plasma soluble CD14 (sCD14) from baseline to week 15/16. Additional soluble biomarkers, and lymphocyte and monocyte activation were assessed.ResultsNinety participants were randomized, and 42 from each arm were included in per-protocol analyses. Evaluable participants were 45% non-Hispanic white, 38% non-Hispanic black, 15% Hispanic, median age of 51 years, 83% male, with median CD4 count 602 cells/mm 3. At week 15/16, there was no difference in sCD14 change between the two arms (p=0.69). Relative to placebo, the sitagliptin arm had 47% greater decline in CXCL10 (95% CI:-57,-35) at week 15 (p
Huang, Y., Alumasa, J. N., Callaghan, L. T., Baugh, S., Rae, C., Keiler, K. C., McGillivray, S. M.
Staphylococcus aureus is a leading cause of infection in the US and, due to the rapid development of resistance, new antibiotics are constantly needed. Trans-translation is a particularly promising antibiotic target because it is conserved in many bacterial species, is critical to bacterial survival, and is unique among prokaryotes. We have investigated the potential of KKL-40, a small molecule inhibitor of trans-translation, and find that it inhibits both methicillin-susceptible and methicillin-resistant strains of S. aureus. KKL-40 is also effective against Gram-positive pathogens including a vancomycin-resistant strain of Enterococcus faecalis, Bacillus subtilis and Streptococcus pyogenes, although its performance with Gram-negatives is mixed. KKL-40 synergistically interacts with the human antimicrobial peptide LL-37, a member of the cathelicidin family, to inhibit S. aureus but not other antibiotics tested including daptomycin, kanamycin or erythromycin. KKL-40 is not cytotoxic to HeLa cells at concentrations that are 100-fold greater than the effective MIC. We also find that S. aureus develops minimal resistance to KKL-40 even after multi-day passage in sub-lethal concentrations. Therefore, trans-translation inhibitors could be a particularly promising drug target against S. aureus, not only because of their ability to inhibit bacterial growth, but also because of their potential to simultaneously render S. aureus more susceptible to host antimicrobial peptides.
Melanie S. Vacchio, Thomas Ciucci, Yayi Gao, Masashi Watanabe, Mariah Balmaceno-Criss, Mitchell T. McGinty, Allan Huang, Qi Xiao, Cameron McConkey, Yongmei Zhao, Jyoti Shetty, Bao Tran, Marion Pepper, Golnaz Vahedi, Marc K. Jenkins, Dorian B. McGavern, Rémy Bosselut
The transcription factor Thpok is essential for the development of CD4+ T cells. Vacchio et al. show that in mature T cells, Thpok drives the expression of the transcriptional regulators Bcl6 and Maf to promote the differentiation of CD4+ T cells into T follicular helper (Tfh) cells, thus linking the CD4+ lineage to Tfh cell differentiation.
Mendez, J. M., Kolora, L. D., Lemon, J. S., Dupree, S. L., Keestra-Gounder, A. M.
Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular pattern-recognition receptor (PRR) responsible for sensing bacterial peptidoglycan fragments. Stimulation of NOD1 leads to a robust innate immune response via activation of the major transcription factor NF-B. In addition to peptidoglycan sensing, NOD1, and the closely related PRR NOD2, have been linked to inflammation by responding to the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR). Here we show, that differential ER stress induction renders cells more susceptible to a Salmonella Typhimurium infection in a NOD1-dependent manner measured by increased NF-kB activation and cytokine expression. In HeLa57A cells, stably transfected with a NF-B::luciferase reporter, we show that cells undergoing ER stress induced by thapsigargin display a significant increase in NF-B activation in response to NOD1 stimulation by C12-iE-DAP and the S. Typhimurium effector protein SopE. Tunicamycin-induced ER stress had no effect on NOD1 stimulated NF-B activation. We further show that the mouse intestinal epithelial cell line MODE-K and RAW264.7 macrophages are more responsive to Salmonella infection when treated with thapsigargin but not with tunicamycin. These profound differences between thapsigargin and tunicamycin treated cells on inflammation suggest that different components downstream of the UPR contribute to NOD1 activation. We found that the NOD1-induced inflammatory response is dependent on protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) activation in conjunction with stimulation of the inositol triphosphate receptor (IP3R). Together, these results suggest that differential UPR activation makes cells more responsive to bacterial infections in a NOD1-dependent manner.
Richards, J. P., Cai, W., Zill, N. A., Zhang, W., Ojha, A. K.
Mycobacterium tuberculosis (Mtb) spontaneously grows at the air-medium interface forming pellicle biofilms, which harbor more drug tolerant persisters than planktonic cultures. The underlying basis for increased persisters in Mtb biofilms is unknown. Using a Tn-seq approach, we show here that multiple genes that are necessary for fitness of Mtb cells within biofilms, but not in planktonic cultures, are also implicated in tolerance of bacilli to a diverse set of stressors and antibiotics. Thus, development of Mtb biofilms appears to be associated with an enrichment of population, in which challenging growth conditions within biofilm architecture select for cells that maintain intrinsic tolerance to exogenous stresses including antibiotic exposure. We further observed that the intrinsic drug tolerance of constituent cells of a biofilm determines the frequency of persisters. These findings together allow us to propose that the selection of elite cells during biofilm development promotes the frequency of persisters. Furthermore, probing the possibility that the population enrichment is an outcome of unique environment within biofilms, we demonstrate biofilm-specific induction in the synthesis of isonitrile lipopeptides (INLP). Mutation analysis indicates that INLP is necessary for the architecture development of Mtb biofilms. In summary, the study offers an insight into persistence of Mtb biofilms under antibiotic exposure, while identifying INLP as a potential biomarker for further investigation of this phenomenon.
Janet J, Myers; Mi-Suk, Kang Dufour; Kimberly A, Koester; Ifeoma, Udoh; Remi, Frazier; Rebecca, Packard; Kristin, Kennedy; Xavier, Erguera; Horowitz, Jessica; Robert, Grant; Jeffrey H, Burack
Young men of color who have sex with men (YMSM) face a continual increase in rates of HIV infection. Pre-exposure prophylaxis (PrEP) is an important prevention method for these young men.
The Connecting Resources for Urban Sexual Health (CRUSH) demonstration project provided sexual health services, including PrEP, to YMSM aged 18-29. We report on adherence and factors influencing it.
Participants were offered HIV and sexually transmitted infection (STI) testing, prevention counseling, PrEP, and when appropriate, STI treatment and post-exposure prophylaxis (PEP). Participants taking PrEP had erythrocyte tenofovir diphosphate (TFV-DP) and emtricitabine levels measured via dried blood spot testing at 4, 12, and 24 weeks to estimate medication adherence.Participants also completed surveys to assess demographic and psychosocial measures.
From February 2014 to November 2015, CRUSH enrolled 257 participants. Ninety-three percent started PrEP, 81% of whom initiated it at their first visit. Twelve percent required PEP prior to starting PrEP. Adherence at protective levels was initially high with 87% demonstrating levels consistent with at least 4 doses per week at week 4, compared to 77% at the 48-week follow-up. African American race, exposure to violence and having survival needs were associated with significantly lower levels of adherence (OR: 0.33; CI: 0.11-0.97, p
Ling-juan Zhang, Stella Xiang Chen, Christian F. Guerrero-Juarez, Fengwu Li, Yun Tong, Yuqiong Liang, Marc Liggins, Xu Chen, Hao Chen, Min Li, Tissa Hata, Ye Zheng, Maksim V. Plikus, Richard L. Gallo
Dermal immature adipocytes fight against Staphylococcus aureus infection by secreting antimicrobial peptides during adipogenesis. Zhang et al. demonstrate that activation of the TGF-β pathway suppresses the adipogenic potential of dermal fibroblasts and therefore leads to an age-dependent loss of antimicrobial protection from dermal fat.
Kim, J.-H., Chaurasia, A. K., Batool, N., Ko, K. S., Kim, K. K.
Precise enumeration of living intracellular bacteria is the key step to estimate invasion potential of pathogens and host immune responses, and understand the mechanism and kinetics of bacterial pathogenesis. Therefore, quantitative assessment of host-pathogen interaction is essential for developing novel antibacterial therapeutics for infectious disease. Gentamicin protection assay (GPA) is the most widely used method for these estimations by counting the colony forming units (CFU) of intracellular living pathogens. Here, we assessed the longstanding drawbacks of GPA by employing an anti-staphylococcal endopeptidase, as a bactericidal agent to kill the extracellular Staphylococcus aureus. We found that the difference between two methods in the recovery of intracellular CFU of S. aureus was about five times. We proved that the accurate intracellular CFU could not be precisely determined by GPA due to the internalization of gentamicin into host cells during the extracellular bacterial killing. We further demonstrated that the lysostaphin-mediated extracellular bacterial clearing has advantages for measuring the kinetics of bacterial internalization within a minute timescale due to the fast and tunable activity, and impermeability of protein to host cell membrane. From these results, we propose that accurate quantification of intracellular bacteria and measurement of internalization kinetics can be achieved by employing an enzyme-mediated killing of extracellular bacteria (enzyme protection assay, EPA) than the host-permeable gentamicin which is known to alter the host physiology.
The ongoing transmission of Mycobacterium (M.) leprae reflected in a very slow decline in leprosy incidence, forces us to be innovative and conduct cutting-edge research. Single dose rifampicin (SDR) as post-exposure prophylaxis (PEP) for contacts of leprosy patients, reduces their risk to develop leprosy by 60%. This is a promising new preventive measure that can be integrated into routine leprosy control programmes, as is being demonstrated in the Leprosy Post-Exposure Programme that is currently ongoing in eight countries.
The limited (60%) effectiveness of SDR is likely due to the fact that some contacts have a preclinical infection beyond the early stages for which SDR is not sufficient to prevent the development of clinical signs and symptoms of leprosy. An enhanced regimen, more potent against a higher load of leprosy bacteria, would increase the effectiveness of this preventive measure significantly.
The Netherlands Leprosy Relief (NLR) is developing a multi-country study aiming to show that breaking the chain of transmission of M. leprae is possible, evidenced by a dramatic reduction in incidence. In this study the assessment of the effectiveness of an enhanced prophylactic regimen for leprosy is an important component. To define the so called PEP++ regimen for this intervention study, NLR convened an Expert Meeting that was attended by clinical leprologists, public health experts, pharmacologists, dermatologists and microbiologists.
The Expert Meeting advised on combinations of available drugs, with known efficacy against leprosy, as well as on the duration of the intake, aiming at a risk reduction of 80–90%. To come to a conclusion the Expert Meeting considered the bactericidal, sterilising and bacteriostatic activity of the potential drugs. The criteria used to determine an optimal enhanced regimen were: effectiveness, safety, acceptability, availability, affordability, feasibility and not inducing drug resistance.
The Expert Meeting concluded that the enhanced regimen for the PEP++ study should comprise three standard doses of rifampicin 600 mg (weight adjusted when given to children) plus moxifloxacin 400 mg given at four-weekly intervals. For children and for adults with contraindications for moxifloxacin, moxifloxacin should be replaced by clarithromycin 300 mg (weight adjusted).
McCall, I. C., Shah, N., Govindan, A., Baquero, F., Levin, B. R.
Non-replicating bacteria are known to be (or at least commonly thought to be) refractory to antibiotics to which they are genetically susceptible. Here, we explore the sensitivity to killing by bactericidal antibiotics of three classes of non-replicating populations of planktonic bacteria; (1) stationary phase, when the concentration of resources and/or nutrients are too low to allow for population growth; (2) persisters, minority subpopulations of susceptible bacteria surviving exposure to bactericidal antibiotics; (3) antibiotic-static cells, bacteria exposed to antibiotics that prevent their replication but kill them slowly if at all, the so-called bacteriostatic drugs. Using experimental populations of Staphylococcus aureus Newman and Escherichia coli K12 (MG1655) and respectively 9 and 7 different bactericidal antibiotics, we estimate the rates at which these drugs kill these different types of non-replicating bacteria. Contrary to the common belief that bacteria that are non-replicating are refractory to antibiotic-mediated killing, all three types of non-replicating populations of these Gram-positive and Gram-negative bacteria are consistently killed by aminoglycosides and the peptide antibiotics, daptomycin and colistin, respectively. This result indicates that non-replicating cells, irrespectively of why they do not replicate, have an almost identical response to bactericidal antibiotics. We discuss the implications of these results to our understanding of the mechanisms of action of antibiotics and the possibility of adding a short-course of aminoglycosides or peptide antibiotics to conventional therapy of bacterial infections.
Pepper, Dominique J.; Sun, Junfeng; Cui, Xizhong; Welsh, Judith; Natanson, Charles; Eichacker, Peter Q.
To address three controversial components in the Centers for Medicare and Medicaid Service’s sepsis bundle for performance measure (SEP-1): antibiotics within 3 hours, a 30 mL/kg fluid infusion for all hypotensive patients, and repeat lactate measurements within 6 hours if initially elevated. We hypothesized that antibiotic- and fluid-focused bundles like SEP-1 would probably show benefit, but evidence supporting specific antibiotic timing, fluid dosing, or serial lactate requirements would not be concordant. Therefore, we performed a meta-analysis of studies of sepsis bundles like SEP-1.
PubMed, Embase, ClinicalTrials.gov through March 15, 2018.
Studies comparing survival in septic adults receiving versus not receiving antibiotic- and fluid-focused bundles.
Two investigators (D.J.P., P.Q.E.).
Seventeen observational studies (11,303 controls and 4,977 bundle subjects) met inclusion criteria. Bundles were associated with increased odds ratios of survival (odds ratio [95% CI]) in 15 studies with substantial heterogeneity (I2 = 61%; p < 0.01). Survival benefits were consistent in the five largest (1,697–12,486 patients per study) (1.20 [1.11–1.30]; I2 = 0%) and six medium-sized studies (167–1,029) (2.03 [1.52–2.71]; I2 = 8%) but not the six smallest (64–137) (1.25 [0.42–3.66]; I2 = 57%). Bundles were associated with similarly increased survival benefits whether requiring antibiotics within 1 hour (n = 7 studies) versus 3 hours (n = 8) versus no specified time (n = 2); or 30 mL/kg fluid (n = 7) versus another volume (≥ 2 L, n = 1; ≥ 20 mL/kg, n = 2; 1.5–2 L or 500 mL, n = 1 each; none specified, n = 4) (p = 0.19 for each comparison). In the only study employing serial lactate measurements, survival was not increased versus others. No study had a low risk of bias or assessed potential adverse bundle effects.
Available studies support the notion that antibiotic- and fluid-focused sepsis bundles like SEP-1 improve survival but do not demonstrate the superiority of any specific antibiotic time or fluid volume or of serial lactate measurements. Until strong reproducible evidence demonstrates the safety and benefit of any fixed requirement for these interventions, the present findings support the revision of SEP-1 to allow flexibility in treatment according to physician judgment.
The National Institutes of Health had no role in study design or data collection, analysis, or interpretation.
Drs. Pepper and Eichacker had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects, and drafted the article. Dr. Pepper, Dr. Sun, Ms. Welsh, and Drs. Cui, Natanson, and Eichacker contributed substantially to the study design, data analysis, and interpretation, and approve the final version to be published. Dr. Sun, Ms. Welsh, and Drs. Cui and Natanson revised the article critically for important intellectual content.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).
Supported, in part, by National Institutes of Health intramural funding.
Drs. Pepper, Sun, Cui, Natanson, and Eichacker received support for article research from the National Institutes of Health. Drs. Pepper, Sun, and Cui, Ms. Welsh, and Dr. Eichacker disclosed government work.
Clinical Trial Registration numbers: International Prospective Register of Systematic Reviews (PROSPERO) 2017: CRD42017080258.
For information regarding this article, E-mail: firstname.lastname@example.org
Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Andreoni, F., Toyofuku, M., Menzi, C., Kalawong, R., Mairpady Shambat, S., Francois, P., Zinkernagel, A. S., Eberl, L.
Bacterial membrane vesicles research has so far mainly focussed on Gram-negative bacteria. Only recently Gram-positive bacteria have been demonstrated to produce and release extracellular membrane vesicles (MVs) that contribute to bacterial virulence. Although treatment of bacteria with antibiotics is a well-established trigger of bacterial MVs formation, the underlying mechanisms are poorly understood. In this study we show that antibiotics can induce MVs through different routes in the important human pathogen Staphylococcus aureus. DNA damaging agents and antibiotics inducing the SOS response triggered vesicle formation in lysogenic strains of S. aureus but not in their phage-devoid counterparts. β-lactam antibiotics flucloxacillin and ceftaroline increased vesicle formation in a prophage-independent manner by weakening the peptidoglycan layer. We present evidence that the amount of DNA associated with MVs formed by phage lysis is higher than that of MVs formed by β-lactam antibiotics-induced blebbing. The purified MVs derived from S. aureus protected the bacteria from challenge with daptomycin, a membrane-targeting antibiotic, both in vitro and ex vivo in whole blood. In addition, the MVs protected S. aureus from killing in whole blood, indicating that antibiotic-induced MVs function as a decoy and thereby contribute to the survival of the bacterium.
Bettina Winzeler, Nicole Cesana-Nigro, Julie Refardt, Deborah R Vogt, Cornelia Imber, Benedict Morin, Milica Popovic, Michelle Steinmetz, Clara O Sailer, Gabor Szinnai, Irina Chifu, Martin Fassnacht, Mirjam Christ-Crain
Arginine-stimulated copeptin measurements are an innovative test for diabetes insipidus with high diagnostic accuracy, and could be a simplified, novel, and safe diagnostic approach to diabetes insipidus in clinical practice.
McLean, K., Holmes, E. A., Penewit, K., Lee, D. K., Hardy, S. R., Ren, M., Krist, M. P., Huang, K., Waalkes, A., Salipante, S. J.
Adaptation of Staphylococcus aureus to host microenvironments during chronic infection involves spontaneous mutations, yet changes underlying adaptive phenotypes remain incompletely explored. Here we employed artificial selection and whole genome sequencing to better characterize spontaneous chromosomal mutations that alter two pathogenicity phenotypes relevant to chronic infection in S. aureus: intracellular invasiveness and intracellular cytotoxicity. We identified 23 genes whose alteration coincided with enhanced virulence, 11 that were previously known and 12 of which (52%) had no previously described role in S. aureus pathogenicity. Using precision genome editing, transposon mutants, and gene complementation, we empirically assessed the contributions of individual genes to the two virulence phenotypes. We functionally validated 14 of 21 genes tested as measurably influencing invasion and/or cytotoxicity, including 8 newly implicated by this study. We identified inactivating mutations (murA, ndhC, and a hypothetical membrane protein) and gain-of-function mutations (aroE Thr182Ile, yhcF Thr74Ile, and Asp486Glu in a hypothetical peptidase) in previously unrecognized S. aureus virulence genes that enhance pathogenesis when introduced into a clean genetic background, as well as a novel activating mutation in known virulence regulator saeS (Ala106Thr). Investigation of potentially epistatic interactions identified a tufA mutation (Ala271Val) that enhances virulence only in the context of purine operon repressor (purR) inactivation. This project reveals a functionally diverse range of genes affected by gain- or loss-of-function mutations that contribute to S. aureus adaptive virulence phenotypes. More generally, the work establishes artificial selection as a means to determine the genetic mechanisms underlying complex bacterial phenotypes relevant to adaptation during infection.
Nakamura, I., Ohsumi, K., Takeda, S., Katsumata, K., Matsumoto, S., Akamatsu, S., Mitori, H., Nakai, T.
Current therapies against invasive pulmonary aspergillosis (IPA) have a limited cure rate. Given that a delay in treatment initiation may be fatal, a new drug with rapid -onset and potent antifungicidal activity is needed. The novel cyclic hexapeptide ASP2397 (currently known as VL-2397) exhibited antifungal activity against Aspergillus fumigatus (including azole-sensitive and azole-resistant isolates), A. terreus, and A. flavus at a MIC range of 1 to 4 μg/ml in human serum. Time-kill curve experiments showed that ASP2397 reduced germinated conidia of A. fumigatu by more than 1-log10 CFUs within 6 hours. In addition, ASP2397 inhibited hyphal elongation from germinated conidia of A. fumigatus, A. terreus, and A. flavus more rapidly than voriconazole. When treatment initiation was delayed in an IPA mouse model, ASP2397 had superior efficacy over posaconazole, with 100% survival and over 1-log10 CFU/g reduction in lung fungal burden. Histopathological investigation of lungs also showed that ASP2397 markedly suppressed disease progression. To clarify its mechanism of action, we generated a UV-induced mutant of A. fumigatus with low susceptibility to ASP2397. The mutant had a point mutation in the siderophore transporter gene sit1, which is absent in mammalian cells. These findings suggest that ASP2397 may improve clinical treatment options for IPA.
Ascher, Simon B.; Scherzer, Rebecca; Nishtala, Arvind; Jotwani, Vasantha; Grunfeld, Carl; Parikh, Chirag R.; Ng, Derek; Wang, Ruibin; Palella, Frank J.; Shlipak, Michael G.; Estrella, Michelle M.
Chronic kidney disease (CKD) occurs commonly among HIV-infected persons. Statins may delay CKD onset and progression via their cholesterol-lowering and pleiotropic effects.
Among 850 HIV-infected men from the Multicenter AIDS Cohort Study with stored urine samples (2009-2011), we evaluated cross-sectional associations of statin use with urine biomarkers of kidney damage (albumin-to-creatinine ratio [ACR], alpha-1-microglobulin, interleukin-18, kidney injury molecule-1, and procollagen type III N-terminal propeptide) using multivariable linear regression. We evaluated the longitudinal associations of statin use with annual change in estimated glomerular filtration rate by creatinine (eGFR) using linear mixed models, and with incident proteinuria and incident CKD (eGFR
Carlos Iniesta, Débora Álvarez-del Arco, Luis Miguel García-Sousa, Belén Alejos, Asunción Díaz, Nieves Sanz, Jorge Garrido, Michael Meulbroek, Ferran Pujol, Santiago Moreno, María José Fuster-Ruiz de Apocada, Pep Coll, Antonio Antela, Jorge del Romero, Oskar Ayerdi, Melchor Riera, Juanse Hernández, Julia del Amo
by Carlos Iniesta, Débora Álvarez-del Arco, Luis Miguel García-Sousa, Belén Alejos, Asunción Díaz, Nieves Sanz, Jorge Garrido, Michael Meulbroek, Ferran Pujol, Santiago Moreno, María José Fuster-Ruiz de Apocada, Pep Coll, Antonio Antela, Jorge del Romero, Oskar Ayerdi, Melchor Riera, Juanse Hernández, Julia del Amo
Objective To assess the awareness, knowledge, use, and willingness to use and need of PrEP among men who have sex with men (MSM) and transgender women (TW) who attended World Gay Pride (WGP) 2017 in Madrid. Design and methods Online survey. Participants were recruited through gay-oriented dating apps and HIV Non-Governmental Organizations´ social media. Inclusion criteria included being MSM or TW, age 18 years old or above, and having attended WGP in Madrid. Information regarding the participant’s awareness and knowledge, use or willingness to use, and need for PrEP was collected, as well as sociodemographic characteristics. Participants were considered to be in need of PrEP if they met one of the following indication criteria: having practiced unprotected anal intercourse with more than 2 partners, having practiced chemsex, or having engaged in commercial sex—all in the preceding 6 months. Descriptive and multivariable analyses with logistic regression were conducted. Results 472 participants met the inclusion criteria and completed the questionnaire. The mean age was 38, 97.7% were MSM, 77% had a university education, and 85% were living in Spain, mostly in big cities. Overall, 64% of participants were aware of PrEP, but only 33% knew correctly what PrEP was. 67% of HIV-negative participants were willing to take PrEP, although only 5% were taking it during WGP, mostly due to lack of access. 43% of HIV-negative respondents met at least one PrEP indication criteria. For HIV-negative men living in Spain, university education and living in big cities was associated with PrEP awareness. Lower education level and meeting PrEP criteria was associated with willingness to use PrEP. Conclusions Our study shows that among MSM attending WGP 2017 in Madrid, there was limited PrEP awareness, low accuracy of PrEP knowledge, and a high need and willingness to use PrEP. Health authorities should strengthen existing preventive strategies and implement PrEP.
Patrick Ebner, Friedrich GÃ¶tz
The excretion of cytoplasmic and signal-peptide-less proteins (ECP) by microorganisms and eukaryotes remains a fascinating topic. In principle, it appears to be a waste of energy. However, it turns out that â€“ extracellularly â€“ some cytoplasmic proteins (CPs) exert a completely different function such as contributing to pathogenicity or evasion of the immune system. Such CPs have been referred to as â€˜moonlightingâ€™ proteins. ECP is boosted by many endogenous or external factors that impair the membrane or cell wall structure.
Ersoy, S. C., Abdelhady, W., Li, L., Chambers, H. F., Xiong, Y. Q., Bayer, A. S.
Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major healthcare concern, especially infective endocarditis (IE). Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as ‘resistant' to β-lactams, often leading to use of costly and/or toxic treatment regimens. In this investigation, five prototype MRSA strains, representing the range of genotypes in current clinical circulation, were studied. We identified two distinct MRSA phenotypes upon AST using standard media, with or without sodium bicarbonate (NaHCO3) supplementation: one highly susceptible to the anti-staphylococcal β-lactams, oxacillin and cefazolin (‘NaHCO3-responsive’) and one resistant to such agents (‘NaHCO3-nonresponsive’). These phenotypes accurately predicted clearance profiles of MRSA from target tissues in experimental MRSA IE treated with each β-lactam. Mechanistically, NaHCO3 reduced expression of two key genes involved in the MRSA phenotype, mecA and sarA, leading to decreased production of penicillin-binding protein (PBP) 2a (that mediates methicillin resistance), in NaHCO3-responsive (but not in NaHCO3-nonresponsive) strains. Moreover, both cefazolin and oxacillin synergistically killed NaHCO3-responsive strains in the presence of the host defense antimicrobial peptide (LL-37) in NaHCO3-supplemented media. These findings suggest that AST of MRSA strains in NaHCO3-containing media may potentially identify infections caused by NaHCO3-responsive strains that are appropriate for β-lactam therapy.
Joris Koetsveld, Alexander E. Platonov, Konstantin Kuleshov, Alex Wagemakers, Dieuwertje Hoornstra, Wim Ang, Sandor Szekeres, Gilian L.A. van Duijvendijk, Erol Fikrig, Monica E. Embers, Hein Sprong, Joppe W. Hovius
Borrelia miyamotoi is a relapsing fever Borrelia, transmitted by hard (Ixodes) ticks, which are also the main vector for Borrelia burgdorferi. A widely used test for serodiagnosis of Lyme borreliosis is an EIA based on the C6 peptide of the B. burgdorferi sl VlsE protein. We set out to study C6 reactivity upon infection with B. miyamotoi in a large well-characterized set of Borrelia miyamotoi disease (BMD) patient sera and in experimental murine infection.
Helene Botella, Julien Vaubourgeix
Fluorescent amino acid analogs have proven to be useful tools for studying the dynamics of peptidoglycan metabolism. García-Heredia and colleagues showed that their route of incorporation differs depending on the adjunct fluorophore and applied this property to investigate mycobacterial peptidoglycan synthesis and remodeling with heightened granularity.
Rebecca J Gordon, Michael A Levine
X-linked hypophosphataemia is the most common form of genetic rickets, and is characterised by low circulating concentrations of phosphorus that impair skeletal mineralisation and result in rickets in growing children and osteomalacia in adults.1 X-linked hypophosphataemia is caused by mutations in PHEX (phosphate-regulating endopeptidase homolog, X-linked), which encodes a transmembrane endopeptidase.2 Although the mechanism is uncertain, loss of PHEX leads to raised plasma concentrations of fibroblast growth factor 23 (FGF23), the best-characterised member of a family of phosphate-regulating hormones termed phosphatonins.
Swidergall M, Khalaji M, Solis N, et al.
AbstractBackgroundCandidalysin is a cytolytic peptide toxin secreted by Candida albicans hyphae and has significantly advanced our understanding of fungal pathogenesis. Candidalysin is critical for mucosal C albicans infections and is known to activate epithelial cells to induce downstream innate immune responses that are associated with protection or immunopathology during oral or vaginal infections. Furthermore, candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes. However, the role of candidalysin in driving systemic infections is unknown.MethodsIn this study, using candidalysin-producing and candidalysin-deficient C albicans strains, we show that candidalysin activates mitogen-activated protein kinase (MAPK) signaling and chemokine secretion in endothelial cells in vitro.ResultsCandidalysin induces immune activation and neutrophil recruitment in vivo, and it promotes mortality in zebrafish and murine models of systemic fungal infection.ConclusionsThe data demonstrate a key role for candidalysin in neutrophil recruitment and fungal virulence during disseminated systemic C albicans infections.
This Medical Letter review summarizes the cardiovascular benefits and adverse effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors (empagliflozin, canagliflozin) and glucagon-like peptide 1 (GLP-1) receptor agonists (liraglutide, semaglutide) in patients with type 2 diabetes at risk for cardiovascular disease.
Derek B. Laskar, Michael Rose, Raavi Gupta, Herbert B. Tanowitz and M. A. Haseeb
A 63-year-old woman who migrated from Nigeria to the United States was found to have an elevated total serum protein, anemia, and eosinophilia. Serum protein electrophoresis (SPEP) and serum protein immunofixation electrophoresis (SPIFE) demonstrated monoclonal immunoglobulin G (IgG) Îº restricted bands (IgG 3,820 mg/dL; Îº/Î» ratio 4.47), indicative of monoclonal gammopathy of unknown significance (MGUS). A rapid diagnostic test (RDT) for malaria was positive for Plasmodium falciparum (BinaxNOWÂ®; Alere Scarborough Inc., Scarborough, ME). Giemsa-stained blood smears were negative for malarial parasites, however, Loa loa microfilariae were identified. Reverse transcription polymerase chain reaction for P. falciparum, Plasmodium ovale, Plasmodium malariae, and Plasmodium vivax yielded a negative result. She was treated for loiasis with diethylcarbamazine and received no malaria medication. Treatment resulted in a resolution of the microfilaremia and eosinophilia, a negative RDT for malaria, and marked reduction in the monoclonal gammopathy. This is the first reported human case of MGUS associated with loiasis and its resolution after antiparasitic treatment.
Wuerth, K., Lee, A. H. Y., Falsafi, R., Gill, E. E., Hancock, R. E. W.
Pseudomonas aeruginosa is an opportunistic pathogen that causes nosocomial pneumonia and infects patients with cystic fibrosis. P. aeruginosa lung infections are difficult to treat due to bacterial resistance to antibiotics, and strains with multi-drug resistance are becoming more prevalent. Here we examined the use of a small host defense peptide, innate defense regulator 1002 (IDR-1002), in an acute P. aeruginosa lung infection in vivo. IDR-1002 significantly reduced the bacterial burden in the bronchoalveolar lavage fluid (BALF) as well as MCP-1 in the BALF and serum, KC in the serum, and IL-6 in the BALF. RNA-Seq was conducted on lungs and whole blood and the effects of P. aeruginosa, IDR-1002, or the combination of P. aeruginosa and IDR-1002 were evaluated. Differential gene expression analysis showed that P. aeruginosa increased multiple inflammatory and innate immune pathways as well as affected hemostasis, matrix metalloproteinases, collagen biosynthesis, and various metabolism pathways in the lungs and/or blood. Infected mice treated with IDR-1002 had significant changes in gene expression compared to untreated infected mice, with fewer differentially expressed genes associated with the inflammatory and innate immune responses to microbial infection, and treatment also affected morphogenesis, certain metabolic pathways, and lymphocyte activation. Overall, these results show that IDR-1002 was effective in treating P. aeruginosa acute lung infections and associated inflammation.
Gupta, S., Thakur, J., Pal, S., Gupta, R., Mishra, D., Kumar, S., Yadav, K., Saini, A., Yavvari, P. S., Vedantham, M., Singh, A., Srivastava, A., Prasad, R., Bajaj, A.
Interkingdom polymicrobial biofilms formed by gram-positive Staphylococcus aureus and Candida albicans pose serious threats of chronic systemic infections due to absence of any common therapeutic target for their elimination. Herein, we present the structure-activity relationship (SAR) of membrane-targeting Cholic Acid Peptide conjugates (CAPs) against gram-positive bacterial and fungal strains. Structure-activity investigations validated by mechanistic studies witnessed that valine-glycine dipeptide-derived CAP 3 is most effective broad-spectrum antimicrobial against S. aureus and C. albicans. CAP 3 was able to degrade the pre-formed single species and polymicrobial biofilms formed by S. aureus and C. albicans, and CAP 3-coated materials could prevent the formation of biofilms. Murine wound and catheter infection models further confirmed the equally potent bactericidal and fungicidal effect of CAP 3 against bacterial, fungal and polymicrobial infections. Taken together, these results demonstrate that CAPs, as potential broad-spectrum antimicrobials, can effectively clear the frequently encountered polymicrobial infections and can be fine-tuned further for future applications.
Brynildsen, Jon; Petäjä, Liisa; Myhre, Peder L.; Lyngbakken, Magnus N.; Nygård, Ståle; Stridsberg, Mats; Christensen, Geir; Ottesen, Anett H.; Pettilä, Ville; Omland, Torbjørn; Røsjø, Helge
Secretoneurin is associated with cardiomyocyte Ca2+ handling and improves risk prediction in patients with acute myocardial dysfunction. Whether secretoneurin improves risk assessment on top of established cardiac biomarkers and European System for Cardiac Operative Risk Evaluation II in patients undergoing cardiac surgery is not known.
Prospective, observational, single-center sub-study of a multicenter study.
Prospective observational study of survival in patients undergoing cardiac surgery.
A total of 619 patients undergoing cardiac surgery.
Patients underwent either isolated coronary artery bypass graft surgery, single noncoronary artery bypass graft surgery, two procedures, or three or more procedures. Procedures other than coronary artery bypass graft were valve surgery, surgery on thoracic aorta, and other cardiac surgery.
Measurements and Main Results:
We measured preoperative and postoperative secretoneurin concentrations and adjusted for European System for Cardiac Operative Risk Evaluation II, N-terminal pro-B-type natriuretic peptide, and cardiac troponin T concentrations in multivariate analyses. During 961 days of follow-up, 59 patients died (9.5%). Secretoneurin concentrations were higher among nonsurvivors compared with survivors, both before (168 pmol/L [quartile 1–3, 147–206 pmol/L] vs 160 pmol/L [131–193 pmol/L]; p = 0.039) and after cardiac surgery (173 pmol/L [129–217 pmol/L] vs 143 pmol/L [111–173 pmol/L]; p < 0.001). Secretoneurin concentrations decreased from preoperative to postoperative measurements in survivors, whereas we observed no significant decrease in secretoneurin concentrations among nonsurvivors. Secretoneurin concentrations were weakly correlated with established risk indices. Patients with the highest postoperative secretoneurin concentrations had worse outcome compared with patients with lower secretoneurin concentrations (p < 0.001 by the log-rank test) and postoperative secretoneurin concentrations were associated with time to death in multivariate Cox regression analysis: hazard ratio lnsecretoneurin 2.96 (95% CI, 1.46–5.99; p = 0.003). Adding postoperative secretoneurin concentrations to European System for Cardiac Operative Risk Evaluation II improved patient risk stratification, as assessed by the integrated discrimination index: 0.023 (95% CI, 0.0043–0.041; p = 0.016).
Circulating postoperative secretoneurin concentrations provide incremental prognostic information to established risk indices in patients undergoing cardiac surgery.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).
Akershus University Hospital and the Research Council of Norway supported this study. The FINNish Acute Kidney Injury Study got the special state subsidy (EVO) grants from Helsinki University (TYH 2013343, TYH 2013106, and T102010070), from Academy of Finland.
Dr. Petäjä’s institutions received funding from EVO grants from Helsinki University (TYH 2013343, TYH 2013106, and T102010070), and they disclosed that the Academy of Finland supported FINNish Acute Kidney Injury Study. Drs. Christensen, Omland, and Røsjø disclosed that they are partners in a patent (PCT/GB0818650.4) filed by the University of Oslo regarding the use of secretoneurin as a biomarker in patients with cardiovascular disease and patients with critical illness, and they have financial interests in CardiNor AS, which holds the license to commercialize secretoneurin. They have also received personal fees from CardiNor AS. Drs. Myhre, Omland, and Røsjø have also received personal fees from Novartis. Dr. Omland received funding as a member of the editorial board of the journal Circulation, and from Abbott, Bayer, Roche, and Novartis. He has also received research funding from Abbott, Roche, Singulex, and AstraZeneca. Dr. Omland has served on advisory boards and received speaker´s honoraria and travel funding from Roche Diagnostics and Roche Diagnostics provided high-sensitivity troponin T and N-terminal pro-B-type natriuretic peptide kits at a reduced price via Akershus University Hospital. Drs. Omland and Rosjo disclosed that Akershus University Hospital and the Research Council of Norway supported this study. The remaining authors have disclosed that they do not have any potential conflicts of interest.
Address requests for reprints to: Helge Røsjø, MD, PhD, Division of Medicine, Akershus University Hospital, Sykehusveien 25, 1478 Lørenskog, Norway. E-mail: email@example.com
Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Visitors to the Catch Your Breath temporary exhibition at the Royal College of Physicians (London, UK) start learning about breathlessness before they even reach the main displays—as they climb the steps in the central atrium to see the exhibition on the first floor, the staircase is peppered with facts about inhaling and exhaling, from “We take about 7 million breaths per year” and “The world record for holding your breath is an incredible 24 minutes”, through to “Spread out flat, the surface area of the lungs is about the same size as half a tennis court”, and “Breathlessness activates the same brain pathways as pain, hunger, and thirst.” Once visitors ascend, they are greeted with traditional museum display cases along either side of the walkway, with posters on the wall and audio-visual elements, including a television screen showing six short films and two listening posts, playing tracks relating to patients' and doctors' perspectives on breathlessness.
Vivax malaria is the predominant form of malaria outside Africa, affecting about 14 million people worldwide, with about 2.5 billion people exposed. Development of a Plasmodium vivax vaccine is a priority, and merozoite surface protein 7 (MSP-7) has been proposed as a plausible candidate. The P. vivax genome contains 12 MSP-7 genes, which contribute to erythrocyte invasion during blood-stage infection. Previous analysis of MSP-7 sequence diversity suggested that not all paralogs are functionally equivalent. To explore MSP-7 functional diversity, and to identify the best vaccine candidate within the family, MSP-7 expression and antigenicity during bloodstream infections were examined directly from clinical isolates.
Merozoite surface protein 7 gene expression was profiled using RNA-seq data from blood samples isolated from ten human patients with vivax malaria. Differential expression analysis and co-expression cluster analysis were used to relate PvMSP-7 expression to genetic markers of life cycle stage. Plasma from vivax malaria patients was also assayed using a custom peptide microarray to measure antibody responses against the coding regions of 12 MSP-7 paralogs.
Ten patients presented diverse transcriptional profiles that comprised four patient groups. Two MSP-7 paralogs, 7A and 7F, were expressed abundantly in all patients, while other MSP-7 genes were uniformly rare (e.g. 7J). MSP-7H and 7I were significantly more abundant in patient group 4 only, (two patients having experienced longer patency), and were co-expressed with a schizont-stage marker, while negatively associated with liver-stage and gametocyte-stage markers. Screening infections with a PvMSP-7 peptide array identified 13 linear B-cell epitopes in five MSP-7 paralogs that were recognized by plasma from all patients.
These results show that MSP-7 family members vary in expression profile during blood infections; MSP-7A and 7F are expressed throughout the intraerythrocytic development cycle, while expression of other paralogs is focused on the schizont. This may reflect developmental regulation, and potentially functional differentiation, within the gene family. The frequency of B-cell epitopes among paralogs also varies, with MSP-7A and 7L consistently the most immunogenic. Thus, MSP-7 paralogs cannot be assumed to have equal potential as vaccines. This analysis of clinical infections indicates that the most abundant and immunogenic paralog is MSP-7A.
The island of Anjouan (Comoros) is highly endemic for leprosy with an annual incidence of 5–10/10,000. In May/June, 2015 single-dose Rifampicin post-exposure prophylaxis (SDR-PEP) was administered to 269 close contacts of 70 leprosy-patients in four villages as a pilot programmatic intervention. Two years later we revisited the villages for follow-up investigations. The main aim of our study was to quantify spatial associations between reported leprosy cases before and after PEP implementation. A secondary aim was to assess the effect of this single round of SDR-PEP at the individual level.
We conducted door-to-door leprosy screening in all four villages in August/September, 2017. We screened all consenting individuals for leprosy and recorded geographic coordinates of their household. We also recorded whether they had received SDR-PEP and whether they had been diagnosed with leprosy, before or after the 2015 intervention. We fitted a Poisson model with leprosy as outcome and distance to the nearest pre-intervention case and SDR-PEP as predictors.
During the survey we found 114 new cases among 5760 contacts screened (2.0% prevalence), in addition to the 39 cases detected in the two preceding years. We found statistically significant associations of incident leprosy with physical distance to index cases ranging from 2.4 (95% confidence interval (95% CI) 1.5–3.6) for household contacts to 1.8 (95% CI 1.3–2.5) for those living at 1–25 m, compared to individuals living at ≥75 m.
The effect of SDR-PEP appeared protective but did not reach statistical significance due to the low numbers, with an incidence rate ratio (IRR) of 0.6 (95% CI 0.3–1.2) overall, and 0.5 (95% CI 0.2–1.3) when considering only household contacts.
This pilot demonstrated an increased risk of leprosy in contacts beyond the household, therefore a wider circle should be considered for chemoprophylaxis. Baseline surveys and extended contact definitions are essential for improving SDR-PEP effectiveness.
Yang, H., Gong, Y., Zhang, H., Etobayeva, I., Miernikiewicz, P., Luo, D., Li, X., Zhang, X., Dabrowska, K., Nelson, D. C., He, J., Wei, H.
Streptococcus pneumoniae is one of the leading pathogens that cause a variety of mucosal and invasive infections. With the increased emergence of multidrug-resistant S. pneumoniae, new antimicrobials with mechanisms of action different from conventional antibiotics are urgently needed. In this study, we identified a putative lysin (gp20) encoded by the Streptococcus phage SPSL1 using the LytA autolysin as a template. Molecular dissection of gp20 revealed a binding domain (GPB) containing choline-binding repeats (CBRs) that are high specificity for S. pneumoniae. By fusing GPB to the CHAP (cysteine, histidine-dependent amidohydrolase/peptidase) catalytic domain of the PlyC lysin, we constructed a novel chimeric lysin, ClyJ, with improved activity to the pneumococcal Cpl-1 lysin. No resistance was observed in S. pneumoniae strains after exposure to incrementally doubling concentrations of ClyJ for 8 continuous days in vitro. In a mouse bacteremia model using penicillin G as a control, a single intraperitoneal injection of ClyJ improved the survival rate of lethal S. pneumoniae infected mice in a dose-dependent manner. Giving its high lytic activity and safety profile, ClyJ may represent a promising alternative to combat pneumococcal infections.
Habib Hasan Farooqui, Sakthivel Selvaraj, Aashna Mehta, David L. Heymann
by Habib Hasan Farooqui, Sakthivel Selvaraj, Aashna Mehta, David L. Heymann
India was the largest consumer of antibiotics in 2010 in the world. Evidence suggests that countries with high per-capita antibiotic consumption have higher rates of antibiotic resistance. To control antibiotic resistance, not only reduction in antibiotic consumption is required, socio-economic factors like access to clean water and sanitation, regulation of private healthcare sector and better governance are equally important. The key objective of this research was to investigate the five year trends in consumption of major antibiotic classes in India and compare them with European Surveillance of Antimicrobial Consumption Network (ESAC-Net) countries. We used Intercontinental Marketing Statistics (IMS) Health (now IQVIA) medicine sales audit data of antibiotic sales in the retail private sector (excluding the hospitals sector) in India. We then standardized dosage trends and assigned defined daily dose (DDD) to all formulations based on the ATC/DDD index. We expressed our data in standardized matrices of DDD per 1000 inhabitants’ per day (DID) to compare antibiotic use in India with ESAC-Net countries. The antibiotic use was plotted and reported by year and antibiotic class. Our main findings are—per capita antibiotic consumption in the retail sector in India has increased from 13.1 DID in 2008 to 16.0 DID in 2012—an increase of ~22%; use of newer class of antibiotics like carbapenems (J01DH), lincosamides (J01FF), glycopeptides (J01XA), 3rd generation cephalosporins (J01DD) and penicillin’s with beta-lactamase inhibitors has risen; and antibiotic consumption rates in India are still low as compared to ESAC-Net countries (16.0 DID vs. 21.54 DID). To conclude our study has provided the first reliable estimates of antibiotic use in the retail sector in India vis-à-vis ESAC-Net countries. In addition, our study could provide a reference point to measure the impact of interventions directed towards reducing antibiotic use.
Falcipains are major cysteine proteases of Plasmodium falciparum involved in haemoglobin degradation and remain attractive anti-malarial drug targets. Several inhibitors against these proteases have been identified, yet none of them has been approved for malaria treatment. Other Plasmodium species also possess highly homologous proteins to falcipains. For selective therapeutic targeting, identification of sequence and structure differences with homologous human cathepsins is necessary. The substrate processing activity of these proteins is tightly controlled via a prodomain segment occluding the active site which is chopped under low pH conditions exposing the catalytic site. Current work characterizes these proteases to identify residues mediating the prodomain regulatory function for the design of peptide based anti-malarial inhibitors.
Sequence and structure variations between prodomain regions of plasmodial proteins and human cathepsins were determined using in silico approaches. Additionally, evolutionary clustering of these proteins was evaluated using phylogenetic analysis. High quality partial zymogen protein structures were modelled using homology modelling and residue interaction analysis performed between the prodomain segment and mature domain to identify key interacting residues between these two domains. The resulting information was used to determine short peptide sequences which could mimic the inherent regulatory function of the prodomain regions. Through flexible docking, the binding affinity of proposed peptides on the proteins studied was evaluated.
Sequence, evolutionary and motif analyses showed important differences between plasmodial and human proteins. Residue interaction analysis identified important residues crucial for maintaining prodomain integrity across the different proteins as well as the pro-segment responsible for inhibitory mechanism. Binding affinity of suggested peptides was highly dependent on their residue composition and length.
Despite the conserved structural and catalytic mechanism between human cathepsins and plasmodial proteases, current work revealed significant differences between the two protein groups which may provide valuable information for selective anti-malarial inhibitor development. Part of this study aimed to design peptide inhibitors based on endogenous inhibitory portions of protease prodomains as a novel aspect. Even though peptide inhibitors may not be practical solutions to malaria at this stage, the approach followed and results offer a promising means to find new malarial inhibitors.
Romero-Saavedra F, Laverde D, Kalfopoulou E, et al.
AbstractEnterococci have emerged as important nosocomial pathogens due to their resistance against the most commonly used antibiotics. Alternative treatments or prevention options are aimed at polysaccharides and surface-related proteins that play important roles in pathogenesis. Previously, we have shown that two Enterococcus faecium proteins, the secreted antigen A and the peptidyl-prolyl cis-trans isomerase, as well as the Enterococcus faecalis polysaccharide diheteroglycan are able to induce opsonic and cross-protective antibodies. Here, we evaluate the use of glycoconjugates consisting of these proteins and an enterococcal polysaccharide to develop a vaccine with broader strain coverage. Diheteroglycan was conjugated to these two enterococcal proteins. Rabbit sera raised against these glycoconjugates showed IgG titers towards the corresponding conjugate, as well as to the respective protein and carbohydrate antigens. Effective opsonophagocytic killing for the two sera was observed against different E. faecalis and E. faecium strains. ELISA against whole bacterial cells showed immune recognition of the sera towards 22 enterococcal strains. Moreover, sera conferred protection in a mouse infection model against E. faecalis and E. faecium strains. Our results suggest that these glycoconjugates are promising candidates for vaccine formulations with a broader coverage against these nosocomial pathogens and that the evaluated proteins are potential carrier proteins.
Marta Sisteré-Oró, Júlia Vergara-Alert, Thomas Stratmann, Sergi López-Serrano, Sonia Pina-Pedrero, Lorena Córdoba, Mónica Pérez-Maillo, Patrícia Pleguezuelos, Enric Vidal, Veljko Veljkovic, Joaquim Segalés, Jens Nielsen, Anders Fomsgaard, Ayub Darji
by Marta Sisteré-Oró, Júlia Vergara-Alert, Thomas Stratmann, Sergi López-Serrano, Sonia Pina-Pedrero, Lorena Córdoba, Mónica Pérez-Maillo, Patrícia Pleguezuelos, Enric Vidal, Veljko Veljkovic, Joaquim Segalés, Jens Nielsen, Anders Fomsgaard, Ayub Darji
Swine influenza viruses (SIVs), the causal agents of swine influenza, are not only important to control due to the economic losses in the swine industry, but also can be pandemic pathogens. Vaccination is one of the most relevant strategies to control and prevent influenza infection. Current human vaccines against influenza induce strain-specific immunity and annual update is required due to the virus antigenic shift phenomena. Previously, our group has reported the use of conserved hemagglutinin peptides (HA-peptides) derived from H1-influenza virus as a potential multivalent vaccine candidate. Immunization of swine with these HA-peptides elicited antibodies that recognized and neutralized heterologous influenza viruses in vitro and demonstrated strong hemagglutination-inhibiting activity. In the present work, we cloned one HA-peptide (named NG34) into a plasmid fused with cytotoxic T lymphocyte-associated antigen (CTLA4) which is a molecule that modifies T cell activation and with an adjuvant activity interfering with the adaptive immune response. The resulting plasmid, named pCMV-CTLA4-Ig-NG34, was administered twice to animals employing a needle-free delivery approach. Two studies were carried out to test the efficacy of pCMV-CTLA4-Ig-NG34 as a potential swine influenza vaccine, one in seronegative and another in seropositive pigs against SIV. The second one was aimed to evaluate whether pCMV-CTLA4-Ig-NG34 vaccination would overcome maternally derived antibodies (MDA). After immunization, all animals were intranasally challenged with an H3N2 influenza strain. A complete elimination or significant reduction in the viral shedding was observed within the first week after the challenge in the vaccinated animals from both studies. In addition, no challenged heterologous virus load was detected in the airways of vaccinated pigs. Overall, it is suggested that the pCMV-CTLA4-Ig-NG34 vaccine formulation could potentially be used as a multivalent vaccine against influenza viruses.
Lucy Mackenzie-Impoinvil, Gareth D. Weedall, Juan C. Lol, Jesús Pinto, Lucrecia Vizcaino, Nicole Dzuris, Jacob Riveron, Norma Padilla, Charles Wondji, Audrey Lenhart
by Lucy Mackenzie-Impoinvil, Gareth D. Weedall, Juan C. Lol, Jesús Pinto, Lucrecia Vizcaino, Nicole Dzuris, Jacob Riveron, Norma Padilla, Charles Wondji, Audrey Lenhart
Decades of unmanaged insecticide use and routine exposure to agrochemicals have left many populations of malaria vectors in the Americas resistant to multiple classes of insecticides, including pyrethroids. The molecular basis of pyrethroid resistance is relatively uncharacterised in American malaria vectors, preventing the design of suitable resistance management strategies. Using whole transcriptome sequencing, we characterized the mechanisms of pyrethroid resistance in Anopheles albimanus from Peru and Guatemala. An. albimanus were phenotyped as either deltamethrin or alpha-cypermethrin resistant. RNA from 1) resistant, 2) unexposed, and 3) a susceptible laboratory strain of An. albimanus was sequenced and analyzed using RNA-Seq. Expression profiles of the three groups were compared based on the current annotation of the An. albimanus reference genome. Several candidate genes associated with pyrethroid resistance in other malaria vectors were found to be overexpressed in resistant An. albimanus. In addition, gene ontology terms related to serine-type endopeptidase activity, extracellular activity and chitin metabolic process were also commonly overexpressed in the field caught resistant and unexposed samples from both Peru and Guatemala when compared to the susceptible strain. The cytochrome P450 CYP9K1 was overexpressed 14x in deltamethrin and 8x in alpha-cypermethrin-resistant samples from Peru and 2x in deltamethrin-resistant samples from Guatemala, relative to the susceptible laboratory strain. CYP6P5 was overexpressed 68x in deltamethrin-resistant samples from Peru but not in deltamethrin-resistant samples from Guatemala. When comparing overexpressed genes between deltamethrin-resistant and alpha-cypermethrin-resistant samples from Peru, a single P450 gene, CYP4C26, was overexpressed 9.8x (p
Cosgriff, C. J., White, C. R., Teoh, W. P., Grayczyk, J. P., Alonzo, F.
Gram-positive bacteria process and release small peptides or "pheromones" that act as signals for the induction of adaptive traits including those involved in pathogenesis. One class of small signaling pheromones is the cyclic auto-inducing peptides (AIPs), which regulate expression of genes that orchestrate virulence and persistence in a range of microbes including Staphylococci, Listeria, Clostridia, and Enterococci. In a genetic screen for Staphylococcus aureus secreted virulence factors, we identified a S. aureus mutant containing an insertion in gene SAUSA300_1984 (mroQ), which encodes a putative membrane-embedded metalloprotease. A mroQ mutant exhibits impaired induction of TLR2-dependent inflammatory responses from macrophages, but elicits greater production of the inflammatory cytokine IL-1β and is attenuated in a murine skin and soft tissue infection model. The mroQ mutant phenocopies a S. aureus mutant containing a deletion of the accessory gene regulatory system (Agr), wherein both strains have significantly reduced production of secreted toxins and virulence factors, but increased surface Protein A abundance. The Agr system controls virulence factor gene expression in S. aureus through sensing accumulation of AIP via the histidine kinase AgrC and response regulator AgrA. We provide evidence to suggest that MroQ acts within the Agr pathway to facilitate optimal processing or export of AIP for signal amplification through AgrC/A and induction of virulence factor gene expression. Mutation of MroQ active site residues significantly reduces AIP signaling and attenuates virulence. Altogether, this work identifies a new component of the Agr quorum sensing circuit that is critical for the production of S. aureus virulence factors.
To the Editor: In their study of the value of copeptin for diagnosing diabetes insipidus, Fenske et al. (Aug. 2 issue) overlook two possible methodologic flaws. First, some of their patients appear to have had an element of a solute diuresis. For example, among patients with primary polydipsia, the…
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