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  • Journal article
    Garnett JP, Baker EH, Naik S, Lindsay JA, Knight GM, Gill S, Tregoning JS, Baines DLet al., 2013,

    Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose

    , Thorax, Vol: 68, Pages: 835-845, ISSN: 0040-6376

    Background Diabetes is a risk factor for respiratoryinfection, and hyperglycaemia is associated withincreased glucose in airway surface liquid and risk ofStaphylococcus aureus infection.Objectives To investigate whether elevation ofbasolateral/blood glucose concentration promotes airwayStaphylococcus aureus growth and whether pretreatmentwith the antidiabetic drug metformin affects thisrelationship.Methods Human airway epithelial cells grown atair–liquid interface (±18 h pre-treatment, 30 μM–1 mMmetformin) were inoculated with 5×105 colony-formingunits (CFU)/cm2 S aureus 8325-4 or JE2 orPseudomonas aeruginosa PA01 on the apical surfaceand incubated for 7 h. Wild-type C57BL/6 or db/db(leptin receptor-deficient) mice, 6–10 weeks old, weretreated with intraperitoneal phosphate-buffered saline or40 mg/kg metformin for 2 days before intranasalinoculation with 1×107 CFU S aureus. Mice were culled24 h after infection and bronchoalveolar lavage fluidcollected.Results Apical S aureus growth increased withbasolateral glucose concentration in an in vitro airwayepithelia–bacteria co-culture model. S aureus reducedtransepithelial electrical resistance (RT) and increasedparacellular glucose flux. Metformin inhibited theglucose-induced growth of S aureus, increased RT anddecreased glucose flux. Diabetic (db/db) mice infectedwith S aureus exhibited a higher bacterial load in theirairways than control mice after 2 days and metformintreatment reversed this effect. Metformin did notdecrease blood glucose but reduced paracellular fluxacross ex vivo murine tracheas.Conclusions Hyperglycaemia promotes respiratoryS aureus infection, and metformin modifies glucose fluxacross the airway epithelium to limit hyperglycaemiainducedbacterial growth. Metformin might, therefore, beof additional benefit in the prevention and treatment ofrespiratory infection.
  • Journal article
    Hu K, Luo S, Tong L, Huang X, Jin W, Huang W, Du T, Yan Y, He S, Griffin GE, Shattock RJ, Hu Qet al., 2013,

    CCL19 and CCL28 Augment Mucosal and Systemic Immune Responses to HIV-1 gp140 by Mobilizing Responsive Immunocytes into Secondary Lymph Nodes and Mucosal Tissue

    , JOURNAL OF IMMUNOLOGY, Vol: 191, Pages: 1935-1947, ISSN: 0022-1767
  • Journal article
    Mann JFS, Mckay PF, Arokiasamy S, Patel RK, Tregoning JS, Shattock RJet al., 2013,

    Mucosal Application of gp140 Encoding DNA Polyplexes to Different Tissues Results in Altered Immunological Outcomes in Mice

    , PLOS ONE, Vol: 8, ISSN: 1932-6203
  • Journal article
    Tregoning JS, Wang BL, McDonald JU, Yamaguchi Y, Harker JA, Goritzka M, Johansson C, Bukreyev A, Collins PL, Openshaw PJet al., 2013,

    Neonatal antibody responses are attenuated by interferon-γ produced by NK and T cells during RSV infection

    , PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 5576-5581, ISSN: 0027-8424
  • Journal article
    Stieh DJ, Phillips JL, Rogers PM, King DF, Cianci GC, Jeffs SA, Gnanakaran S, Shattock RJet al., 2013,

    Dynamic electrophoretic fingerprinting of the HIV-1 envelope glycoprotein

    , Retrovirology, Vol: 10, ISSN: 1742-4690

    Background: Interactions between the HIV-1 envelope glycoprotein (Env) and its primary receptor CD4 areinfluenced by the physiological setting in which these events take place. In this study, we explored the surfacechemistry of HIV-1 Env constructs at a range of pH and salinities relevant to mucosal and systemic compartmentsthrough electrophoretic mobility (EM) measurements. Sexual transmission events provide a more acidicenvironment for HIV-1 compared to dissemination and spread of infection occurring in blood or lymph node. Wehypothesize functional, trimeric Env behaves differently than monomeric forms.Results: The dynamic electrophoretic fingerprint of trimeric gp140 revealed a change in EM from strongly negativeto strongly positive as pH increased from that of the lower female genital tract (pHx) to that of the blood (pHy).Similar findings were observed using a trimeric influenza Haemagglutinin (HA) glycoprotein, indicating that thismay be a general attribute of trimeric viral envelope glycoproteins. These findings were supported bycomputationally modeling the surface charge of various gp120 and HA crystal structures. To identify the behaviorof the infectious agent and its target cells, EM measurements were made on purified whole HIV-1 virions andprimary T-lymphocytes. Viral particles had a largely negative surface charge, and lacked the regions of positivitynear neutral pH that were observed with trimeric Env. T cells changed their surface chemistry as a function ofactivation state, becoming more negative over a wider range of pH after activation. Soluble recombinant CD4(sCD4) was found to be positively charged under a wide range of conditions. Binding studies between sCD4 andgp140 show that the affinity of CD4-gp140 interactions depends on pH.Conclusions: Taken together, these findings allow a more complete model of the electrochemical forces involvedin HIV-1 Env functionality. These results indicate that the influence of the localized environment on the inter
  • Journal article
    King DFL, Siddiqui AA, Buffa V, Fischetti L, Gao Y, Stieh D, McKay PF, Rogers P, Ochsenbauer C, Kappes JC, Arts EJ, Shattock RJet al., 2013,

    Mucosal Tissue Tropism and Dissemination of HIV-1 Subtype B Acute Envelope-Expressing Chimeric Virus

    , JOURNAL OF VIROLOGY, Vol: 87, Pages: 890-899, ISSN: 0022-538X
  • Journal article
    Garnett JP, Baker EH, Tregoning JS, Baines DLet al., 2013,

    Metformin Inhibits Hyperglycemia-Induced Airway Bacterial Growth And Is Associated With Reduced Transepithelial Glucose Permeability

    , AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 187, ISSN: 1073-449X
  • Journal article
    Buffa V, Klein K, Fischetti L, Shattock RJet al., 2012,

    Evaluation of TLR Agonists as Potential Mucosal Adjuvants for HIV gp140 and Tetanus Toxoid in Mice

    , PLOS ONE, Vol: 7, ISSN: 1932-6203
  • Journal article
    Merbah M, Arakelyan A, Edmonds T, Ochsenbauer C, Kappes JC, Shattock RJ, Grivel J-C, Margolis LBet al., 2012,

    HIV-1 Expressing the Envelopes of Transmitted/Founder or Control/Reference Viruses Have Similar Infection Patterns of CD4 T-Cells in Human Cervical Tissue <i>Ex Vivo</i>

    , PLOS ONE, Vol: 7, ISSN: 1932-6203
  • Journal article
    Yamaguchi Y, Harker JA, Wang B, Openshaw PJ, Tregoning JS, Culley FJet al., 2012,

    Preexposure to CpG Protects against the Delayed Effects of Neonatal Respiratory Syncytial Virus Infection

    , JOURNAL OF VIROLOGY, Vol: 86, Pages: 10456-10461, ISSN: 0022-538X

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