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Raz A, Serrano A, Thaker M, Alston T, Fischetti VA
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Lysostaphin Lysibody Leads to Effective Opsonization and Killing of Methicillin-Resistant Staphylococcus aureus in a Murine Model

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 2018 OCT; 62(10):? Article e01056-18
The cell wall of Gram-positive bacteria contains abundant surfaceexposed carbohydrate structures that are highly conserved. While these properties make surface carbohydrates ideal targets for immunotherapy, carbohydrates elicit a poor immune response that results primarily in low-affinity IgM antibodies. In a previous publication, we introduced the lysibody approach to address this shortcoming. Lysibodies are engineered molecules that combine a high-affinity carbohydrate-binding domain of bacterial or bacteriophage origin and an Fc effector portion of a human IgG antibody, thus directing effective immunity to conserved bacterial surface carbohydrates. Here, we describe the first example of a lysibody containing the binding domain from a bacteriocin, lysostaphin. We also describe the creation of five lysibodies with binding domains derived from phage lysins, directed against Staphylococcus aureus. The lysostaphin and LysK lysibodies showed the most promise and were further characterized. Both lysibodies bound a range of clinically important staphylococcal strains, fixed complement on the staphylococcal surface, and induced phagocytosis of S. aureus by macrophages and human neutrophils. The lysostaphin lysibody had superior in vitro activity compared to that of the LysK lysibody, as well as that of the previously characterized ClyS lysibody, and it effectively protected mice in a kidney abscess/bacteremia model. These results further demonstrate that the lysibody approach is a reproducible means of creating antibacterial antibodies that cannot be produced by conventional means. Lysibodies therefore are a promising solution for opsonic antibodies that may be used passively to both treat and prevent infection by drug-resistant pathogens.
Perez-Garijo A
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When dying is not the end: Apoptotic caspases as drivers of proliferation

SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY 2018 OCT; 82(?):86-95
Caspases are well known for their role as executioners of apoptosis. However, recent studies have revealed that these lethal enzymes also have important mitogenic functions. Caspases can promote proliferation through autonomous regulation of the cell cycle, as well as by induction of secreted signals, which have a profound impact in neighboring tissues. Here, I review the proliferative role of caspases during development and homeostasis, in addition to their key regenerative function during tissue repair upon injury. Furthermore, the emerging properties of apoptotic caspases as drivers of carcinogenesis are discussed, as well as their involvement in other diseases. Finally, I examine further effects of caspases regulating death and survival in a non-autonomous manner. (C) 2017 The Author. Published by Elsevier Ltd.
Seidel JA, Vukmanovic-Stejic M, Muller-Durovic B, Patel N, Fuentes-Duculan J, Henson SM, Krueger JG, Rustin MHA, Nestle FO, Lacy KE, Akbar AN
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Skin resident memory CD8(+) T cells are phenotypically and functionally distinct from circulating populations and lack immediate cytotoxic function

CLINICAL AND EXPERIMENTAL IMMUNOLOGY 2018 OCT; 194(1):79-92
The in-depth understanding of skin resident memory CD8(+) T lymphocytes (T-RM) may help to uncover strategies for their manipulation during disease. We investigated isolated T-RM from healthy human skin, which expressed the residence marker CD69, and compared them to circulating CD8(+) T cell populations from the same donors. There were significantly increased proportions of CD8(+)CD45RA(-)CD27(-) T cells in the skin that expressed low levels of killer cell lectin-like receptor G1 (KLRG1), CD57, perforin and granzyme B. The CD8(+) T-RM in skin were therefore phenotypically distinct from circulating CD8(+)CD45RA(-)CD27(-) T cells that expressed high levels of all these molecules. Nevertheless, the activation of CD8(+) T-RM with T cell receptor (TCR)/CD28 or interleukin (IL)-2 or IL-15 in vitro induced the expression of granzyme B. Blocking signalling through the inhibitory receptor programmed cell death 1 (PD)-1 further boosted granzyme B expression. A unique feature of some CD8(+) T-RM cells was their ability to secrete high levels of tumour necrosis factor (TNF)- and IL-2, a cytokine combination that was not seen frequently in circulating CD8(+) T cells. The cutaneous CD8(+) T-RM are therefore diverse, and appear to be phenotypically and functionally distinct from circulating cells. Indeed, the surface receptors used to distinguish differentiation stages of blood T cells cannot be applied to T cells in the skin. Furthermore, the function of cutaneous T-RM appears to be stringently controlled by environmental signals in situ.
Fiedorczuk K, Sazanov LA
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Mammalian Mitochondrial Complex I Structure and Disease-Causing Mutations

TRENDS IN CELL BIOLOGY 2018 OCT; 28(10):835-867
Complex I has an essential role in ATP production by coupling electron transfer from NADH to quinone with translocation of protons across the inner mitochondrial membrane. Isolated complex I deficiency is a frequent cause of mitochondrial inherited diseases. Complex I has also been implicated in cancer, ageing, and neurodegenerative conditions. Until recently, the understanding of complex I deficiency on the molecular level was limited due to the lack of high-resolution structures of the enzyme. However, due to developments in single particle cryoelectron microscopy (cryo-EM), recent studies have reported nearly atomic resolution maps and models of mitochondrial complex I. These structures significantly add to our understanding of complex I mechanism and assembly. The disease-causing mutations are discussed here in their structural context.
Lutter L, van Konijnenburg DPH, Brand EC, Oldenburg B, van Wijk F
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The elusive case of human intraepithelial T cells in gut homeostasis and inflammation

NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY 2018 OCT; 15(10):637-649
The epithelial barrier of the gastrointestinal tract is home to numerous intraepithelial T cells (IETs). IETs are functionally adapted to the mucosal environment and are among the first adaptive immune cells to encounter microbial and dietary antigens. They possess hallmark features of tissue-resident T cells: they are long-lived nonmigratory cells capable of rapidly responding to antigen challenges independent of T cell recruitment from the periphery. Gut-resident T cells have been implicated in the relapsing and remitting course and persisting low-grade inflammation of chronic gastrointestinal diseases, including IBD and coeliac disease. So far, most data IETs have been derived from experimental animal models; however, IETs and the environmental makeup differ between mice and humans. With advances in techniques, the number of human studies has grown exponentially in the past 5 years. Here, we review the literature on the involvement of human IETs in gut homeostasis and inflammation, and how these cells are influenced by the microbiota and dietary antigens. Finally, targeting of IETs in therapeutic interventions is discussed. Broad insight into the function and role of human IETs in gut homeostasis and inflammation is essential to identify future diagnostic, prognostic and therapeutic strategies.
Czarnowicki T, He H, Leonard A, Malik K, Magidi S, Rangel S, Patel K, Ramsey K, Murphrey M, Song T, Estrada Y, Wen HC, Krueger JG, Guttman-Yassky E, Paller AS
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The Major Orphan Forms of Ichthyosis Are Characterized by Systemic T-Cell Activation and Th-17/Tc-17/Th-22/Tc-22 Polarization in Blood

JOURNAL OF INVESTIGATIVE DERMATOLOGY 2018 OCT; 138(10):2157-2167
The ichthyoses are rare skin disorders with immune and barrier aberrations. Identifying blood phenotypes may advance targeted therapeutics. We aimed to compare frequencies of skin homing/cutaneous lymphocyte antigen (+) versus systemic/cutaneous lymphocyte antigen (-) "polar" CD4(+)/CD8(+) and activated T-cell subsets in ichthyosis versus atopic dermatitis, psoriasis, and control blood, with appropriate clinical correlations. Flow cytometry was used to measure IFN-gamma, IL-13, IL-9, IL-17, and IL-22 cytokines in CD4(+)/CD8(+) T cells, with inducible co-stimulator molecule and HLA-DR defining mid-and long-term T-cell activation, respectively. We compared peripheral blood from 47 patients with ichthyosis (congenital ichthyosiform erythroderma, lamellar ichthyosis, epidermolytic ichthyosis, and Netherton syndrome) with 43 patients with atopic dermatitis and 24 patients with psoriasis and 59 age-matched controls. Clinical measures included the ichthyosis severity score, with subsets for erythema and scaling, trans-epidermal water loss, and pruritus. All ichthyoses had excessive inducible co-stimulator molecule activation (P<0.001), particularly epidermolytic ichthyosis. Significantly elevated IL-17-(P<0.05) and IL-22-producing (P<0.01) T cells characterized ichthyoses, mainly Netherton syndrome and congenital ichthyosiform erythroderma (P<0.05). Increased T helper 2/cytotoxic T cell 2/T helper 9 (P<0.05) and similar IFN-gamma frequencies (P>0.1) versus controls were also noted. IL-17/IL-22-producing cells clustered with clinical measures, whereas IFN-gamma clustered with age. Our data show peripheral blood IL-17/IL-22 activation across the ichthyoses, correlating with clinical measures. Targeted therapies should dissect the relative contribution of polar cytokines to disease pathogenesis.
Watt K, Newsted D, Voorand E, Gooding RJ, Majewski A, Truesdell P, Yao B, Tuschl T, Renwick N, Craig AW
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MicroRNA-206 suppresses TGF-beta signalling to limit tumor growth and metastasis in lung adenocarcinoma

CELLULAR SIGNALLING 2018 OCT; 50(?):25-36
MicroRNA-206 (miR-206) has demonstrated tumor suppressive effects in a variety of cancers. Numerous studies have identified aberrantly expressed targets of miR-206 that contribute to tumor progression and metastasis, however, the broader gene-networks and pathways regulated by miR-206 remain poorly defined. Here, we have ectopically expressed miR-206 in lung adenocarcinoma cell lines and tumors to identify differentially expressed genes, and study the effects on tumor growth and metastasis. In H1299 tumor xenograft assays, stable expression of miR-206 suppressed both tumor growth and metastasis in mice. Profiling of xenograft tumors using small RNA sequencing and a targeted panel of tumor progression and metastasis-related genes revealed a network of genes involved in TGF-beta signalling that were regulated by miR-206. Among these were the TGFB1 ligand, as well as direct transcriptional targets of Smad3. Other differentially expressed genes included components of the extracellular matrix involved in TGF-beta activation and signalling, including Thrombospondin-1, which is responsible for the activation of latent TGF-beta in the stroma. In cultured lung adenocarcinoma cells treated with recombinant TGF-beta, ectopic expression of miR-206 impaired canonical signalling, and expression of TGF-beta target genes linked to epithelial-mesenchymal transition. This was due at least in part to the suppression of Smad3 protein levels in lung adenocarcinoma cells with ectopic miR-206 expression. Together, these findings indicate that miR-206 can suppress tumor progression and metastasis by limiting autocrine production of TGF-beta, and highlight the potential utility of TGF-beta inhibitors for the treatment of lung adenocarcinomas.
Galea S, Vaughan RD
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Population Health Science as the Basic Science of Public Health: A Public Health of Consequence, October 2018

AMERICAN JOURNAL OF PUBLIC HEALTH 2018 OCT; 108(10):1288-1289
Todt D, Moeller N, Praditya D, Kinast V, Friesland M, Engelmann M, Verhoye L, Sayed IM, Behrendt P, Thi VLD, Meuleman P, Steinmann E
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The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo

ANTIVIRAL RESEARCH 2018 SEP; 157(?):151-158
Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and a member of the genus Orthohepevirus in the family Hepeviridae. HEV infections are the common cause of acute hepatitis but can also take chronic courses. Ribavirin is the treatment of choice for most patients and type I interferon (IFN) has been evaluated in a few infected transplantation patients in vivo. However, no effective and specific treatments against HEV infections are currently available. In this study, we evaluated the natural compound silvestrol, isolated from the plant Aglaia foveolata, and known for its specific inhibition of the DEAD-box RNA helicase eIF4A in state-of-the-art HEV experimental model systems. Silvestrol blocked HEV replication of different subgenomic replicons in a dose-dependent manner at low nanomolar concentrations and acted additive to ribavirin (RBV). In addition, HEV p6-based full length replication and production of infectious particles was reduced in the presence of silvestrol. A pangenotypic effect of the compound was further demonstrated with primary isolates from four different human genotypes in HEV infection experiments of hepatocyte-like cells derived from human embryonic and induced pluripotent stem cells. In vivo, HEV RNA levels rapidly declined in the feces of treated mice while no effect was observed in the vehicle treated control animals. In conclusion, silvestrol could be identified as pangenotypic HEV replication inhibitor in vitro with additive effect to RBV and further demonstrated high potency in vivo. The compound therefore may be considered in future treatment strategies of chronic hepatitis E in immunocompromised patients.
Dominguez-Pinilla N, Allende LM, Rosain J, Gallego MD, Chaves F, Deswarte C, Viedma E, Arocena JD, Ruiz-Contreras J, Bustamante J, Gonzalez-Granado LI
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Disseminated abscesses due to Mycoplasma faucium in a patient with activated PI3K delta syndrome type 2

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2018 SEP-OCT; 6(5):1796-1798.e2