Publications by authors named "Lukasz Kedzierski"

56 Publications

The thiol-based reduction of Bi(V) and Sb(V) anti-leishmanial complexes.

J Inorg Biochem 2021 Aug 29;221:111470. Epub 2021 Apr 29.

School of Chemistry, Monash University, Clayton, Melbourne, VIC 3800, Australia. Electronic address:

Low molecular weight thiols including trypanothione and glutathione play an important function in the cellular growth, maintenance and reduction of oxidative stress in Leishmania species. In particular, parasite specific trypanothione has been established as a prime target for new anti-leishmania drugs. Previous studies into the interaction of the front-line Sb(V) based anti-leishmanial drug meglumine antimoniate with glutathione, have demonstrated that a reduction pathway may be responsible for its effective and selective nature. The new suite of organometallic complexes, of general formula [MAr(OCR)] (M = Sb or Bi) have been shown to have potential as new selective drug candidates. However, their behaviour towards the critical thiols glutathione and trypanothione is still largely unknown. Using NMR spectroscopy and mass spectrometry we have examined the interaction of the analogous Sb(V) and Bi(V) organometallic complexes, [SbPh(OCCH(CHCH))] S1 and [BiPh(OCCH(CHCH))] B1, with the trifluoroacetate (TFA) salt of trypanothione and L-glutathione. In the presence of trypanothione or glutathione at the clinically relevant pH of 4-5 for Leishmania amastigotes, both complexes undergo facile and rapid reduction, with no discernible difference. However, at a higher pH (6-7), the complexes behave quite differently towards glutathione. The Bi(V) complex is again reduced rapidly but the Sb(V) complex undergoes slow reduction over 8 h (t = 54 min.) These results give the first insights into why the highly oxidising Bi(V) complexes display low selectivity in their cytotoxicity towards leishmanial and mammalian cells, while the Sb(V) complexes show good selectivity.
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http://dx.doi.org/10.1016/j.jinorgbio.2021.111470DOI Listing
August 2021

CD8 T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope display high naive precursor frequency and TCR promiscuity.

Immunity 2021 05 15;54(5):1066-1082.e5. Epub 2021 Apr 15.

Department of Infectious Diseases, Austin Hospital, Heidelberg, VIC 3084, Australia; Department of Medicine and Radiology, The University of Melbourne, Parkville, VIC 3000, Australia; Data Analytics Research and Evaluation (DARE) Centre, Austin Health and The University of Melbourne, Heidelberg, VIC 3084, Australia.

To better understand primary and recall T cell responses during coronavirus disease 2019 (COVID-19), it is important to examine unmanipulated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells. By using peptide-human leukocyte antigen (HLA) tetramers for direct ex vivo analysis, we characterized CD8 T cells specific for SARS-CoV-2 epitopes in COVID-19 patients and unexposed individuals. Unlike CD8 T cells directed toward subdominant epitopes (B7/N, A2/S, and A24/S) CD8 T cells specific for the immunodominant B7/N epitope were detected at high frequencies in pre-pandemic samples and at increased frequencies during acute COVID-19 and convalescence. SARS-CoV-2-specific CD8 T cells in pre-pandemic samples from children, adults, and elderly individuals predominantly displayed a naive phenotype, indicating a lack of previous cross-reactive exposures. T cell receptor (TCR) analyses revealed diverse TCRαβ repertoires and promiscuous αβ-TCR pairing within B7/NCD8 T cells. Our study demonstrates high naive precursor frequency and TCRαβ diversity within immunodominant B7/N-specific CD8 T cells and provides insight into SARS-CoV-2-specific T cell origins and subsequent responses.
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http://dx.doi.org/10.1016/j.immuni.2021.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049468PMC
May 2021

Development of new combination anti-leishmanial complexes: Triphenyl Sb(V) mono-hydroxy mono-quinolinolates.

J Inorg Biochem 2021 Jun 10;219:111385. Epub 2021 Feb 10.

School of Chemistry, Monash University, Clayton, Melbourne, VIC 3800, Australia. Electronic address:

In seeking to develop single entity combination anti-Leishmanial complexes six heteropletic organometallic Sb(V) hydroxido quinolinolate complexes of general formula [SbPh(CHNORR')(OH)] have been synthesised and characterised, derived from a series of halide substituted quinolinols (8-hydroxyquinolines). Single crystal X-ray diffraction on all the complexes show a common distorted six-coordinate octahedral environment at the Sb(V) centre, with the aryl groups and nitrogen atom of quinolinolate ligand bonding in the equatorial planes, with the two oxygen atoms (hydroxyl and quinolinolate) occupying the axial plane in an almost linear configuration. Each complex was tested for their anti-promastigote activity and mammalian cytotoxicity and a selectivity indices established. The complexes displayed excellent anti-promastigote activity (IC: 2.03-3.39 μM) and varied mammalian cytotoxicity (IC: 12.7-46.9 μM), leading to a selectivity index range of 4.52-16.7. All complexes displayed excellent anti-amastigote activity with a percentage infection range of 2.25%-9.00%. All complexes performed substantially better than the parent quinolinols and comparable carboxylate complexes [SbPh(OCRR')] indicating the synergistic role of the Sb(V) and quinolinol moieties in increasing parasite mortality. Two of the complexes [SbPh(CHNOBr)(OH)] 4, [SbPh(CHNOI)(OH)] 5, provide an ideal combination of high selective and good activity towards the leishmanial amastigotes and offer the potential as good lead compounds.
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http://dx.doi.org/10.1016/j.jinorgbio.2021.111385DOI Listing
June 2021

Integrated immune dynamics define correlates of COVID-19 severity and antibody responses.

Cell Rep Med 2021 Mar 5;2(3):100208. Epub 2021 Feb 5.

Department of Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia.

SARS-CoV-2 causes a spectrum of COVID-19 disease, the immunological basis of which remains ill defined. We analyzed 85 SARS-CoV-2-infected individuals at acute and/or convalescent time points, up to 102 days after symptom onset, quantifying 184 immunological parameters. Acute COVID-19 presented with high levels of IL-6, IL-18, and IL-10 and broad activation marked by the upregulation of CD38 on innate and adaptive lymphocytes and myeloid cells. Importantly, activated CXCR3cT1 cells in acute COVID-19 significantly correlate with and predict antibody levels and their avidity at convalescence as well as acute neutralization activity. Strikingly, intensive care unit (ICU) patients with severe COVID-19 display higher levels of soluble IL-6, IL-6R, and IL-18, and hyperactivation of innate, adaptive, and myeloid compartments than patients with moderate disease. Our analyses provide a comprehensive map of longitudinal immunological responses in COVID-19 patients and integrate key cellular pathways of complex immune networks underpinning severe COVID-19, providing important insights into potential biomarkers and immunotherapies.
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http://dx.doi.org/10.1016/j.xcrm.2021.100208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862905PMC
March 2021

Glycolipid-peptide vaccination induces liver-resident memory CD8 T cells that protect against rodent malaria.

Sci Immunol 2020 06;5(48)

Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.

Liver resident-memory CD8 T cells (T cells) can kill liver-stage -infected cells and prevent malaria, but simple vaccines for generating this important immune population are lacking. Here, we report the development of a fully synthetic self-adjuvanting glycolipid-peptide conjugate vaccine designed to efficiently induce liver T cells. Upon cleavage in vivo, the glycolipid-peptide conjugate vaccine releases an MHC I-restricted peptide epitope (to stimulate -specific CD8 T cells) and an adjuvant component, the NKT cell agonist α-galactosylceramide (α-GalCer). A single dose of this vaccine in mice induced substantial numbers of intrahepatic malaria-specific CD8 T cells expressing canonical markers of liver T cells (CD69, CXCR6, and CD101), and these cells could be further increased in number upon vaccine boosting. We show that modifications to the peptide, such as addition of proteasomal-cleavage sequences or epitope-flanking sequences, or the use of alternative conjugation methods to link the peptide to the glycolipid improved liver T cell generation and led to the development of a vaccine able to induce sterile protection in C57BL/6 mice against sporozoite challenge after a single dose. Furthermore, this vaccine induced endogenous liver T cells that were long-lived (half-life of ~425 days) and were able to maintain >90% sterile protection to day 200. Our findings describe an ideal synthetic vaccine platform for generating large numbers of liver T cells for effective control of liver-stage malaria and, potentially, a variety of other hepatotropic infections.
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http://dx.doi.org/10.1126/sciimmunol.aaz8035DOI Listing
June 2020

Viral burden, inflammatory milieu and CD8 T-cell responses to influenza virus in a second-generation thiazolide (RM-5061) and oseltamivir combination therapy study.

Influenza Other Respir Viruses 2020 11 25;14(6):678-687. Epub 2020 Jun 25.

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.

Background: Influenza viruses cause significant morbidity and mortality, especially in young children, elderly, pregnant women and individuals with co-morbidities. Patients with severe influenza disease are typically treated with one neuraminidase inhibitor, oseltamivir or zanamivir. These antivirals need to be taken early to be most effective and often lead to the emergence of drug resistance and/or decreased drug susceptibility. Combining oseltamivir with another antiviral with an alternative mode of action has the potential to improve clinical effectiveness and reduce drug resistance.

Methods: In this study, we utilized a host-targeting molecule RM-5061, a second-generation thiazolide, in combination with oseltamivir to determine whether these compounds could reduce viral burden and understand their effects on the immune response to influenza virus infection in mice, compared with either monotherapy or placebo.

Results: The combination of RM-5061 and OST administered for 5 days after influenza infection reduced viral burden at day 5 post-infection, when compared to placebo and RM-5061 monotherapy, but was not significantly different from oseltamivir monotherapy. The inflammatory cytokine milieu was also reduced in animals which received a combination therapy when compared to RM-5061 and placebo-treated animals. Antiviral treatment in all groups led to a reduction in CD8 T-cell responses in the BAL when compared to placebo.

Conclusions: To our knowledge, this is the first time a combination of a host-targeting compound, RM-5061, and neuraminidase inhibitor, OST, has been tested in vivo. This antiviral combination was safe in mice and led to reduced inflammatory responses following viral infection when compared to untreated animals.
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http://dx.doi.org/10.1111/irv.12776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578329PMC
November 2020

Anti-leishmanial activity and cytotoxicity of a series of tris-aryl Sb(V) mandelate cyclometallate complexes.

J Inorg Biochem 2020 02 23;203:110932. Epub 2019 Nov 23.

School of Chemistry, Monash University, Clayton, Melbourne, VIC 3800, Australia. Electronic address:

A series of ten cyclometallates and two μ-peroxo bridged tris-aryl Sb(V) complexes derived from R/S-mandelic acid (= R/S-ManH) were synthesised and characterised. As confirmed by X-ray crystallography the complexes 1Sr/s, [Sb(o-tol)(man)], 2Sr/s, [Sb(m-tol)(man)], 4Sr/s, [Sb(o-PhOMe)(man)], 5Sr/s, [Sb(Mes)(man)] and 6Sr/s, [Sb(p-tert-BuPh)(man)] are all cyclometallates. Complexes 3Sr/s, [(Sb(p-tol)(manH)O], contain a bridging O anion in the solid-state but convert to the cyclometallates in DMSO solution with concomitant release of HO and formation of complexes [Sb(p-tol)(man)], 3Sr'/s'. All complexes underwent initial testing against both human fibroblasts and L. major V121 promastigotes. IC values were found to range from 2.07 (6Sr) to >100 (4Sr) μM and 0.21 (5Ss) to >100 (4Ss) μM for fibroblasts and parasites respectively. Two of the complexes were found to be ineffective, displaying no toxicity (4S/r). Despite the degree of mammalian toxicity, the selectivity of most complexes exceeded an SI of three and so were assessed for their anti-amastigote activity. Excellent anti-amastigote activity was observed for complexes at both 10 μM and 5 μM, with percentage infection value ranging from 0.15-3.00% for those tested at 10 μM and 0.25-2.50% for those at 5 μM.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110932DOI Listing
February 2020

Alkyl gallium(III) quinolinolates: A new class of highly selective anti-leishmanial agents.

Eur J Med Chem 2020 Jan 18;186:111895. Epub 2019 Nov 18.

School of Chemistry, Monash University, Clayton, Melbourne, VIC, 3800, Australia. Electronic address:

A series of eight alkyl gallium complexes of general formulae [GaMe(L)] and [Ga(Me)L] have been synthesised, characterised and their antimicrobial activity against bacteria, cancer cells and Leishmania assessed. All eight complexes are novel, with the solid-state structures of all complexes successfully authenticated by single crystal X-ray diffraction. The dimethyl complexes all adopt a four-coordinate tetrahedral confirmation, while the monomethyl complexes are five-coordinate trigonal bipyramidal. All complexes were screened for their anti-bacterial activity either by solution state diffusion, or a solid-state stab test. The five soluble complexes underwent testing against two differing mammalian cell controls, with excellent selectivity observed against COS-7 cells, with an IC range of 88.5 μM to ≥100 μM. Each soluble complex was also tested for their anti-cancer capabilities, with no significant activity observed. Excellent activity was exhibited against the protozoan parasite Leishmania major (strain: V121) in both the promastigote and amastigote forms, with IC values ranging from 1.11 μM-13.4 μM for their anti-promastigote activity and % infection values of 3.5% ± 0.65-11.5% ± 0.65 for the more clinically relevant amastigote. Selectivity indices for each were found to be in the ranges of 6.61-64.7, with significant selectivity noted for two of the complexes. At minimum, the gallium complexes show a 3-fold enhancement in activity towards the Leishmaniaamastigotes over the parent quinolinols alone.
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http://dx.doi.org/10.1016/j.ejmech.2019.111895DOI Listing
January 2020

RIPLET, and not TRIM25, is required for endogenous RIG-I-dependent antiviral responses.

Immunol Cell Biol 2019 10 19;97(9):840-852. Epub 2019 Aug 19.

The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

The innate immune system is our first line of defense against viral pathogens. Host cell pattern recognition receptors sense viral components and initiate immune signaling cascades that result in the production of an array of cytokines to combat infection. Retinoic acid-inducible gene-I (RIG-I) is a pattern recognition receptor that recognizes viral RNA and, when activated, results in the production of type I and III interferons (IFNs) and the upregulation of IFN-stimulated genes. Ubiquitination of RIG-I by the E3 ligases tripartite motif-containing 25 (TRIM25) and Riplet is thought to be requisite for RIG-I activation; however, recent studies have questioned the relative importance of these two enzymes for RIG-I signaling. In this study, we show that deletion of Trim25 does not affect the IFN response to either influenza A virus (IAV), influenza B virus, Sendai virus or several RIG-I agonists. This is in contrast to deletion of either Rig-i or Riplet, which completely abrogated RIG-I-dependent IFN responses. This was consistent in both mouse and human cell lines, as well as in normal human bronchial cells. With most of the current TRIM25 literature based on exogenous expression, these findings provide critical evidence that Riplet, and not TRIM25, is required endogenously for the ubiquitination of RIG-I. Despite this, loss of TRIM25 results in greater susceptibility to IAV infection in vivo, suggesting that it may have an alternative role in host antiviral defense. This study refines our understanding of RIG-I signaling in viral infections and will inform future studies in the field.
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http://dx.doi.org/10.1111/imcb.12284DOI Listing
October 2019

Flavivirus Receptors: Diversity, Identity, and Cell Entry.

Front Immunol 2018 26;9:2180. Epub 2018 Sep 26.

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.

Flaviviruses are emerging and re-emerging arthropod-borne pathogens responsible for significant mortality and morbidity worldwide. The genus comprises more than seventy small, positive-sense, single-stranded RNA viruses, which are responsible for a spectrum of human and animal diseases ranging in symptoms from mild, influenza-like infection to fatal encephalitis and haemorrhagic fever. Despite genomic and structural similarities across the genus, infections by different flaviviruses result in disparate clinical presentations. This review focusses on two haemorrhagic flaviviruses, dengue virus and yellow fever virus, and two neurotropic flaviviruses, Japanese encephalitis virus and Zika virus. We review current knowledge on host-pathogen interactions, virus entry strategies and tropism.
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http://dx.doi.org/10.3389/fimmu.2018.02180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168832PMC
October 2019

Comparative stability, cytotoxicity and anti-leishmanial activity of analogous organometallic Sb(V) and Bi(V) acetato complexes: Sb confirms potential while Bi fails the test.

J Inorg Biochem 2018 12 1;189:151-162. Epub 2018 Sep 1.

School of Chemistry, Monash University, Clayton, Melbourne, VIC 3800, Australia. Electronic address:

A series of sixteen triphenyl Bi(V) and Sb(V) acetato complexes of general formula [MPh(OCCR)] and one oxido-bridge antimony complex [(SbPh(OCOC(O)Me))O], have been synthesised and characterised, thirteen of which are novel. The solid-state structures of fifteen of the complexes have been successfully authenticated by single crystal X-ray diffraction. All structures, excluding the oxido-bridge antimony complex, adopt a typical trigonal bipyramidal confirmation with the phenyl rings in a propeller-like orientation in the equatorial plane. Fourteen of the complexes were screened for their anti-leishmanial activity and cytotoxicity towards mammalian cells. The Bi(V) complexes were found to be unstable in DMEM culture media and to be severely toxic towards mammalian cells, with IC values in the range 11.4 μM-19.8 μM. In contrast, the Sb(V) complexes demonstrated a high degree of stability and selectivity, with IC values 6.18-19.1 μM for the promastigote assay, and of 73.8-≤100 μM for the human fibroblasts. Assessment of the Sb(V) complexes against the clinically relevant amastigote form of these parasites at 10 μM showed all but the oxido-bridged complex to be effective, with % infection values ranging from 7.0 ± 1.7-40.5 ± 2.0.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.08.015DOI Listing
December 2018

Do bismuth complexes hold promise as antileishmanial drugs?

Future Med Chem 2018 07 2;10(14):1721-1733. Epub 2018 Jul 2.

School of Chemistry, Monash University, Clayton, Melbourne, VIC 3800, Australia.

Even after 70 years, pentavalent antimonials sodium stibogluconate and meglumine antimoniate remain the most important and cost-effective antileishmanial drugs. However, the drugs cannot be delivered orally and treatment involves intravascular or intramuscular injections for 28 days under strict medical monitoring due to the toxicity of Sb(III). The main alternatives, amphotericin B, pentamidine and miltefosine, are expensive and not without their own problems. Bismuth sits below antimony in the periodic table and is considered to be relatively nontoxic to humans while being capable of providing powerful antimicrobial activity. This review describes recent efforts into developing antileishmanial Bi(III) and Bi(V) drugs, which may resemble Sb analogs in effect and mode-of-action while providing lower mammalian cell toxicity and opportunities of oral delivery. Within the last 10 years, various studies concerning bismuth-based compounds as potential antileishmanial agents have been published. This review seeks to summarize the relevant studies and draw a conclusion as to whether bismuth complexes have the potential to be effective drugs.
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http://dx.doi.org/10.4155/fmc-2017-0287DOI Listing
July 2018

Following Acute Encephalitis, Semliki Forest Virus is Undetectable in the Brain by Infectivity Assays but Functional Virus RNA Capable of Generating Infectious Virus Persists for Life.

Viruses 2018 05 18;10(5). Epub 2018 May 18.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, College of Medicine & Veterinary Medicine, University of Edinburgh, Edinburgh, Midlothian EH25 9RG, UK.

Alphaviruses are mosquito-transmitted RNA viruses which generally cause acute disease including mild febrile illness, rash, arthralgia, myalgia and more severely, encephalitis. In the mouse, peripheral infection with Semliki Forest virus (SFV) results in encephalitis. With non-virulent strains, infectious virus is detectable in the brain, by standard infectivity assays, for around ten days. As we have shown previously, in severe combined immunodeficient (SCID) mice, infectious virus is detectable for months in the brain. Here we show that in MHC-II mice, with no functional CD4 T-cells, infectious virus is also detectable in the brain for long periods. In contrast, in the brains of CD8 mice, virus RNA persists but infectious virus is not detectable. In SCID mice infected with SFV, repeated intraperitoneal administration of anti-SFV immune serum rapidly reduced the titer of infectious virus in the brain to undetectable, however virus RNA persisted. Repeated intraperitoneal passive transfer of immune serum resulted in maintenance of brain virus RNA, with no detectable infectious virus, for several weeks. When passive antibody transfer was stopped, antibody levels declined and infectious virus was again detectable in the brain. In aged immunocompetent mice, previously infected with SFV, immunosuppression of antibody responses many months after initial infection also resulted in renewed ability to detect infectious virus in the brain. In summary, antiviral antibodies control and determine whether infectious virus is detectable in the brain but immune responses cannot clear this infection from the brain. Functional virus RNA capable of generating infectious virus persists and if antibody levels decline, infectious virus is again detectable.
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http://dx.doi.org/10.3390/v10050273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977266PMC
May 2018

Clonally diverse CD38HLA-DRCD8 T cells persist during fatal H7N9 disease.

Nat Commun 2018 02 26;9(1):824. Epub 2018 Feb 26.

Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Medical College, Fudan University, 201508, Shangai, China.

Severe influenza A virus (IAV) infection is associated with immune dysfunction. Here, we show circulating CD8 T-cell profiles from patients hospitalized with avian H7N9, seasonal IAV, and influenza vaccinees. Patient survival reflects an early, transient prevalence of highly activated CD38HLA-DRPD-1 CD8 T cells, whereas the prolonged persistence of this set is found in ultimately fatal cases. Single-cell T cell receptor (TCR)-αβ analyses of activated CD38HLA-DRCD8 T cells show similar TCRαβ diversity but differential clonal expansion kinetics in surviving and fatal H7N9 patients. Delayed clonal expansion associated with an early dichotomy at a transcriptome level (as detected by single-cell RNAseq) is found in CD38HLA-DRCD8 T cells from patients who succumbed to the disease, suggesting a divergent differentiation pathway of CD38HLA-DRCD8 T cells from the outset during fatal disease. Our study proposes that effective expansion of cross-reactive influenza-specific TCRαβ clonotypes with appropriate transcriptome signatures is needed for early protection against severe influenza disease.
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http://dx.doi.org/10.1038/s41467-018-03243-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827521PMC
February 2018

Comparative stability, toxicity and anti-leishmanial activity of triphenyl antimony(v) and bismuth(v) α-hydroxy carboxylato complexes.

Dalton Trans 2018 Jan;47(3):971-980

School of Chemistry, Monash University, Clayton, Melbourne, VIC 3800, Australia.

A series of triphenyl Sb(v) and Bi(v) α-hydroxy carboxylato complexes of the general formula [MPh(OCROH)] and [MPh(OCRO)] have been successfully synthesised and characterised, and subsequently assayed for their comparative activity towards Leishmania parasites and human fibroblast cells. Four complexes are novel; [SbPhGly], [BiPh(GlyH)], [SbPh(R-ManH)] and [SbPh(S-ManH)], and have been structurally characterised through X-ray diffraction. These were combined in the study with the known complexes; ([SbPh(R-Man)], [SbPh(S-Man)], [BiPh(R-ManH)], [BiPh(R-ManH)], [SbPh(BenzH)], [BiPh(BenzH)], for which the crystal structures of [BiPh(S-ManH)] and [BiPh(R-Man)] have now been authenticated (GlyH = glycolic acid, R/S-ManH = mandelic acid, BenzH = benzilic acid). The complexes adopt a typical bipyramidal 7-coordinate geometry with the phenyl rings occupying the equatorial plane, and the ligands on the axial. In contrast to previous studies the Bi(v) compounds show a relatively high degree of stability in DMEM culture media. Promastigote and human fibroblast cell assays showed the Bi(v) analogues to be non-selectively toxic with a respective IC range of 3.58-6.33 μM and 5.83-7.01 μM. In contrast, the Sb(v) analogues provided much greater selectivity (promastigotes 12.5-20.7; fibroblasts 72.8-≥100 μM). Assessment of the Sb(v) complexes against amastigotes at 10 μM showed them to be effective with % infection values ranging from 9.5 ± 0.5-30 ± 1.3.
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http://dx.doi.org/10.1039/c7dt04171cDOI Listing
January 2018

Augmenting Influenza-Specific T Cell Memory Generation with a Natural Killer T Cell-Dependent Glycolipid-Peptide Vaccine.

ACS Chem Biol 2017 11 27;12(11):2898-2905. Epub 2017 Oct 27.

The Ferrier Research Institute, Victoria University of Wellington , PO Box 33436, Lower Hutt 5046, New Zealand.

The development of a universal vaccine for influenza A virus (IAV) that does not require seasonal modification is a long-standing health goal, particularly in the context of the increasing threat of new global pandemics. Vaccines that specifically induce T cell responses are of considerable interest because they can target viral proteins that are more likely to be shared between different virus strains and subtypes and hence provide effective cross-reactive IAV immunity. From a practical perspective, such vaccines should induce T cell responses with long-lasting memory, while also being simple to manufacture and cost-effective. Here we describe the synthesis and evaluation of a vaccine platform based on solid phase peptide synthesis and bio-orthogonal conjugation methodologies. The chemical approach involves covalently attaching synthetic long peptides from a virus-associated protein to a powerful adjuvant molecule, α-galactosylceramide (α-GalCer). Strain-promoted azide-alkyne cycloaddition is used as a simple and efficient method for conjugation, and pseudoproline methodology is used to increase the efficiency of the peptide synthesis. α-GalCer is a glycolipid that stimulates NKT cells, a population of lymphoid-resident immune cells that can provide potent stimulatory signals to antigen-presenting cells engaged in driving proliferation and differentiation of peptide-specific T cells. When used in mice, the vaccine induced T cell responses that provided effective prophylactic protection against IAV infection, with the speed of viral clearance greater than that seen from previous viral exposure. These findings are significant because the vaccines are highly defined, quick to synthesize, and easily characterized and are therefore appropriate for large scale affordable manufacture.
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http://dx.doi.org/10.1021/acschembio.7b00845DOI Listing
November 2017

Extrinsically derived TNF is primarily responsible for limiting antiviral CD8+ T cell response magnitude.

PLoS One 2017 8;12(9):e0184732. Epub 2017 Sep 8.

Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.

TNF is a pro-inflammatory cytokine produced by both lymphoid and non-lymphoid cells. As a consequence of the widespread expression of its receptors (TNFR1 and 2), TNF plays a role in many important biological processes. In the context of influenza A virus (IAV) infection, TNF has variably been implicated in mediating immunopathology as well as suppression of the immune response. Although a number of cell types are able to produce TNF, the ability of CD8+ T cells to produce TNF following viral infection is a hallmark of their effector function. As such, the regulation and role of CD8+ T cell-derived TNF following viral infection is of great interest. Here, we show that the biphasic production of TNF by CD8+ T cells following in vitro stimulation corresponds to distinct patterns of epigenetic modifications. Further, we show that a global loss of TNF during IAV infection results in an augmentation of the peripheral virus-specific CD8+ T cell response. Subsequent adoptive transfer experiments demonstrated that this attenuation of the CD8+ T cell response was largely, but not exclusively, conferred by extrinsic TNF, with intrinsically-derived TNF making only modest contributions. In conclusion, TNF exerts an immunoregulatory role on CD8+ T cell responses following IAV infection, an effect that is largely mediated by extrinsically-derived TNF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184732PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590991PMC
October 2017

Structural influences on the activity of bismuth(III) indole-carboxylato complexes towards Helicobacter pylori and Leishmania.

J Inorg Biochem 2017 12 31;177:266-275. Epub 2017 May 31.

School of Chemistry, Monash University, Clayton, Melbourne, VIC 3800, Australia. Electronic address:

Seven new bismuth(III) complexes derived from indole-carboxylic acids have been synthesised: five are homoleptic; [Bi(IAA)] B1, [Bi(IPA)] B2, [Bi(IBA)] B3, [Bi(MICA)] B4, [Bi(IGA)] B6, and two are heteroleptic [BiPh(MICA)] B5 (where IAA-H=2-(1H-indol-3-yl)acetic acid, IPA-H=3-(1H-indol-3-yl)propanoic acid, IBA-H=4-(1H-indol-3-yl)butanoic acid, IGA-H=2-(1H-indol-3-yl)-2-oxoacetic acid, and MICA-H=1-methyl-1H-indole-3-carboxylic acid). All complexes were fully characterised by elemental analysis, infrared and mass-spectroscopy, and nuclear magnetic resonance (H, C) spectroscopy. Complex [BiPh(IGA)] B7 is structurally authenticated by X-ray crystallography as a dimer in the solid-state. The in-vitro anti-bacterial activity of the indole-carboxylic acids and their bismuth(III) complexes was assessed against Helicobacter pylori. While the acids were non-toxic at <100μgmL, all the bismuth compounds showed an MIC of 6.25μgmL, indicating that the anti-bacterial activity is insensitive to the degree of substitution at the Bi(III) centre or the composition of the indole-carboxylate ligands. All compounds were further tested for their anti-parasitic activity against Leishmania major and for their toxicity towards mammalian cells. From the anti-parasitic studies, it was found that the heteroleptic bismuth(III) complexes are the most active, with B5 and B7 showing comparable activity to Amphotericin B, without any toxicity towards the mammalian cells at their effective concentration.
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http://dx.doi.org/10.1016/j.jinorgbio.2017.05.014DOI Listing
December 2017

Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling.

Elife 2017 02 14;6. Epub 2017 Feb 14.

The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.

Influenza virus infections have a significant impact on global human health. Individuals with suppressed immunity, or suffering from chronic inflammatory conditions such as COPD, are particularly susceptible to influenza. Here we show that suppressor of cytokine signaling (SOCS) five has a pivotal role in restricting influenza A virus in the airway epithelium, through the regulation of epidermal growth factor receptor (EGFR). -deficient mice exhibit heightened disease severity, with increased viral titres and weight loss. levels were differentially regulated in response to distinct influenza viruses (H1N1, H3N2, H5N1 and H11N9) and were reduced in primary epithelial cells from COPD patients, again correlating with increased susceptibility to influenza. Importantly, restoration of SOCS5 levels restricted influenza virus infection, suggesting that manipulating SOCS5 expression and/or SOCS5 targets might be a novel therapeutic approach to influenza.
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http://dx.doi.org/10.7554/eLife.20444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354519PMC
February 2017

Establishment of memory CD8+ T cells with live attenuated influenza virus across different vaccination doses.

J Gen Virol 2016 Dec 2;97(12):3205-3214. Epub 2016 Nov 2.

Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3010, Australia.

FluMist has been used in children and adults for more than 10 years. As pre-existing CD8+ T cell memory pools can provide heterologous immunity against distinct influenza viruses, it is important to understand influenza-specific CD8+ T cell responses elicited by different live attenuated influenza virus (LAIV) regimens. In this study, we immunized mice intranasally with two different doses of live-attenuated PR8 virus (PR8 ts, H1N1), low and high, and then assessed protective efficacy by challenging animals with heterosubtypic X31-H3N2 virus at 6 weeks post-vaccination. Different LAIV doses elicited influenza-specific CD8+ T cell responses in lungs and spleen, but unexpectedly not in bronchoalveolar lavage. Interestingly, the immunodominance hierarchy at the acute phase after immunization varied depending on the LAIV dose; however, these differences disappeared at 6 weeks post-vaccination, resulting in generation of comparable CD8+ T cell memory pools. After vaccination with either dose, sufficient numbers of specific CD8+ T cells were generated for recall and protection of mice against heterosubtypic H1N1→H3N2 challenge. As a result, immunized mice displayed reduced weight loss, diminished inflammatory responses and lower viral titres in lungs, when compared to unvaccinated animals. Interestingly, the higher dose led to enhanced viral clearance on day 5 post-challenge, though this was not associated with increased CD8+ T cell responses, but with higher levels of non-neutralizing antibodies against the priming virus. Our study suggests that, while different LAIV doses result in distinct immune profiles, even a low dose produces sufficient protective CD8+ T cell memory against challenge infection, though the high dose results in more rapid viral clearance and reduced inflammation.
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http://dx.doi.org/10.1099/jgv.0.000651DOI Listing
December 2016

A Role of Influenza Virus Exposure History in Determining Pandemic Susceptibility and CD8+ T Cell Responses.

J Virol 2016 08 11;90(15):6936-6947. Epub 2016 Jul 11.

Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia

Unlabelled: Novel influenza viruses often cause differential infection patterns across different age groups, an effect that is defined as heterogeneous demographic susceptibility. This occurred during the A/H2N2 pandemic, when children experienced higher influenza attack rates than adults. Since the recognition of conserved epitopes across influenza subtypes by CD8(+) cytotoxic T lymphocytes (CTLs) limit influenza disease, we hypothesized that conservation of CTL antigenic peptides (Ag-p) in viruses circulating before the pH2N2-1957 may have resulted in differential CTL immunity. We compared viruses isolated in the years preceding the pandemic (1941 to 1957) to which children and adults were exposed to viruses circulating decades earlier (1918 to 1940), which could infect adults only. Consistent with phylogenetic models, influenza viruses circulating from 1941 to 1957, which infected children, shared with pH2N2 the majority (∼89%) of the CTL peptides within the most immunogenic nucleoprotein, matrix 1, and polymerase basic 1, thus providing evidence for minimal pH2N2 CTL escape in children. Our study, however, identified potential CTL immune evasion from pH2N2 irrespective of age, within HLA-A*03:01(+) individuals for PB1471-L473V/N476I variants and HLA-B*15:01(+) population for NP404-414-V408I mutant. Further experiments using the murine model of B-cell-deficient mice showed that multiple influenza infections resulted in superior protection from influenza-induced morbidity, coinciding with accumulation of tissue-resident memory CD8(+) T cells in the lung. Our study suggests that protection against H2N2-1957 pandemic influenza was most likely linked to the number of influenza virus infections prior to the pandemic challenge rather than differential preexisting CTL immunity. Thus, the regimen of a CTL-based vaccine/vaccine-component may benefit from periodic boosting to achieve fully protective, asymptomatic influenza infection.

Importance: Due to a lack of cross-reactive neutralizing antibodies, children are particularly susceptible to influenza infections caused by novel viral strains. Preexisting T cell immunity directed at conserved viral regions, however, can provide protection against influenza viruses, promote rapid recovery and better clinical outcomes. When we asked whether high susceptibility of children (compared to adults) to the pandemic H2N2 influenza strain was associated with immune evasion from T-cell immunity, we found high conservation within T-cell antigenic regions in pandemic H2N2. However, the number of influenza infections prior to the challenge was linked to protective, asymptomatic infections and establishment of tissue-resident memory T cells. Our study supports development of vaccines that prime and boost T cells to elicit cross-strain protective T cells, especially tissue-resident memory T cells, for lifelong immunity against distinct influenza viruses.
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http://dx.doi.org/10.1128/JVI.00349-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944292PMC
August 2016

Avian Influenza Viruses, Inflammation, and CD8(+) T Cell Immunity.

Front Immunol 2016 1;7:60. Epub 2016 Mar 1.

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne , Melbourne, VIC , Australia.

Avian influenza viruses (AIVs) circulate naturally in wild aquatic birds, infect domestic poultry, and are capable of causing sporadic bird-to-human transmissions. AIVs capable of infecting humans include a highly pathogenic AIV H5N1, first detected in humans in 1997, and a low pathogenic AIV H7N9, reported in humans in 2013. Both H5N1 and H7N9 cause severe influenza disease in humans, manifested by acute respiratory distress syndrome, multi-organ failure, and high mortality rates of 60% and 35%, respectively. Ongoing circulation of H5N1 and H7N9 viruses in wild birds and poultry, and their ability to infect humans emphasizes their epidemic and pandemic potential and poses a public health threat. It is, thus, imperative to understand the host immune responses to the AIVs so we can control severe influenza disease caused by H5N1 or H7N9 and rationally design new immunotherapies and vaccines. This review summarizes our current knowledge on AIV epidemiology, disease symptoms, inflammatory processes underlying the AIV infection in humans, and recent studies on universal pre-existing CD8(+) T cell immunity to AIVs. Immune responses driving the host recovery from AIV infection in patients hospitalized with severe influenza disease are also discussed.
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http://dx.doi.org/10.3389/fimmu.2016.00060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4771736PMC
March 2016

Stability and toxicity of tris-tolyl bismuth(V) dicarboxylates and their biological activity towards Leishmania major.

Dalton Trans 2015 Nov 1;44(41):18215-26. Epub 2015 Oct 1.

School of Chemistry, Monash University, Clayton, Melbourne, VIC 3800, Australia.

A series of 29 tris-tolyl bismuth(v) di-carboxylato complexes of composition [Bi(Tol)3(O2CR)2] involving either ortho, meta or para substituted tolyl ligands have been synthesized and characterised. Of these 15 were assessed for their toxicity towards Leishmania promastigotes and human fibroblast cells, with ten then being subsequently assessed against parasite amastigotes. The carboxylate ligands are drawn from a series of substituted and biologically relevant benzoic acids which allow a comparison with earlier studies on [BiPh3(O2CR)2] and analogous Sb(v) [SbAr3(O2CR)2] (Ar = Ph and Tol) complexes. Twelve complexes have been structurally characterized by single crystal X-ray diffraction and shown to adopt a typical trigonal bipyramidal geometry in which the three tolyl ligands occupy the equatorial plane. NMR studies on two illustrative examples indicate that the complexes are stable in D2O and DMSO but only have a half-life of 1.2 hours in culture medium, with glucose being a contributing factor in decomposition and reduction to Bi(Tol)3. Despite their short lifetime many complexes show significant toxicity towards promastigotes at low concentration (<6 μM) and at that concentration provide for good selectivity indices (parasite vs. mammalian cells), for example 114 for [Bi(o-Tol)3(O2CC6H3(2-OH,5-C6H3(2,4-F2)))2] and 838 for [Bi(m-Tol)3(O2CC6H4(2-OAc))2]. Best activity and selectivity is observed with complexes containing o- and m-tolyl ligands, and it appears the primary influence on fibroblast toxicity is the Ar ligand while the carboxylate influences promastigote toxicity. The complexes are less effective in vitro against the parasite amastigotes, where longer incubation times and harsher chemical and biological environments are encountered in the assay. Nevertheless, there were some statistically relevant differences at 1 μM against the positive controls with the best performing complexes being [Bi(o-Tol)3(O2CC6H4(2-EtO))2] and [Bi(m-Tol)3(O2CC6H4(2-OAc))2].
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http://dx.doi.org/10.1039/c5dt03335gDOI Listing
November 2015

Bismuth(III) α-hydroxy carboxylates: highly selective toxicity of glycolates towards Leishmania major.

J Biol Inorg Chem 2015 Oct 28;20(7):1193-203. Epub 2015 Sep 28.

School of Chemistry, Monash University, Clayton, Melbourne, VIC, 3800, Australia.

Eight bismuth(III) complexes derived from the simple α-hydroxycarboxylic acids; gluconic (H₆-glu), tartaric (H₄-tar), mandelic (H₂-man), malic (H₃-mal) and glycolic (H₂-gly) have been synthesised and characterised. The complexes are formed through direct treatment of the organic acids with Bi(NO₃)3·5H₂O ([Bi(H₂-tar)(H₃- tar)] 2, [Bi(mal)(NO₃)(H₂O)₂] 6, [Bi(gly)(NO₃)(H₂O)] 8) or Bi(OtBu)₃ ([Bi(H-tar)(H₂O)₂] 1, [Bi(man)(H-man) (H₂O)] 4, [Bi2(H-mal)₃] 5, [Bi(gly)(H-gly)] 7), or through metathesis of the sodium salts with Bi(NO₃)3·5H₂O ([Bi(H3-glu)]₃). Reactions with both glucuronic and mucic acid proved to be unsuccessful. Small crystals of [Bi(gly)4(NO₃)4(H₂O)₄]·5H₂O 8 were obtained from aqueous solution and analysed by synchrotron X-ray diffraction. The data were relatively poor but composition and connectivity were established, confirming and supporting other analyses. Those complexes which displayed sufficient solubility; 2, 4, 7 and 8, were tested for their anti-Leishmanial activity against parasite promastigotes and amastigotes, and for toxicity against human fibroblast cells. All four complexes and their parent acids showed no toxicity towards either the promastigotes or fibroblast cells. However, the two glycolate complexes showed selective toxicity towards amastigotes with complex 8 providing for a low % viability of 1.8 ± 0.9 at 50.0 μM. Graphical Abstract Novel bismuth(III) complexes derived from α-hydroxycarboxylic acids have been synthesised, characterised and assessed for their anti-leishmanial activity. The glycolate complexes are selectively toxic against parasite amastigotes, with all complexes being nontoxic towards promastigotes and human fibroblast cells.
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http://dx.doi.org/10.1007/s00775-015-1299-6DOI Listing
October 2015

SOCS4 is dispensable for an efficient recall response to influenza despite being required for primary immunity.

Immunol Cell Biol 2015 Nov 16;93(10):909-13. Epub 2015 Jun 16.

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

Suppressor of cytokine signaling (SOCS) proteins are key regulators of innate and adaptive immunity. Mice lacking functional SOCS4 are hypersusceptible to primary infection with influenza A virus (IAV), displaying dysregulated pro-inflammatory cytokine and chemokine production in the lungs, delayed viral clearance and impaired trafficking of influenza-specific CD8(+) T cells to the site of infection. Therefore, we postulated that SOCS4 is a critical regulator of anti-viral immunity. Unexpectedly, SOCS4 was not required for CD8(+) T-cell memory generation, nor was it required to efficiently recall those cells in response to secondary IAV infection. Wild-type or SOCS4-deficient mice primed and re-challenged with serologically different influenza strains, did not show differences in susceptibility to IAV and cleared the virus from the lungs at the same rate. We have not observed differences in trafficking or numbers of IAV-specific cells, numbers of resident memory T cells or in cytokine profiles in lungs of infected animals. Our data show that despite an impaired primary immune response in Socs4(R108X/R108X) mice, SOCS4 is dispensable for an efficient recall response to influenza virus infection.
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http://dx.doi.org/10.1038/icb.2015.55DOI Listing
November 2015

Immune responses during cutaneous and visceral leishmaniasis.

Parasitology 2014 Jul 30:1-19. Epub 2014 Jul 30.

Department of Medical Biology,University of Melbourne,Parkville, Melbourne, Victoria 3010,Australia.

SUMMARY Leishmania are protozoan parasites spread by a sandfly insect vector and causing a spectrum of diseases collectively known as leishmaniasis. The disease is a significant health problem in many parts of the world, resulting in an estimated 1·3 million new cases and 30 000 deaths annually. Current treatment is based on chemotherapy, which is difficult to administer, expensive and becoming ineffective in several endemic regions. To date there is no vaccine against leishmaniasis, although extensive evidence from studies in animal models indicates that solid protection can be achieved upon immunization. This review focuses on immune responses to Leishmania in both cutaneous and visceral forms of the disease, pointing to the complexity of the immune response and to a range of evasive mechanisms utilized by the parasite to bypass those responses. The amalgam of innate and acquired immunity combined with the paucity of data on the human immune response is one of the major problems currently hampering vaccine development and implementation.
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http://dx.doi.org/10.1017/S003118201400095XDOI Listing
July 2014

Stability and toxicity of heteroleptic organometallic Bi(V) complexes towards Leishmania major.

Dalton Trans 2014 Sep;43(34):12904-16

School of Chemistry, Monash University, Clayton, Melbourne, VIC 3800, Australia.

Eleven heteroleptic Bi(V) complexes of the form [BiPh3(O2CR)2] have been synthesised and fully characterised. The carboxylate ligands are derived from a series of simple substituted benzoic acids, four of which are common non-steroidal anti-inflammatories (NSAIDs). The solid-state structures of eight of the complexes were determined by single crystal X-ray diffraction, and all were shown to adopt a typical trigonal bipyramidal geometry with chelating carboxylate ligands. Nine of the complexes were assessed for their anti-parasitic activity against Leishmania major promastigotes and their cytotoxicity towards human fibroblasts. The assays indicated that while the complexes showed good anti-leishmanial activity with IC50 values ranging from 0.6 to 2.5 μM they were also non-selectively toxic towards the fibroblasts at similar or slightly higher concentrations. Using (1)H NMR, the stability of one of the complexes, [Bi(C6H5)3(O2CC6H3(m-OH)2)2] was studied in water, DMSO and in the DMEM culture medium. This showed that while the Bi(v) complex was stable in D2O and DMSO, the complex slowly decomposed in the culture medium undergoing reduction to give BiPh3 and the free acid. Since the acids and BiPh3 were not toxic to either the parasites or fibroblasts at the concentrations studied, the implication is that the Bi(v) complexes are stable enough for long enough to have significant in vitro anti-parasitic activity.
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http://dx.doi.org/10.1039/c4dt00957fDOI Listing
September 2014

Suppressor of cytokine signaling 4 (SOCS4) protects against severe cytokine storm and enhances viral clearance during influenza infection.

PLoS Pathog 2014 May 8;10(5):e1004134. Epub 2014 May 8.

Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria Australia; Department of Medical Biology, The University of Melbourne, Parkville, Melbourne, Victoria, Australia.

Suppressor of cytokine signaling (SOCS) proteins are key regulators of innate and adaptive immunity. There is no described biological role for SOCS4, despite broad expression in the hematopoietic system. We demonstrate that mice lacking functional SOCS4 protein rapidly succumb to infection with a pathogenic H1N1 influenza virus (PR8) and are hypersusceptible to infection with the less virulent H3N2 (X31) strain. In SOCS4-deficient animals, this led to substantially greater weight loss, dysregulated pro-inflammatory cytokine and chemokine production in the lungs and delayed viral clearance. This was associated with impaired trafficking of influenza-specific CD8 T cells to the site of infection and linked to defects in T cell receptor activation. These results demonstrate that SOCS4 is a critical regulator of anti-viral immunity.
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http://dx.doi.org/10.1371/journal.ppat.1004134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014316PMC
May 2014

Bismuth(III) β-thioxoketonates as antibiotics against Helicobacter pylori and as anti-leishmanial agents.

Dalton Trans 2014 Jan 5;43(3):1279-91. Epub 2013 Nov 5.

School of Chemistry, Monash University, P.O. Box 23, Melbourne, Victoria 3800, Australia.

Nine different β-thioxoketones of general formula R(1)C(=O)CH2C(=S)R(2) (R(1) = C6H5, R(2) = C6H5L1; R(1) = C6H5, R(2) = p-CF3C6H4L2; R(1) = p-MeOC6H4, R(2) = C6H5L3; R(1) = p-MeOC6H4, R(2) = p-CF3C6H4L4; R(1) = C5H4N, R(2) = C6H5L5; R(1) = p-IC6H4, R(2) = C6H5L6; R(1) = C6H5, R(2) = p-IC6H4L7; R(1) = C6H5, R(2) = C10H7L8 and R(1) = CH3, R(2) = C6H5L9) and their tris-substituted bismuth(III) complexes having the general formula [Bi{R(1)C(=O)CHC(=S)R(2)}3] were synthesised and fully characterised. The solid state structure of [Bi{C5H4NC(=O)CHC(=S)C6H5}3] B5 was determined by crystallography and revealed that the three β-thioxoketonato ligands are bound to bismuth(III) centre in a bidentate fashion through O and S atoms. The bismuth(III) complexes and the corresponding thioxoketones were assessed for their activity against H. pylori. All of the bismuth(III) complexes were highly active against H. pylori having a MIC of greater than or equal to 3.125 μg mL(-1), while the free acids were essentially not toxic to the bacteria. The anti-leishmanial activity of all the bismuth(III) β-thioxoketonates and the corresponding free acids were assessed against L. major promastigotes. The toxicity towards human fibroblast cells was also assessed. All of the free β-thioxoketones were selectively toxic to the L. major promastigotes displaying some potential as anti-leishmanial agents. Among these [C6H5C(=O)CH2C(=S)C6H5] L1 and [C5H4NC(=O)CH2C(=S)C6H5] L5 showed comparable activity to that of Amphotericin B, killing about 80% of the L. major promastigotes at a concentration of 25 μM (6.0 μg mL(-1)). The bismuth(III) β-thioxoketonate complexes were toxic to both the L. major promastigotes and fibroblast cells at high concentrations, but gave no improvement in anti-leishmanial activity over the free β-thioxoketones.
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http://dx.doi.org/10.1039/c3dt52544aDOI Listing
January 2014