Christopher A Hunter

University of Cambridge, Cambridge, England, United Kingdom

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Publications (207)1418.09 Total impact

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    11/2015; 3(Suppl 2):O5. DOI:10.1186/2051-1426-3-S2-O5
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    ABSTRACT: Dendritic cells (DCs) are critical for resistance to Toxoplasma gondii, and infection with this pathogen leads to increased numbers of DCs at local sites of parasite replication and in secondary lymphoid organs, but the factors that regulate this expansion are poorly understood. The cytokine Flt3 ligand (Flt3L) is critical for the generation and maintenance of DCs, and Flt3L(-/-) mice were found to be highly susceptible to acute toxoplasmosis. This phenotype correlated with decreased production of IL-12 and IFN-γ, as well as impaired NK cell responses. Surprisingly, despite low basal numbers of DCs, Flt3L(-/-) mice infected with T. gondii displayed an expansion of CD8α(+) and CD11b(lo)CD8α(-) DCs. Infection also induced an expansion of parasite-specific CD4(+) and CD8(+) T cells in Flt3L(-/-) mice; however, these cells were reduced in number and displayed impaired ability to produce IFN-γ relative to wild-type controls. Exogenous IL-12 treatment partially restored NK and T cell responses in Flt3L(-/-) mice, as well as acute resistance; however, these mice eventually succumbed to toxoplasmic encephalitis, despite the presence of large numbers of DCs and T cells in the brain. These results highlight the importance of Flt3L for resistance to toxoplasmosis and demonstrate the existence of Flt3L-independent pathways that can mediate infection-induced expansion of DCs and T cell priming.
    The Journal of Immunology 09/2015; 195(9). DOI:10.4049/jimmunol.1500690 · 4.92 Impact Factor
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    ABSTRACT: The association constants and enthalpies for the binding of hydrogen bond donors to group 10 transition metal complexes featuring a single fluoride ligand (trans [Ni(F)(2-C5NF4)(PR3)2] R = Et 1a, Cy 1b, trans [Pd(F)(4-C5NF4)(PCy3)2] 2, trans [Pt(F){2-C5NF2H(CF3)}(PCy3)2] 3 and of group 4 difluorides (Cp2MF2, M = Ti 4a, Zr 5a, Hf 6a; Cp*2MF2, M = Ti 4b, Zr 5b, Hf 6b) are reported. These measurements allow placement of these fluoride ligands on the scales of organic H-bond acceptor strength. The H-bond acceptor capability β (Hunter scale) for the group 10 metal fluorides is far greater (1a 12.1, 1b 9.7, 2 11.6, 3 11.0) than for group 4 metal fluorides (4a 5.8, 5a 4.7, 6a 4.7, 4b 6.9, 5b 5.6, 6b 5.4), demonstrating that the group 10 fluorides are comparable to the strongest organic H-bond acceptors, such as Me3NO, whereas group 4 fluorides fall in the same range as N-bases aniline through to pyridine. Additionally, the measurement of the binding enthalpy of 4-fluorophenol to 1a in carbon tetrachloride (-23.5 ± 0.3 kJ mol-1) interlocks our study with Laurence's scale of H-bond basicity of organic molecules. The much greater polarity of group 10 metal fluorides than that of the group 4 metal fluorides is consistent with the importance of pπ-dπ bonding in the latter. The polarity of the group 10 metal fluorides indicates their potential as building blocks for hydrogen-bonded assemblies. The synthesis of trans [Ni(F){2 C5NF3(NH2)}(PEt3)2] which exhibits an extended chain structure assembled by hydrogen bonds between the amine and metal-fluoride groups confirms this hypothesis.
    Journal of the American Chemical Society 08/2015; 137(36). DOI:10.1021/jacs.5b07509 · 12.11 Impact Factor
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    Christoph Konradt · Christopher A Hunter ·

    Journal of Experimental Medicine 07/2015; 212(8):1141-2. DOI:10.1084/jem.2128insight3 · 12.52 Impact Factor
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    Dataset: b612307b
    Scott L Cockroft · Christopher A Hunter ·

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    ABSTRACT: The protozoan parasite, Toxoplasma, like many intracellular pathogens, suppresses interferon gamma (IFN-γ)-induced signal transducer and activator of transcription 1 (STAT1) activity. We exploited this well-defined host-pathogen interaction as the basis for a high-throughput screen, identifying nine transcription factors that enhance STAT1 function in the nucleus, including the orphan nuclear hormone receptor TLX. Expression profiling revealed that upon IFN-γ treatment TLX enhances the output of a subset of IFN-γ target genes, which we found is dependent on TLX binding at those loci. Moreover, infection of TLX deficient mice with the intracellular parasite Toxoplasma results in impaired production of the STAT1-dependent cytokine interleukin-12 by dendritic cells and increased parasite burden in the brain during chronic infection. These results demonstrate a previously unrecognized role for this orphan nuclear hormone receptor in regulating STAT1 signaling and host defense and reveal that STAT1 activity can be modulated in a context-specific manner by such "modifiers."
    PLoS Biology 07/2015; 13(7):e1002200. DOI:10.1371/journal.pbio.1002200 · 9.34 Impact Factor
  • Hongmei Sun · Kai Guo · Haifeng Gan · Xin Li · Christopher A Hunter ·
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    ABSTRACT: Atropisomers of a series of zinc tetraphenyl porphyrins were synthesized and used as supramolecular receptors. Rotation around the porphyrin-meso phenyl bonds is restricted by installing ortho-chlorine substituents on the phenyl groups. The chlorine substituents allowed chromatographic separation of atropisomers, which did not interconvert at room temperature. The porphyrin meso phenyl groups were also equipped with phenol groups, which led to the formation of intramolecular H-bonds when the zinc porphyrins were bound to pyridine ligands equipped with ester or amide side arms. Binding of the pyridine ligands with the conformationally locked chloroporphyrins was compared with the corresponding unsubstituted porphyrins, which are more flexible. The association constants of 150 zinc porphyrin-pyridine complexes were measured in two different solvents, toluene and 1,1,2,2-tetrachloroethane (TCE). These association constants were then used to construct 120 chemical double mutant cycles to quantify the influence of chlorine substitution on the free energy of intramolecular H-bonds formed between the phenol side arms of the porphyrins and the ester or amide side arms of the pyridine ligands. Conformational restriction leads to increases in the stability of some complexes and decreases in the stability of others with variations in the free energy contribution due to intramolecular H-bonding of -5 to +6 kJ mol(-1).
    Organic & Biomolecular Chemistry 07/2015; 13(29). DOI:10.1039/c5ob00805k · 3.56 Impact Factor
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    ABSTRACT: Intestinal infection with the intracellular parasite Toxoplasma gondii results in the translocation of commensal bacteria to peripheral organs and the development of a T cell response specific to the microbiota. In naïve mice, the recently described RORγt+ group 3 innate lymphoid cell (ILC) population plays a critical role in promoting intestinal barrier function and limiting responses to gut-resident commensal bacteria. Given this role for group 3 ILCs, studies were performed to evaluate whether these cells might influence the immune response to mucosal infection with T. gondii. Phenotypic characterization of RORγt+ ILCs in T. gondii infected mice revealed that this population decreased following challenge but the population that remained expressed costimulatory molecules and IL-22. One factor that influences the maintenance of RORγt+ ILCs is the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, and Ahr-/- mice have a marked defect in the lamina propria group 3 ILC population. When Ahr-/- mice were challenged with T. gondii, they lost more weight than wild type controls. This disease course in Ahr-/- animals was associated with increased T cell responses to Toxoplasma antigen and crude commensal antigen preparations. Together, these data suggest that group 3 ILCs have a role in limiting T cell activation during intestinal infection.
    PLoS ONE 05/2015; 10(5):e0128335. DOI:10.1371/journal.pone.0128335 · 3.23 Impact Factor
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    ABSTRACT: Interleukin-6 (IL-6) and IL-27 signal through a shared receptor subunit and employ the same downstream STAT transcription proteins, but yet are ascribed unique and overlapping functions. To evaluate the specificity and redundancy for these cytokines, we quantified their global transcriptomic changes and determined the relative contributions of STAT1 and STAT3 using genetic models and chromatin immunoprecipitation-sequencing (ChIP-seq) approaches. We found an extensive overlap of the transcriptomes induced by IL-6 and IL-27 and few examples in which the cytokines acted in opposition. Using STAT-deficient cells and T cells from patients with gain-of-function STAT1 mutations, we demonstrated that STAT3 is responsible for the overall transcriptional output driven by both cytokines, whereas STAT1 is the principal driver of specificity. STAT1 cannot compensate in the absence of STAT3 and, in fact, much of STAT1 binding to chromatin is STAT3 dependent. Thus, STAT1 shapes the specific cytokine signature superimposed upon STAT3's action. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 05/2015; 42(5):877-89. DOI:10.1016/j.immuni.2015.04.014 · 21.56 Impact Factor
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    William Cullen · Katie A. Thomas · Christopher A. Hunter · Michael D Ward ·
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    ABSTRACT: We demonstrate the use of a simple pH swing to control the selection of one of three different guests from aqueous solution by a coordination cage host. Switching between different guests is based on the fact that neutral organic guests bind strongly in the cage due to the hydrophobic effect, but for acidic or basic guests, the charged (protonated or deprotonated) forms are hydrophilic and do not bind. The guests used are adamantane-1,3-dicarboxylic acid (H2A) which binds at low pH when it is neutral but not when it is deprotonated; 1-amino-adamantane (B) which binds at high pH when it is neutral but not when it is protonated; and cyclononanone (C) whose binding is not pH dependent and is therefore the default guest at neutral pH. Thus an increase in pH can reversibly switch the host between the three different bound states cage•H2A (at low pH) cage•C (at medium pH) and cage•B (at high pH) in succession.
    Chemical Science 05/2015; 6(7). DOI:10.1039/C5SC01475A · 9.21 Impact Factor
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    Christopher A Hunter · Simon A Jones ·
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    ABSTRACT: Interleukin 6 (IL-6) has a broad effect on cells of the immune system and those not of the immune system and often displays hormone-like characteristics that affect homeostatic processes. IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. However, the signaling cassette that controls the activity of IL-6 is complicated, and distinct intervention strategies can inhibit this pathway. Clinical experience with antagonists of IL-6 has raised new questions about how and when to block this cytokine to improve disease outcome and patient wellbeing. Here we discuss the effect of IL-6 on innate and adaptive immunity and the possible advantages of various antagonists of IL-6 and consider how the immunobiology of IL-6 may inform clinical decisions.
    Nature Immunology 04/2015; 16(5):448-457. DOI:10.1038/ni.3153 · 20.00 Impact Factor
  • Sagie Wagage · Christopher A. Hunter ·
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    ABSTRACT: Cells of the immune system utilize multiple mechanisms to respond to environmental signals and recent studies have demonstrated roles for two closely related proteins, the aryl hydrocarbon receptor (AHR) and hypoxia inducible factor-1α (HIF1α), in these processes. The AHR is a transcription factor that is activated by diverse ligands found in the diet and environmental pollution as well as by microbial and host-derived products. In contrast, HIF1α is a transcription factor that is active under low oxygen conditions and mediates cellular responses to hypoxia. These evolutionarily conserved proteins have roles in the interrelated processes of metabolism, tumorigenesis, and vascular development. Additionally, the AHR and HIF1α have multiple effects on innate and adaptive immunity. This article provides an overview of the biology of these transcription factors and reviews the effects of AHR and HIF1α signaling on immunity to infection. There are many parallels between these two pathways and their functions highlight the importance of AHR and HIF1α activity particularly at barrier surfaces in coordinating responses to pathogens.
    Current Immunology Reviews 04/2015; 11(1). DOI:10.2174/1573395510666141105234917
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    Hongmei Sun · Cristina Navarro · Christopher A Hunter ·
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    ABSTRACT: A family of closely related zinc porphyrin-pyridine complexes were used to examine the influence of linker preorganization on supramolecular effective molarities for formation of intramolecular H-bonds. Each pyridine ligand was equipped with a side-chain containing two H-bond acceptors, one on the end of the chain (terminal) and one in the middle of the chain (linker). These H-bond acceptors make intramolecular interactions with phenol H-bond donors on the porphyrin periphery. Two different H-bonding acceptors were used as linker groups in order to construct frameworks with significantly different degrees of preorganization: ester linkers populate the H-bonded state 60-70% of the time, whereas amide linkers populate the H-bonded state 90-100% of the time. Thus the amide linkers provide a significantly more preorganised ligand framework than the ester linkers. Effective molarities (EM) for intramolecular H-bonds between the terminal H-bond acceptor groups on the ligands (esters and amides) and the porphyrin phenol groups were quantified using 32 chemical double mutant cycles. The values of EM for interactions with the terminal H-bond acceptors are independent of the nature of the linker H-bond acceptor (weakly bonded ester or strongly bonded amide), which indicates that preorganization of the linker has no effect on chelate cooperativity in these systems.
    Organic & Biomolecular Chemistry 03/2015; 13(17). DOI:10.1039/c5ob00231a · 3.56 Impact Factor
  • Hiroki Yoshida · Christopher A Hunter ·
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    ABSTRACT: Interleukin-27 (IL-27) is a cytokine with strikingly diverse influences on the immune response. Although it was initially linked with the development of Th1 responses, it is now recognized as a potent antagonist of different classes of inflammation through its ability to directly modify CD4(+) and CD8(+) T cell effector functions, to induce IL-10, and to promote specialized T regulatory cell responses. Although this aspect of IL-27 biology has provided insights into how the immune system prevents hyperactivity in the setting of infectious and autoimmune inflammation, in vaccination and cancer models the stimulatory effects of IL-27 on CD8(+) T cell function appear prominent. Additionally, associations between IL-27 and antibody-mediated disease have led to an interest in defining the impact of IL-27 on innate immunity and humoral responses in different disease states. The maturation of this literature has been accompanied by attempts to translate these findings from experimental models into human diseases and by efforts to define where IL-27 might represent a viable therapeutic target.
    Annual Review of Immunology 03/2015; 33(1):417-43. DOI:10.1146/annurev-immunol-032414-112134 · 39.33 Impact Factor
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    Mike D Ward · William Cullen · Simon Turega · Christopher A. Hunter ·
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    ABSTRACT: The protein/ligand docking software GOLD, which was originally developed for drug discovery, has been used in a virtual screen to identify small molecules that bind with extremely high affinities (K ≈ 107 M-1) in the cavity of a cubic coordination cage in water. A scoring function was developed using known guests as a training set and modified by introducing an additional term to take account of loss of guest flexibility on binding. This function was then used in GOLD to successfully identify 13 new guests and accurately predict the binding constants. This approach provides a powerful predictive tool for virtual screening of large compound libraries to identify new guests for synthetic hosts, thereby greatly simplifying and accelerating the process of identifying guests by removing the reliance on experimental trial-and-error.
    Chemical Science 03/2015; 6(5). DOI:10.1039/C5SC00534E · 9.21 Impact Factor
  • J. L. Coombes · C. A. Hunter ·

    Parasite Immunology 03/2015; 37(3). DOI:10.1111/pim.12177 · 2.14 Impact Factor
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    William Cullen · Christopher A Hunter · Michael D Ward ·
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    ABSTRACT: The self-assembly between a water-soluble bis-bidentate ligand L(18w) and Co(II) salts in water affords three high-spin Co(II) products: a dinuclear meso-helicate [Co2(L(18w))3]X4; a tetrahedral cage [Co4(L(18w))6]X8; and a dodecanuclear truncated-tetrahedral cage [Co12(L(18w))18]X24 (X = BF4 or ClO4). All three products were crystallized under different conditions and structurally characterized. In [Co2(L(18w))3]X4 all three bridging ligands span a pair of metal ions; in the two larger products, there is a metal ion at each vertex of the Co4 or Co12 polyhedral cage array with a bridging ligand spanning a pair of metal ions along every edge. All three structural types are known: what is unusual here is the presence of all three from the same reaction. The assemblies Co2, Co4, and Co12 are in slow equilibrium (hours/days) in aqueous solution, and this can be conveniently monitored by (1)H NMR spectroscopy because (i) the paramagnetism of Co(II) disperses the signals over a range of ca. 200 ppm and (ii) the different symmetries of the three species give characteristically different numbers of independent (1)H NMR signals, which makes identification easy. From temperature- and concentration-dependent (1)H NMR studies it is clear that increasing temperature and increasing dilution favors fragmentation to give a larger proportion of the smaller assemblies for entropic reasons. High concentrations and low temperature favor the larger assembly despite the unfavorable entropic and electrostatic factors associated with its formation. We suggest that this arises from the hydrophobic effect: reorganization of several smaller complexes into one larger one results in a smaller proportion of the hydrophobic ligand surface being exposed to water, with a larger proportion of the ligand surface protected in the interior of the assembly. In agreement with this, (1)H NMR spectra in a nonaqueous solvent (MeNO2) show formation of only [Co2(L(18w))3]X4 because the driving force for reorganization into larger assemblies is now absent. Thus, we can identify the contributions of temperature, concentration, and solvent on the result of the metal/ligand self-assembly process and have determined the speciation behavior of the Co2/Co4/Co12 system in aqueous solution.
    Inorganic Chemistry 02/2015; 54(6). DOI:10.1021/ic502780b · 4.76 Impact Factor
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    Christopher A Hunter · Rafel Prohens ·
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    ABSTRACT: A new model for cocrystal formation could be a powerful tool for formulation scientists – no crystal structures required, it's all about the surface contacts. Cocrystals – two or more molecular entities combined in a homogenous crystalline structure – have recently become attractive targets for the pharmaceutical industry, as cocrystallization can have a positive effect on the properties of solid dosage forms. However, predicting which potential coformers will successfully cocrystallize with a given active pharmaceutical ingredient (API) has proved difficult. Here, we describe a new computational method that does not require any knowledge or prediction of three-dimensional crystal structures, making it fast enough to virtually screen very large libraries of compounds to successfully identify new API cocrystals. Hunting cocrystals Formulation of a drug as a cocrystal can change the bioavailability, dissolution rate, physical and chemical stability, compressibility and hygroscopicity, and new multicomponent solid forms offer the possibility of releasing an API without infringing the originator's patent (1). Cocrystals may also occur as multiple polymorphs, suggesting additional options to modify properties, increased patent protection and improved formulations. In 2012, the FDA issued a set of guidelines to regulate the use of pharmaceutical cocrystals and concluded that a cocrystal should be considered as a drug product intermediate and not as a new API (2). In July 2014, the European Medicines Agency (EMA) published a reflection on the use of cocrystals of active substances in medicinal products and determined that cocrystals were eligible for generic applications in the same way as salts (3). Cocrystals have a number of advantages over salts. For example, there are a large number of potential coformers contained in the GRAS (Generally Regarded as Safe) and EAFUS (Everything Added to Food in the United States) lists published by the FDA. In contrast to salts, the formation of a cocrystal does not rely on ionization, so it is not limited to APIs containing acidic or basic functional groups. This means that the structure space of potential formulations with improved properties is vast. However, this spectacular potential presents the experimental scientist with a difficult challenge: how can we navigate such a vast molecular landscape?
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    ABSTRACT: IFNγ signaling drives dendritic cells (DCs) to promote type I T cell (Th1) immunity. Here, we show that activation of DCs by IFNγ is equally crucial for the differentiation of a population of T-bet+ regulatory T (Treg) cells specialized to inhibit Th1 immune responses. Conditional deletion of IFNγ receptor in DCs but not in Treg cells resulted in a severe defect in this specific Treg cell subset, leading to exacerbated immune pathology during parasitic infections. Mechanistically, IFNγ-unresponsive DCs failed to produce sufficient amount of IL-27, a cytokine required for optimal T-bet induction in Treg cells. Thus, IFNγ signalling endows DCs with the ability to efficiently control a specific type of T cell immunity through promoting a corresponding Treg cell population.
    PLoS Pathogens 02/2015; 11(2):e1004635. DOI:10.1371/journal.ppat.1004635 · 7.56 Impact Factor
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    Edward J Banigan · Tajie H Harris · David A Christian · Christopher A Hunter · Andrea J Liu ·
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    ABSTRACT: Author Summary Migration is fundamental to immune cell function, and accurate quantitative methods are crucial for analyzing and interpreting migration statistics. However, existing methods of analysis cannot uniquely describe cell behavior and suffer from various limitations. This complicates efforts to address questions such as to what extent chemotactic signals direct cellular behaviors and how random migration of many cells leads to coordinated immune response. We therefore develop methods that provide a complete description of migration with a minimum of assumptions and describe specific quantities for characterizing directional motion. Using numerical simulations and experimental data, we evaluate these measures and discuss methods to minimize the effects of experimental artifacts. These methodologies may be applied to various migrating cells or organisms. We apply our approach to an important model system, T cells migrating in lymph node. Surprisingly, we find that the canonical Brownian-walker-like model does not accurately describe migration. Instead, we find that T cells move heterogeneously and are described by a two-population model of persistent and diffusive random walkers. This model is completely different from the generalized Lévy walk model that describes activated T cells in brains infected with Toxoplasma gondii, indicating that T cells exhibit distinct migration statistics in different tissues.
    PLoS Computational Biology 02/2015; 11(2):e1004058. DOI:10.1371/journal.pcbi.1004058 · 4.62 Impact Factor

Publication Stats

8k Citations
1,418.09 Total Impact Points


  • 2014-2015
    • University of Cambridge
      • Department of Chemistry
      Cambridge, England, United Kingdom
  • 1993-2014
    • The University of Sheffield
      • Department of Chemistry
      Sheffield, England, United Kingdom
  • 2007
    • University of Nottingham
      Nottigham, England, United Kingdom
  • 2006
    • Catalan Institution for Research and Advanced Studies
      Barcino, Catalonia, Spain
  • 2003
    • Università degli studi di Parma
      • Department of Chemistry
      Parma, Emilia-Romagna, Italy
  • 1996
    • University of Birmingham
      • School of Chemistry
      Birmingham, England, United Kingdom
  • 1991-1996
    • University of Otago
      • Department of Chemistry
      Taieri, Otago Region, New Zealand