Publications by authors named "Patricia Martin"

196 Publications

Human challenge study with a Shigella bioconjugate vaccine: Analyses of clinical efficacy and correlate of protection.

EBioMedicine 2021 Apr 13;66:103310. Epub 2021 Apr 13.

LimmaTech Biologics AG, Schlieren, Switzerland.

Background: Shigellosis is a major cause of moderate to severe diarrhoea and dysentery in children under 5 years of age in low and middle-income countries. The Flexyn2a vaccine conjugates the O-polysaccharide of Shigella flexneri 2a to Pseudomonas aeruginosa exotoxin A. We describe a Phase 2b proof-of-concept challenge study that evaluated safety, immunogenicity, and efficacy of the Flexyn2a vaccine to protect against shigellosis.

Methods: In this randomized, double blind, placebo-controlled trial, healthy adults were randomized 1:1 to receive Flexyn2a (10 µg) or placebo intramuscularly, twice, 4 weeks apart, followed by challenge 4 weeks later with 1500 colony forming units (CFUs) of S. flexneri 2a strain 2457T. The primary outcome was vaccine-induced protection. S. flexneri 2a lipopolysaccharide (LPS)-specific immune responses were assessed.

Findings: Sixty-seven subjects were enrolled, 34 received vaccine and 33 placebo. The vaccine was well tolerated; the majority of adverse events were mild in nature. Thirty vaccinees and 29 placebo recipients received the S. flexneri 2a challenge. Vaccination resulted in a 30.2% reduction in shigellosis compared with placebo (13/30 vs. 18/29; p = 0.11; 95% CI -15 to 62.6). Vaccine efficacy was more robust against severe disease, reaching 51.7% (p = 0.015, 95% CI 5.3 to 77.9) against moderate/severe diarrhoea or dysentery concurrent with fever or severe enteric symptoms and 72.4% (p = 0.07) against more severe diarrhoea (≥10 lose stools or ≥1000 g loose stools/24 h). Vaccinated subjects were less likely to need early antibiotic intervention following challenge (protective efficacy 51.7%, p = 0.01; 95% CI 9 to 76.8). In those who developed shigellosis, vaccinated subjects had a lower disease severity score (p = 0.002) than placebo-recipients. Additionally, LPS-specific serum IgG responses in Flexyn2a recipients were associated with protection against disease (p = 0.0016) and with a decreased shigellosis disease score (p = 0.002).

Interpretation: The Flexyn2a bioconjugate vaccine was immunogenic, well tolerated and protected against severe illness after Shigella challenge and is a promising Shigella vaccine construct. We identified a strong association between anti-S. flexneri 2a serum IgG and a reduction in disease outcomes. (Clinicaltrials.gov, NCT02646371.) FUNDING: Funding for this study was through a grant from the Wellcome Trust.
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http://dx.doi.org/10.1016/j.ebiom.2021.103310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054157PMC
April 2021

Immune response characterization in a human challenge study with a Shigella flexneri 2a bioconjugate vaccine.

EBioMedicine 2021 Apr 1;66:103308. Epub 2021 Apr 1.

Department of Enteric Infections, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States. Electronic address:

Background: Diarrheal diseases are a leading cause of global morbidity and mortality affecting all ages, but especially children under the age of five in resource-limited settings. Shigella is a leading contributor to diarrheal diseases caused by bacterial pathogens and is considered a significant antimicrobial resistance threat. While improvements in hygiene, and access to clean water help as control measures, vaccination remains one of the most viable options for significantly reducing morbidity and mortality.

Methods: Flexyn2a is a bioconjugate vaccine manufactured using novel conjugation methodologies enzymatically linking the O-polysaccharide of S. flexneri 2a to exotoxin A of Pseudomonas aeruginosa. The protective capacity of Flexyn2a was assessed in a controlled human infection model after two intramuscular immunizations. Immune responses pre- and post-immunization and/or infection were investigated and are described here.

Findings: Flexyn2a induced lipopolysaccharide (LPS)-specific serum IgG responses post-immunization which were associated with protection against shigellosis. Additionally, several other immune parameters, including memory B cell responses, bactericidal antibodies and serum IgA, were also elevated in vaccinees protected against shigellosis. Immunization with Flexyn2a also induced gut-homing, LPS-specific IgG and IgA secreting B cells, indicating the vaccine induced immune effectors functioning at the site of intestinal infection.

Interpretation: Collectively, the results of these immunological investigations provide insights into protective immune mechanisms post-immunization with Flexyn2a which can be used to further guide vaccine development and may have applicability to the larger Shigella vaccine field.

Funding: Funding for this study was provided through a Wellcome Trust grant.
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http://dx.doi.org/10.1016/j.ebiom.2021.103308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047506PMC
April 2021

Insights into the Use of Peripherally Acting μ-Opioid Receptor Antagonists (PAMORAs) in Oncologic Patients: from Scientific Evidence to Real Clinical Practice.

Curr Treat Options Oncol 2021 Feb 26;22(3):26. Epub 2021 Feb 26.

Medical Oncology, Hospitales Universitarios Regional y Virgen de la Victoria, IBIMA, Málaga, Spain.

Opinion Statement: Management of chronic pain is crucial to improve the quality of life of cancer and palliative care patients. Opioid-based treatments used to control pain can be prolonged over time. Unfortunately, constipation is one of the most disturbing adverse effects of long-term use of opioids. Opioid-induced constipation (OIC) occurs when opioids bind to the specific receptors present in the gastrointestinal (GI) tract, and can affect any patients receiving chronic opioid therapy, including cancer patients. The limited efficacy of laxatives to treat OIC symptoms prompted the search for new therapeutic strategies. Peripherally acting μ-opioid receptor antagonists (PAMORAs) have recently emerged as new effective drugs for OIC management due to their specific binding to enteric μ-receptors. Little information is available on the use of PAMORAs in real-life practice for OIC treatment in cancer patients. In this paper, a panel of experts specializing in cancer and palliative care pools their clinical experience with PAMORAs in cancer patients presenting OIC and highlights the importance of timing and choice of therapy in achieving prompt OIC management and benefitting patients.
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http://dx.doi.org/10.1007/s11864-021-00816-5DOI Listing
February 2021

Uropathogenic E. coli induces DNA damage in the bladder.

PLoS Pathog 2021 Feb 25;17(2):e1009310. Epub 2021 Feb 25.

IRSD, INSERM, Université de Toulouse, INRA, ENVT, UPS, Toulouse, France.

Urinary tract infections (UTIs) are among the most common outpatient infections, with a lifetime incidence of around 60% in women. We analysed urine samples from 223 patients with community-acquired UTIs and report the presence of the cleavage product released during the synthesis of colibactin, a bacterial genotoxin, in 55 of the samples examined. Uropathogenic Escherichia coli strains isolated from these patients, as well as the archetypal E. coli strain UTI89, were found to produce colibactin. In a murine model of UTI, the machinery producing colibactin was expressed during the early hours of the infection, when intracellular bacterial communities form. We observed extensive DNA damage both in umbrella and bladder progenitor cells. To the best of our knowledge this is the first report of colibactin production in UTIs in humans and its genotoxicity in bladder cells.
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http://dx.doi.org/10.1371/journal.ppat.1009310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906301PMC
February 2021

Type III Collagen is Required for Adipogenesis and Actin Stress Fibre Formation in 3T3-L1 Preadipocytes.

Biomolecules 2021 01 25;11(2). Epub 2021 Jan 25.

Department of Biological & Biomedical Sciences, School of Health & Life Sciences, City Campus, Glasgow Caledonian University, Cowcaddens Road, Glasgow G4 OBA, UK.

GPR56 is required for the adipogenesis of preadipocytes, and the role of one of its ligands, type III collagen (ColIII), was investigated here. ColIII expression was examined by reverse transcription quantitative polymerase chain reaction, immunoblotting and immunostaining, and its function investigated by knockdown and genome editing in 3T3-L1 cells. Adipogenesis was assessed by oil red O staining of neutral cell lipids and production of established marker and regulator proteins. siRNA-mediated knockdown significantly reduced 3a1 transcripts, ColIII protein and lipid accumulation in 3T3-L1 differentiating cells. 3a1 3T3-L1 genome-edited cell lines abolished adipogenesis, demonstrated by a dramatic reduction in adipogenic moderators: Pparγ (88%) and C/ebpα (96%) as well as markers aP2 (93%) and oil red O staining (80%). 3a1 3T3-L1 cells displayed reduced cell adhesion, sustained active β-catenin and deregulation of fibronectin () and collagen (4a1, 6a1) extracellular matrix gene transcripts. 3a1 3T3-L1 cells also had dramatically reduced actin stress fibres. We conclude that ColIII is required for 3T3-L1 preadipocyte adipogenesis as well as the formation of actin stress fibres. The phenotype of 3a1 3T3-L1 cells is very similar to that of 56 3T3-L1 cells, suggesting a functional relationship between ColIII and Gpr56 in preadipocytes.
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http://dx.doi.org/10.3390/biom11020156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911635PMC
January 2021

Connexins and the Epithelial Tissue Barrier: A Focus on Connexin 26.

Biology (Basel) 2021 Jan 14;10(1). Epub 2021 Jan 14.

Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, UK.

Epithelial tissue responds rapidly to environmental triggers and is constantly renewed. This tissue is also highly accessible for therapeutic targeting. This review highlights the role of connexin mediated communication in avascular epithelial tissue. These proteins form communication conduits with the extracellular space (hemichannels) and between neighboring cells (gap junctions). Regulated exchange of small metabolites less than 1kDa aide the co-ordination of cellular activities and in spatial communication compartments segregating tissue networks. Dysregulation of connexin expression and function has profound impact on physiological processes in epithelial tissue including wound healing. Connexin 26, one of the smallest connexins, is expressed in diverse epithelial tissue and mutations in this protein are associated with hearing loss, skin and eye conditions of differing severity. The functional consequences of dysregulated connexin activity is discussed and the development of connexin targeted therapeutic strategies highlighted.
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http://dx.doi.org/10.3390/biology10010059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829877PMC
January 2021

A heterozygous mutation in GJB2 (Cx26F142L) associated with deafness and recurrent skin rashes results in connexin assembly deficiencies.

Exp Dermatol 2020 10 22;29(10):970-979. Epub 2020 Sep 22.

Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK.

Mutations in GJB2 encoding Connexin 26 (CX26) are associated with hearing loss and hyperproliferative skin disorders of differing severity including keratitis-ichthyosis-deafness (KID) and Vohwinkel syndrome. A 6-year-old Caucasian girl who presented with recurrent skin rashes and sensorineural hearing loss harboured a heterozygous point mutation in GJB2 (c.424T > C; p.F142L). To characterize the impact of CX26F142L on cellular events. Plasmids CX26WT, CX26F142L, CX26G12R (KID) or CX26D66H (Vohwinkel) were transfected into HeLa cells expressing Cx26 or Cx43 or into HaCaT cells, a model keratinocyte cell line. Confocal microscopy determined protein localization. MTT assays assessed cell viability in the presence or absence of carbenoxolone, a connexin-channel blocker. Co-immunoprecipitation/Western blot analysis determined Cx43:Cx26 interactions. Quantitative real-time polymerase chain reaction assessed changes in gene expression of ER stress markers. Dye uptake assays determined Connexin-channel functionality. F142L and G12R were restricted to perinuclear areas. Collapse of the microtubule network, rescued by co-treatment with paclitaxel, occurred. ER stress was not involved. Cell viability was reduced in cells expressing F142L and G12R but not D66H. Unlike G12R that forms "leaky" hemichannels, F142L had restricted permeability. Cell viability of F142L and G12R transfected cells was greater in HeLa cells expressing Cx43 than in native Cx-free HeLa cells. Co-immunoprecipitation suggested a possible interaction between Cx43 and the three mutations. Expression of CX26F142L and G12R results in microtubule collapse, rescued by interaction with Cx43. The GJB2 mutations interacted with Cx43 suggesting that unique Cx43:Cx26 channels are central to the diverse phenotype of CX26 skin-related channelopathies.
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http://dx.doi.org/10.1111/exd.14187DOI Listing
October 2020

Further studies of neuroangiostrongyliasis (rat lungworm disease) in Australian dogs: 92 new cases (2010-2020) and results for a novel, highly sensitive qPCR assay.

Parasitology 2021 Feb 24;148(2):178-186. Epub 2020 Aug 24.

Centre for Veterinary Education, B22, University of Sydney, NSW2006, Australia.

The principal aim of this study was to optimize the diagnosis of canine neuroangiostrongyliasis (NA). In total, 92 cases were seen between 2010 and 2020. Dogs were aged from 7 weeks to 14 years (median 5 months), with 73/90 (81%) less than 6 months and 1.7 times as many males as females. The disease became more common over the study period. Most cases (86%) were seen between March and July. Cerebrospinal fluid (CSF) was obtained from the cisterna magna in 77 dogs, the lumbar cistern in f5, and both sites in 3. Nucleated cell counts for 84 specimens ranged from 1 to 146 150 cells μL-1 (median 4500). Percentage eosinophils varied from 0 to 98% (median 83%). When both cisternal and lumbar CSF were collected, inflammation was more severe caudally. Seventy-three CSF specimens were subjected to enzyme-linked immunosorbent assay (ELISA) testing for antibodies against A. cantonensis; 61 (84%) tested positive, titres ranging from <100 to ⩾12 800 (median 1600). Sixty-one CSF specimens were subjected to real-time quantitative polymerase chain reaction (qPCR) testing using a new protocol targeting a bioinformatically-informed repetitive genetic target; 53/61 samples (87%) tested positive, CT values ranging from 23.4 to 39.5 (median 30.0). For 57 dogs, it was possible to compare CSF ELISA serology and qPCR. ELISA and qPCR were both positive in 40 dogs, in 5 dogs the ELISA was positive while the qPCR was negative, in 9 dogs the qPCR was positive but the ELISA was negative, while in 3 dogs both the ELISA and qPCR were negative. NA is an emerging infectious disease of dogs in Sydney, Australia.
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http://dx.doi.org/10.1017/S0031182020001572DOI Listing
February 2021

Patterns of progression in patients treated for immuno-oncology antibodies combination.

Cancer Immunol Immunother 2021 Jan 22;70(1):221-232. Epub 2020 Jul 22.

Drug Development Department (DITEP), Gustave Roussy, Université Paris-Saclay, Villejuif, 94805, France.

Background: New patterns of progression under immune-oncology (IO) antibodies (mAb) have been described such as pseudoprogression. Except for melanoma, variations between studies reveal difficulties to establish their prevalence.

Methods: This retrospective study enrolled patients participating in IO phase I trials at Gustave Roussy cancer center for solid tumors excluding melanoma. Radiological assessment according to iRECIST was correlated with prospectively registered patient characteristics and outcomes. Pseudoprogression (PsPD) was defined as RECIST-defined progression followed by stabilization or decrease at the next imaging, and dissociated response (DisR) as concomitant decrease in some tumor lesions and increase in others at a same timepoint.

Results: Among 360 patients included, 74% received IO mAb combination: 45% with another IO mAb, 20% with targeted therapy and 10% with radiotherapy. The overall response rate was 19.7%. PsPD were observed in 10 (2.8%) patients and DisR in 12 (3.3%) patients. Atypical responses (AR), including PsPD and DisR, were not associated with any patient's baseline characteristics. Compare with typical responder patients, patients experiencing AR presented a shorter iPFS (HR 0.34; p < 0.001) and OS (HR 0.27; p = 0.026). Among the 203 patients who progressed in 12 weeks, 80 (39.4%) patients were treated beyond progression. PD was confirmed in 80% of cases, while 10% of patients presented a response.

Conclusion: Pseudoprogression and dissociated response are uncommon patterns of progression. Their prevalence should be balanced with the rate of real progressing patients treated beyond progression. Prognosis or on-treatment biomarkers are needed to identify early patients who will benefit from immunotherapy.
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http://dx.doi.org/10.1007/s00262-020-02647-zDOI Listing
January 2021

Connexin 43 plays a role in proliferation and migration of pulmonary arterial fibroblasts in response to hypoxia.

Pulm Circ 2020 Jul-Sep;10(3):2045894020937134. Epub 2020 Jul 6.

Department of Biological and Biomedical Science, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK.

Pulmonary hypertension (PH) is a disease associated with vasoconstriction and remodelling of the pulmonary vasculature. Pulmonary artery fibroblasts (PAFs) play an important role in hypoxic-induced remodelling. Connexin 43 (Cx43) is involved in cellular communication and regulation of the pulmonary vasculature. Using both and models of PH, the aims of this study were to (i) investigate the role of Cx43 in hypoxic-induced proliferation and migration of rat PAFs (rPAFs) and rat pulmonary artery smooth muscle cells (rPASMCs) and (ii) determine whether Cx43 expression is dysregulated in the rat sugen5416/hypoxic model of PH. The role of Cx43 in hypoxic-induced proliferation and migration was investigated using Gap27 (a pharmacological inhibitor of Cx43) or genetic knockdown of Cx43 using siRNA. Cx43 protein expression was increased by hypoxia in rPAFs but not rPASMCs. Hypoxic exposure, in the presence of serum, resulted in an increase in proliferation of rPAFs but not rPASMCs. Hypoxic exposure caused migration of rPAFs but not rPASMCs. Phosphorylation of p38 mitogen-activated protein kinase (MAPK) and ERK1/2 were increased by hypoxia in rPAFs. The effects of hypoxia on proliferation, migration and MAPK phosphorylation in rPAFs were attenuated in the presence of Gap27 or Cx43 siRNA. Cx43 protein expression was increased in sugen5416/hypoxic rat lung; this increased expression was not observed in sugen5416/hypoxic rats treated with the MAPK pathway inhibitor GS-444217. In conclusion, Cx43 is involved in the proliferation and migration of rPAFs in response to hypoxia via the MAPK signalling pathway.
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http://dx.doi.org/10.1177/2045894020937134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338651PMC
July 2020

The Genotoxin Colibactin Shapes Gut Microbiota in Mice.

mSphere 2020 07 1;5(4). Epub 2020 Jul 1.

IRSD, Université de Toulouse, INSERM, INRAE, ENVT, UPS, Toulouse, France

The genotoxin colibactin produced by resident bacteria of the gut microbiota may have tumorigenic effect by inducing DNA double-strand breaks in host cells. Yet, the effect of colibactin on gut microbiota composition and functions remains unknown. To address this point, we designed an experiment in which pregnant mice were colonized with the following: (i) a commensal strain, (ii) a commensal strain plus a genotoxic strain, (iii) a commensal strain plus a nongenotoxic mutant strain unable to produce mature colibactin. Then, we analyzed the gut microbiota in pups at day 15 and day 35 after birth. At day 15, mice that were colonized at birth with the genotoxic strain showed lower levels of and taxa belonging to the , a modest effect on overall microbial diversity, and no effect on gut microbiome. At day 35, mice that received the genotoxic strain showed lower and taxa belonging to the , together with a strong effect on overall microbial diversity and higher microbial functions related to DNA repair. Moreover, the genotoxic strain strongly affected gut microbial diversity evolution of pups receiving the genotoxic strain between day 15 and day 35. Our data show that colibactin, beyond targeting the host, may also exert its genotoxic effect on the gut microbiota. Infections of genotoxic spread concomitantly with urbanized progression. These bacteria may prompt cell senescence and affect DNA stability, inducing cancer via the production of colibactin, a genotoxin shown capable of affecting host DNA in eukaryotic cells. In this study, we show that the action of colibactin may also be directed against other bacteria of the gut microbiota in which genotoxic bacteria have been introduced. Indeed, the presence of genotoxic induced a change in both the structure and function of the gut microbiota. Our data indicate that genotoxic may use colibactin to compete for gut niche utilization.
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http://dx.doi.org/10.1128/mSphere.00589-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333578PMC
July 2020

Cx31.1 expression is modulated in HaCaT cells exposed to UV-induced damage and scrape-wounding.

J Cell Physiol 2021 Feb 27;236(2):911-920. Epub 2020 Jun 27.

Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK.

Connexin31.1 (Cx31.1) is a gap junction protein associated with apoptosis. In the skin, apoptosis is modulated by diabetes. A HaCaT skin model investigated whether normal (NGI) and high glucose and insulin (HGI; diabetic) conditions altered Cx31.1 expression, and if these were apoptosis linked. Cx31.1 was found in HaCaT and HeLa Ohio cells, with HaCaT Cx31.1 protein increased in HGI conditions, and around apoptotic cells. HeLa Cx31.1 channels were noncommunicative. Post scrape-wounding, Cx31.1 increased at wound edges. Caspase 3/7 in scrape-wounds media (containing cells) elevated in HGI. UV exposure raised Cx31.1, and caspase 3/7, in NGI and HGI. UV reduced cell viability in NGI cells, although not significantly in HGI. Cx31.1 is modulated during HaCaT cell wound closure, and associated with 'diabetic' conditions. Cx31.1 expression matched apoptosis levels, higher in HGI cultures. Cx31.1 is noncommunicating, modulated after wounding, linked to apoptosis, and may be associated with tissue turn-over around diabetic wounds.
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http://dx.doi.org/10.1002/jcp.29901DOI Listing
February 2021

Attenuation of the pro-inflammatory signature of lung cancer-derived mesenchymal stromal cells by statins.

Cancer Lett 2020 08 8;484:50-64. Epub 2020 May 8.

Experimental Pathology Service, Institute of Pathology, CHUV, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 25, 1011, Lausanne, Switzerland.

Solid tumor growth triggers a dynamic host response, which recapitulates wound healing and defines the tumor microenvironment (TME). In addition to the action of the tumor cells themselves, the TME is maintained by a myriad of immune and stromal cell-derived soluble mediators and extracellular matrix components whose combined action supports tumor progression. However, therapeutic targeting of the TME has proven challenging because of incomplete understanding of the tumor-host crosstalk at the molecular level. Here, we investigated the crosstalk between mesenchymal stromal cells (MSCs) and primary cancer cells (PCCs) from human squamous cell lung carcinoma (SCC). We discovered that PCCs secrete CCL3 and stimulate IL-6, CCL2, ICAM-1 and VCAM-1 expression in MSCs and that the MSC-PCC crosstalk can be disrupted by the lipid-lowering drug simvastatin, which displays pleiotropic effects on cell metabolism and suppresses IL-6 and CCL2 production by MSCs and CCL3 secretion by PCCs. In addition, simvastatin inhibited spheroid formation by PCCs and negatively affected PCC survival. Our observations demonstrate that commonly used statins may be repurposed to target the TME in lung carcinoma.
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http://dx.doi.org/10.1016/j.canlet.2020.05.005DOI Listing
August 2020

LIN28B Underlies the Pathogenesis of a Subclass of Ewing Sarcoma LIN28B Control of EWS-FLI1 Stability.

Cell Rep 2020 03;30(13):4567-4583.e5

Experimental Pathology Service, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland. Electronic address:

Ewing sarcoma (EwS) is associated with poor prognosis despite current multimodal therapy. Targeting of EWS-FLI1, the fusion protein responsible for its pathogenesis, and its principal downstream targets has not yet produced satisfactory therapeutic options, fueling the search for alternative approaches. Here, we show that the oncofetal RNA-binding protein LIN28B regulates the stability of EWS-FLI1 mRNA in ~10% of EwSs. LIN28B depletion in these tumors leads to a decrease in the expression of EWS-FLI1 and its direct transcriptional network, abrogating EwS cell self-renewal and tumorigenicity. Moreover, pharmacological inhibition of LIN28B mimics the effect of LIN28B depletion, suggesting that LIN28B sustains the emergence of a subset of EwS in which it also serves as an effective therapeutic target.
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http://dx.doi.org/10.1016/j.celrep.2019.12.053DOI Listing
March 2020

Genome wide analysis of gene expression changes in skin from patients with type 2 diabetes.

PLoS One 2020 21;15(2):e0225267. Epub 2020 Feb 21.

University of Texas at Austin, Department of Biomedical Engineering, Austin, TX.

Non-healing chronic ulcers are a serious complication of diabetes and are a major healthcare problem. While a host of treatments have been explored to heal or prevent these ulcers from forming, these treatments have not been found to be consistently effective in clinical trials. An understanding of the changes in gene expression in the skin of diabetic patients may provide insight into the processes and mechanisms that precede the formation of non-healing ulcers. In this study, we investigated genome wide changes in gene expression in skin between patients with type 2 diabetes and non-diabetic patients using next generation sequencing. We compared the gene expression in skin samples taken from 27 patients (13 with type 2 diabetes and 14 non-diabetic). This information may be useful in identifying the causal factors and potential therapeutic targets for the prevention and treatment of diabetic related diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225267PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034863PMC
May 2020

The Brazillian version of the hand mobility in scleroderma (HAMIS) test: translation and validation.

Adv Rheumatol 2019 11 21;59(1):51. Epub 2019 Nov 21.

Department of Rheumatology at Mackenzie Evangelical School of Medicine, R. Padre Anchieta 2770, Curitiba, Paraná, 80730-000, Brazil.

Background: The Hand Mobility in Scleroderma (HAMIS) test was created to measure the degree of dysfunction of hand movements imposed by systemic sclerosis (SSc). The modified version (mHAMIS), with 4 of the 9 original items, was developed later. The goal of the present study was to translate and validate HAMIS and mHAMIS into Brazilian Portuguese and culture.

Methods: After direct and reverse translation and comprehension test in 10 SSc patients, HAMIS-Br was applied to another 32 patients with SSc. To evaluate internal consistency, intraobserver and interobserver agreement, and intraobserver and interobserver reliability, we used respectively the Cronbach's α coefficient, kappa concordance and intraclass correlation (ICC). The correlation between HAMIS-Br and mHAMIS-Br was evaluated and a factorial analysis was performed.

Results: HAMIS-Br showed excellent internal consistency (Cronbach's α = 0.997), good intraobserver agreement (kappa between 0.78 [95%CI =0.57-0.99] and 1) and intraobserver and interobserver reliability (ICC = 0.993, 95% CI = 0.973-0.993 and ICC = 0.994, 95% CI = 0.987-0.997, respectively). The mHAMIS-Br presented similar results and excellent correlation with HAMIS-Br (r = 0.923). The factorial analysis extracted three groups of questions that explain 84.4% of the total variance, and that can be understood through the influence of certain movements in the interpretation of others: [1] questions whose interpretation is influenced by the extension of the fingers, [2] questions whose interpretation is influenced by flexion of the fingers, [3] volar flexion of the fingers, with similar correlation with both other factors.

Conclusions: HAMIS-Br and mHAMIS-Br showed good agreement, intraobserver and interobserver reliability, and internal validity. It is necessary to be attentive to the influence of certain limitations of movements in the interpretation of others.
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http://dx.doi.org/10.1186/s42358-019-0093-5DOI Listing
November 2019

The Polyamine Spermidine Modulates the Production of the Bacterial Genotoxin Colibactin.

mSphere 2019 10 2;4(5). Epub 2019 Oct 2.

CHU Toulouse, Service de Bactériologie-Hygiène, Toulouse, France

Colibactin is a polyketide/nonribosomal peptide produced by strains that harbor the island. This toxin induces DNA double-strand breaks and DNA interstrand cross-links in infected eukaryotic cells. Colibactin-producing strains are found associated with colorectal cancer biopsy specimens and promote intestinal tumor progression in various murine models. Polyamines are small polycationic molecules produced by both microorganisms and eukaryotic cells. Their levels are increased in malignancies, where they contribute to disease progression and metastasis. In this study, we demonstrated that the endogenous spermidine synthase SpeE is required for full genotoxic activity of colibactin-producing Supplying spermidine in a Δ strain restored genotoxic activity. Spermidine is involved in the autotoxicity linked to colibactin and is required for direct damaging activity on DNA. The production of the colibactin prodrug motif is impaired in Δ mutants. Therefore, we demonstrated that spermidine has a direct impact on colibactin synthesis. Colibactin-producing strains are associated with cancerous and precancerous colorectal tissues and are suspected of promoting colorectal carcinogenesis. In this study, we describe a new interplay between the synthesis of the genotoxin colibactin and the polyamine spermidine. Polyamines are highly abundant in cancer tissue and are associated with cell proliferation. The need for spermidine in genotoxic activity provides a new perspective on the role of these metabolites in the pathogenicity of colibactin-producing strains in colorectal cancer.
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http://dx.doi.org/10.1128/mSphere.00414-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796968PMC
October 2019

Deciphering the interplay between the genotoxic and probiotic activities of Escherichia coli Nissle 1917.

PLoS Pathog 2019 09 23;15(9):e1008029. Epub 2019 Sep 23.

IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France.

Although Escherichia coli Nissle 1917 (EcN) has been used therapeutically for over a century, the determinants of its probiotic properties remain elusive. EcN produces two siderophore-microcins (Mcc) responsible for an antagonistic activity against other Enterobacteriaceae. EcN also synthesizes the genotoxin colibactin encoded by the pks island. Colibactin is a virulence factor and a putative pro-carcinogenic compound. Therefore, we aimed to decouple the antagonistic activity of EcN from its genotoxic activity. We demonstrated that the pks-encoded ClbP, the peptidase that activates colibactin, is required for the antagonistic activity of EcN. The analysis of a series of ClbP mutants revealed that this activity is linked to the transmembrane helices of ClbP and not the periplasmic peptidase domain, indicating the transmembrane domain is involved in some aspect of Mcc biosynthesis or secretion. A single amino acid substitution in ClbP inactivates the genotoxic activity but maintains the antagonistic activity. In an in vivo salmonellosis model, this point mutant reduced the clinical signs and the fecal shedding of Salmonella similarly to the wild type strain, whereas the clbP deletion mutant could neither protect nor outcompete the pathogen. The ClbP-dependent antibacterial effect was also observed in vitro with other E. coli strains that carry both a truncated form of the Mcc gene cluster and the pks island. In such strains, siderophore-Mcc synthesis also required the glucosyltransferase IroB involved in salmochelin production. This interplay between colibactin, salmochelin, and siderophore-Mcc biosynthetic pathways suggests that these genomic islands were co-selected and played a role in the evolution of E. coli from phylogroup B2. This co-evolution observed in EcN illustrates the fine margin between pathogenicity and probiotic activity, and the need to address both the effectiveness and safety of probiotics. Decoupling the antagonistic from the genotoxic activity by specifically inactivating ClbP peptidase domain opens the way to the safe use of EcN.
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http://dx.doi.org/10.1371/journal.ppat.1008029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776366PMC
September 2019

Adhesion G-protein coupled receptor 56 is required for 3T3-L1 adipogenesis.

J Cell Physiol 2020 02 15;235(2):1601-1614. Epub 2019 Jul 15.

Department of Biological & Biomedical Sciences, School of Health & Life Sciences, Glasgow Caledonian University, Glasgow, Scotland.

Obesity-associated conditions represent major global health and financial burdens and understanding processes regulating adipogenesis could lead to novel intervention strategies. This study shows that adhesion G-protein coupled receptor 56 (GPR56) gene transcripts are reduced in abdominal visceral white adipose tissue derived from obese Zucker rats versus lean controls. Immunostaining in 3T3-L1 preadipocytes reveals both mitotic cell restricted surface and low level general expression patterns of Gpr56. Gpr56 transcripts are differentially expressed in 3T3-L1 cells during adipogenesis. Transient knockdown (KD) of Gpr56 in 3T3-L1 cells dramatically inhibits differentiation through reducing the accumulation of both neutral cellular lipids (56%) and production of established adipogenesis Pparγ (60-80%), C/ebpα (40-78%) mediator, and Ap2 (56-80%) marker proteins. Furthermore, genome editing of Gpr56 in 3T3-L1 cells created CW2.2.4 and RM4.2.5.5 clones (Gpr56 cells) with compound heterozygous deletion frameshift mutations which abolish adipogenesis. Genome edited cells have sustained levels of the adipogenesis inhibitor β-catenin, reduced proliferation, reduced adhesion, altered profiles, and or abundance of extracellular matrix component gene transcripts for fibronectin, types I, III, and IV collagens and loss of actin stress fibers. β-catenin KD alone is insufficient to restore adipogenesis in Gpr56 cells. Together these data show that Gpr56 is required for adipogenesis in 3T3-L1 cells. This report is the first demonstration that Gpr56 participates in regulation of the adipogenesis developmental program. Modulation of the levels of this protein and/or its biological activity may represent a novel target for development of therapeutic agents for the treatment of obesity.
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http://dx.doi.org/10.1002/jcp.29079DOI Listing
February 2020

Adults with Housing Insecurity Have Worse Access to Primary and Preventive Care.

J Am Board Fam Med 2019 Jul-Aug;32(4):521-530

From Unity Health Care, Washington, D.C. (PM); Department of Health Systems and Population Health Sciences, University of Houston College of Medicine, Houston (WL); Robert Graham Center: Policy Studies in Family Medicine and Primary Care, Washington D.C. (AB, AJ, SP); Center for Vulnerable Populations, University of California, San Francisco/Zuckerberg San Francisco General, San Francisco (MK).

Objective: Housing insecurity has been linked to high-risk behaviors and chronic disease, although less is known about the pathways leading to poor health. We sought to determine whether housing insecurity is associated with access to preventive and primary care.

Methods: We conducted weighted univariate, bivariate, and multivariate analyses by using 2011 to 2015 Behavioral Risk factor Surveillance Survey data (N = 228,131 adults). The independent variable was housing insecurity derived from the question on worry about paying rent or mortgage. The outcome measures were health services utilization (no usual source of care, no routine checkup in the past 1 year, and delayed medical care due to cost), self-rated health (number of days reported physical, mental health not good, and poor overall health), and number of chronic diseases (0, 1, 2 or more). The covariates included age, sex, race/ethnicity, income, level of education, marital status, and number of children in the family. We also adjusted for state fixed effects and survey year. We performed χ tests and binary logistic regressions on categorical variables and ran tests and estimated linear regression models on continuous variables. Multinomial logistic regressions were estimated for the number of chronic diseases.

Results: Of the 228,131 adults in the study sample, 28,704 adults reported housing insecurity. We found that those with housing insecurity were more likely to forgo routine check-ups and lack usual sources of care. Low-income individuals, minorities, the unmarried, and middle-aged adults were more likely to report housing insecurity.

Conclusion: Housing insecurity is associated with worse access to preventive and primary care. Interventions to enhance access for these patients should be developed and studied.
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http://dx.doi.org/10.3122/jabfm.2019.04.180374DOI Listing
August 2020

Comparing immunochromatography with latex antigen agglutination testing for the diagnosis of cryptococcosis in cats, dogs and koalas.

Med Mycol 2020 Jan;58(1):39-46

Centre for Veterinary Education, Veterinary Science Conference Centre, B22, University of Sydney NSW Australia 2006; Adjunct Professor Charles Sturt University.

Although the point-of-care cryptococcal antigen lateral flow assay (LFA) has revolutionized the diagnosis of cryptococcosis in human patients, to date there has been no large-scale examination of this test in animals. We therefore assessed the LFA in cats, dogs and koalas suspected of having cryptococcosis. In sum, 528 serum specimens (129 from cats, 108 from dogs, 291 from koalas) were tested using the LFA and one of two commercially available latex cryptococcal antigen agglutination test (LCAT) kits. The LCAT is a proven and well-accepted method in veterinary patients and therefore taken as the "gold standard" against which the LFA was compared. The LFA achieved a sensitivity of 92%, 100%, and 98% in cats, dogs, and koalas, respectively, with corresponding negative predictive values of 94%, 100%, and 98%. The specificity of the LFA was 81%, 84%, and 62% for cats, dogs, and koalas, respectively, with corresponding positive predictive values of 76%, 48%, and 69%. These findings suggest the most appropriate role for the LFA is as a screening test to rule out a diagnosis of cryptococcosis in cats, dogs, and koalas. Point-of-care accessibility makes it equally suited for use in the field and as a cage-side test in veterinary hospitals. The suboptimal specificity of the LFA makes it less suited to definitive confirmation of cryptococcosis in animals; therefore, all LFA-positive test results should be confirmed by LCAT testing. The discrepancy between these observations and the high specificity of the LFA in humans may reflect differences in the host-pathogen interactions amongst the species.
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http://dx.doi.org/10.1093/mmy/myz010DOI Listing
January 2020

Regulation of interferon signaling in response to gut microbes by autophagy.

Gut Microbes 2020 23;11(1):126-134. Epub 2019 May 23.

Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY, USA.

The cellular degradative pathway of autophagy prevents unrestrained inflammatory signaling by removing intracellular microbes, damaged organelles, and other factors that trigger immune reactions. Consistent with this function, a common variant of the autophagy gene is associated with susceptibility to inflammatory bowel disease (IBD), a disorder characterized by a chronic immune reaction directed against the gut microbiota. We recently contributed to our understanding of the link between autophagy and inflammatory signaling in the intestine by demonstrating that autophagy proteins including ATG16L1 are necessary in the epithelium to prevent a spontaneous type I interferon response to the gut microbiota. Enhanced innate immunity that occurs upon autophagy inhibition is protective in mouse models of infection by an enteric bacterial pathogen and acute epithelial injury. Although avoiding excess immune reactions towards the microbiota is necessary to prevent IBD, these observations indicate that autophagy hampers productive immunity at the intestinal epithelial barrier in certain contexts. Here, we discuss how this counterintuitive consequence of autophagy inhibition can be reconciled with the established beneficial role of the pathway.
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http://dx.doi.org/10.1080/19490976.2019.1614395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973319PMC
June 2020

Vasculature-associated fat macrophages readily adapt to inflammatory and metabolic challenges.

J Exp Med 2019 04 12;216(4):786-806. Epub 2019 Mar 12.

Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY

Tissue-resident macrophages are the most abundant immune cell population in healthy adipose tissue. Adipose tissue macrophages (ATMs) change during metabolic stress and are thought to contribute to metabolic syndrome. Here, we studied ATM subpopulations in steady state and in response to nutritional and infectious challenges. We found that tissue-resident macrophages from healthy epididymal white adipose tissue (eWAT) tightly associate with blood vessels, displaying very high endocytic capacity. We refer to these cells as vasculature-associated ATMs (VAMs). Chronic high-fat diet (HFD) results in the accumulation of a monocyte-derived CD11cCD64 double-positive (DP) macrophage eWAT population with a predominant anti-inflammatory/detoxifying gene profile, but reduced endocytic function. In contrast, fasting rapidly and reversibly leads to VAM depletion, while acute inflammatory stress induced by pathogens transiently depletes VAMs and simultaneously boosts DP macrophage accumulation. Our results indicate that ATM populations dynamically adapt to metabolic stress and inflammation, suggesting an important role for these cells in maintaining tissue homeostasis.
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http://dx.doi.org/10.1084/jem.20181049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446877PMC
April 2019

Staphylococcus aureus Leukocidins Target Endothelial DARC to Cause Lethality in Mice.

Cell Host Microbe 2019 Mar 21;25(3):463-470.e9. Epub 2019 Feb 21.

Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA; Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.

The pathogenesis of Staphylococcus aureus is thought to depend on the production of pore-forming leukocidins that kill leukocytes and lyse erythrocytes. Two leukocidins, Leukocidin ED (LukED) and γ-Hemolysin AB (HlgAB), are necessary and sufficient to kill mice upon infection and toxin challenge. We demonstrate that LukED and HlgAB cause vascular congestion and derangements in vascular fluid distribution that rapidly cause death in mice. The Duffy antigen receptor for chemokines (DARC) on endothelial cells, rather than leukocytes or erythrocytes, is the critical target for lethality. Consistent with this, LukED and HlgAB injure primary human endothelial cells in a DARC-dependent manner, and mice with DARC-deficient endothelial cells are resistant to toxin-mediated lethality. During bloodstream infection in mice, DARC targeting by S. aureus causes increased tissue damage, organ dysfunction, and host death. The potential for S. aureus leukocidins to manipulate vascular integrity highlights the importance of these virulence factors.
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http://dx.doi.org/10.1016/j.chom.2019.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468323PMC
March 2019

Connexin 26 and 43 play a role in regulating proinflammatory events in the epidermis.

J Cell Physiol 2019 Feb 2. Epub 2019 Feb 2.

Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, Scotland, UK.

Dysregulation of Connexin (CX) expression and function is associated with a range of chronic inflammatory conditions including psoriasis and nonhealing wounds. To mimic a proinflammatory environment, HaCaT cells, a model human keratinocyte cell line, were challenged with 10 µg/ml peptidoglycan (PGN) isolated from Staphylococcus aureus for 15 min to 24 hr in the presence or absence of CX blockers and/or following CX26, CX43, PANX1 and TLR2 small interfering RNA (siRNA) knockdown (KD). Expression levels of IL-6, IL-8, CX26, CX43, PANX1, TLR2 and Ki67 were assessed by quantitative real-time polymerase chain reaction, western blot analysis and/or immunocytochemistry. Nuclear factor kappa β (NF-κβ) was blocked with BAY 11-7082, CX-channel function was determined by adenosine 5'-triphosphate (ATP) release assays. Enzyme-linked immunosorbent assay monitored IL6 release following PGN challenge in the presence or absence of siRNA or blockers of CX or purinergic signalling. Exposure to PGN induced IL-6, IL-8, CX26 and TLR2 gene expression but it did not influence CX43, PANX1 or Ki67 messenger RNA expression levels. CX43 protein levels were reduced following 24 hr PGN exposure. PGN-induced CX26 and IL-6 expression were also aborted by TLR2-KD and inhibition of NF-κβ. ATP and IL-6 release were stimulated following 15 min and 1-24 hr challenge with PGN, respectively. Release of both agents was inhibited by coincubation with CX-channel blockers, CX26-, CX43- and TLR2-KD. The IL-6 response was also reduced by purinergic blockers. CX-signalling plays a role in the innate immune response in the epidermis. PGN is detected by TLR2, which via NF-κβ, directly activates CX26 and IL-6 expression. CX43 and CX26 maintain proinflammatory signalling by permitting ATP release, however, PANX1 does not participate.
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http://dx.doi.org/10.1002/jcp.28206DOI Listing
February 2019

Why does this patient have chronic diarrhea?

JAAPA 2019 Jan;32(1):52-53

At the time this article was written, Victoria M. Verkest was a student in the PA program at Marietta (Ohio) College. She now practices at Pinnacle Dermatology in Birmingham, Mich. Patricia G. Martin is a retired PA and assistant professor in the PA program at Marietta College. Rajiv Agrawal practices family medicine in Shelby Township and St. Clair Shores, Mich., and is an associate clinical instructor of family medicine in the PA program at Marietta College. The authors have no potential conflicts of interest, financial or otherwise to disclose.

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http://dx.doi.org/10.1097/01.JAA.0000550298.75971.2bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774619PMC
January 2019

Long term survival of a dog with disseminated infection without definitive treatment.

Med Mycol Case Rep 2018 Dec 10;22:1-3. Epub 2018 Jul 10.

Sydney School of Veterinary Science, Faculty of Science, Evelyn Williams Building B10, University of Sydney, NSW 2006, Australia.

Canine disseminated fungal infection by species carries a guarded to grave prognosis as they often rapidly progress and are refractory to treatment with many euthanased soon after diagnosis. This case report describes a 2.5 year old female spayed German Shepherd Dog diagnosed with disseminated infection for which definitive treatment was declined by the owners. With only palliative management the dog survived three years and two months before succumbing to chronic kidney disease.
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http://dx.doi.org/10.1016/j.mmcr.2018.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235754PMC
December 2018

An Overview of the Focus of the International Gap Junction Conference 2017 and Future Perspectives.

Int J Mol Sci 2018 Sep 18;19(9). Epub 2018 Sep 18.

Department of Pathology and Immunology, University of Geneva, CH-1211 Geneva, Switzerland.

This Special Issue relates to the 18th biannual International Gap Junction Conference (IGJC2017), held at the Crowne Plaza Hotel, Glasgow, U.K., from the 29 July⁻2 August 2017 [...].
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http://dx.doi.org/10.3390/ijms19092823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164644PMC
September 2018

Autophagy proteins suppress protective type I interferon signalling in response to the murine gut microbiota.

Nat Microbiol 2018 10 10;3(10):1131-1141. Epub 2018 Sep 10.

Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY, USA.

As a conserved pathway that lies at the intersection between host defence and cellular homeostasis, autophagy serves as a rheostat for immune reactions. In particular, autophagy suppresses excess type I interferon (IFN-I) production in response to viral nucleic acids. It is unknown how this function of autophagy relates to the intestinal barrier where host-microbe interactions are pervasive and perpetual. Here, we demonstrate that mice deficient in autophagy proteins are protected from the intestinal bacterial pathogen Citrobacter rodentium in a manner dependent on IFN-I signalling and nucleic acid sensing pathways. Enhanced IFN-stimulated gene expression in intestinal tissue of autophagy-deficient mice in the absence of infection was mediated by the gut microbiota. Additionally, monocytes infiltrating into the autophagy-deficient intestinal microenvironment displayed an enhanced inflammatory profile and were necessary for protection against C. rodentium. Finally, we demonstrate that the microbiota-dependent IFN-I production that occurs in the autophagy-deficient host also protects against chemical injury of the intestine. Thus, autophagy proteins prevent a spontaneous IFN-I response to microbiota that is beneficial in the presence of infectious and non-infectious intestinal hazards. These results identify a role for autophagy proteins in controlling the magnitude of IFN-I signalling at the intestinal barrier.
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http://dx.doi.org/10.1038/s41564-018-0229-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179362PMC
October 2018