%0 Journal Article
%~ PubMed
%A Fox, Gregory J
%A Barry, Simone E
%A Britton, Warwick J
%A Marks, Guy B
%T Contact investigation for tuberculosis: a systematic review and meta-analysis.
%B The European Respiratory Journal
%D 2013
%C Switzerland
%I European Respiratory Society
%V 41
%N 1
%P 140-156
%@ 1399-3003
%X Investigation of contacts for patients with tuberculosis is a priority for tuberculosis control in high-income countries, and is increasingly being considered in resource-limited settings. This review was commissioned for a World Health Organization Expert Panel to develop global contact investigation guidelines.We performed a systematic review and meta-analysis of all studies reporting the prevalence of tuberculosis and latent tuberculosis infection, and the annual incidence of tuberculosis among contacts of patients with tuberculosis.After screening 9555 titles, we included 203 published studies. In 95 studies from low and middle-income settings, the prevalence of active tuberculosis in all contacts was 3.1% (95% CI 2.2%-4.4%, I(2)=99.4%), microbiologically proven tuberculosis 1.2% (95% CI 0.9-1.8%, I(2)=95.9%), and latent tuberculosis infection 51.5% (95% CI 47.1-55.8%, I(2)=98.9%). The prevalence of tuberculosis among household contacts was 3.1% (95% CI 2.1-4.5%, I(2)=98.8%) and among contacts of patients with multi-drug resistant or extensively drug resistant tuberculosis was 3.4% (95% CI 0.8-12.6%, I(2)=95.7%). Incidence was greatest in the first year after exposure. In 108 studies from high-income settings, the prevalence of TB among contacts was 1.4% (95% CI 1.1-1.8%, I(2)=98.7%), and the prevalence of latent infection was 28.1% (95% CI 24.2-32.4%, I(2)=99.5%). There was substantial heterogeneity among published studies.Contacts of tuberculosis patients are a high-risk group for developing tuberculosis, particularly within the first year. Children under 5 years and people living with HIV are particularly at risk. Policy recommendations must consider evidence of the cost-effectiveness of various contact tracing strategies, and also incorporate complementary strategies to enhance case finding.
%Z FOR Codes: 111799 110203 110309


%0 Journal Article
%~ PubMed
%A Pinto, Rachel
%A Leotta, Lisa
%A Shanahan, Erin R
%A West, Nicholas P
%A Leyh, Thomas S
%A Britton, Warwick
%A Triccas, James A
%T Host cell-induced components of the sulfate assimilation pathway are major protective antigens of Mycobacterium tuberculosis.
%B Journal of Infectious Diseases
%D 2013
%C United States
%I University of Chicago Press
%V 207
%N 5
%P 778-785
%@ 0022-1899
%X 
%Z FOR Codes: 110801 110704 111716


%0 Journal Article
%~ PubMed
%A Walters, Shaun B
%A Kieckbusch, Jens
%A Nagalingam, Gayathri
%A Swain, Ashleigh
%A Latham, Sharissa L
%A Grau, Georges E R
%A Britton, Warwick J
%A Combes, Valéry
%A Saunders, Bernadette M
%T Microparticles from Mycobacteria-Infected Macrophages Promote Inflammation and Cellular Migration.
%B Journal of Immunology
%D 2013
%C United States
%I American Association of Immunologists
%V 190
%N 2
%P 669-677
%@ 1550-6606
%X 
%Z FOR Codes: 110704 110801 110707


%0 Journal Article
%~ PubMed
%A Ritz, Nicole
%A Strach, Madeleine
%A Yau, Carmen
%A Dutta, Binita
%A Tebruegge, Marc
%A Connell, Tom G
%A Hanekom, Willem A
%A Britton, Warwick J
%A Robins-Browne, Roy
%A Curtis, Nigel
%T A comparative analysis of polyfunctional T cells and secreted cytokines induced by Bacille Calmette-Guérin immunisation in children and adults.
%B PLoS One
%D 2012
%C United States
%I Public Library of Science
%V 7
%N 7
%P e37535
%@ 1932-6203
%X 
%Z FOR Codes: 110704 110801


%0 Journal Article
%~ PubMed
%A Fox, Gregory James
%A Nhung, Nguyen Viet
%A Sy, Dinh Ngoc
%A Lien, Luu Thi
%A Cuong, Nguyen Kim
%A Britton, Warwick John
%A Marks, Guy Barrington
%T Contact investigation in households of patients with tuberculosis in hanoi, Vietnam: a prospective cohort study.
%B PLoS One
%D 2012
%C United States
%I Public Library of Science
%V 7
%N 11
%P e49880
%@ 1932-6203
%X 
%Z FOR Codes: 110203 111799 110309


%0 Journal Article
%~ PubMed
%A Tran, Anh Thu
%A West, Nicholas P
%A Britton, Warwick J
%A Payne, Richard J
%T Elucidation of Mycobacterium tuberculosis type II dehydroquinase inhibitors using a fragment elaboration strategy.
%B ChemMedChem
%D 2012
%C Germany
%I Wiley - VCH Verlag GmbH & Co. KGaA
%V 7
%N 6
%P 1031-1043
%@ 1860-7187
%X A library of novel Mycobacterium tuberculosis type II dehydroquinase (DHQase) inhibitors were discovered through the use of a fragment elaboration approach. Putative active site binding fragments were initially assessed in silico which led to the selection of two small aromatic fragments for further investigation. Synthetic elaboration of the fragments provided a library of 34 inhibitors that exhibited low-micromolar inhibition of type II DHQase. A number of these inhibitors also showed antibacterial activity in the low-micromolar range in screens against M. tuberculosis in vitro; these now serve as lead compounds for further development of therapeutics for the treatment of tuberculosis.
%Z FOR Codes: 30401 110801


%0 Journal Article
%~ PubMed
%A Blumenthal, Antje
%A Nagalingam, Gayathri
%A Huch, Jennifer H
%A Walker, Lara
%A Guillemin, Gilles J
%A Smythe, George A
%A Ehrt, Sabine
%A Britton, Warwick J
%A Saunders, Bernadette M
%T M. tuberculosis Induces Potent Activation of IDO-1, but This Is Not Essential for the Immunological Control of Infection.
%B PLoS One
%D 2012
%C United States
%I Public Library of Science
%V 7
%N 5
%P e37314
%@ 1932-6203
%X Indoleamine 2,3-dioxygenesae-1 (IDO-1) catalyses the initial, rate-limiting step in tryptophan metabolism, thereby regulating tryptophan availability and the formation of downstream metabolites, including picolinic and quinolinic acid. We found that Mycobacterium tuberculosis infection induced marked upregulation of IDO-1 expression in both human and murine macrophages in vitro and in the lungs of mice following aerosol challenge with M. tuberculosis. The absence of IDO-1 in dendritic cells enhanced the activation of mycobacteria-specific T cells in vitro. Interestingly, IDO-1-deficiency during M. tuberculosis infection in mice was not associated with altered mycobacteria-specific T cell responses in vivo. The bacterial burden of infected organs, pulmonary inflammatory responses, and survival were also comparable in M. tuberculosis-infected IDO-1 deficient and wild type animals. Tryptophan is metabolised into either picolinic acid or quinolinic acid, but only picolinic acid inhibited the growth of M. tuberculosis in vitro. By contrast macrophages infected with pathogenic mycobacteria, produced quinolinic, rather than picolinic acid, which did not reduce M. tuberculosis growth in vitro. Therefore, although M. tuberculosis induces robust expression of IDO-1 and activation of tryptophan metabolism, IDO-1-deficiency fails to impact on the immune control and the outcome of the infection in the mouse model of tuberculosis.
%Z FOR Codes: 60501


%0 Journal Article
%~ PubMed
%A Nambiar, Jonathan K
%A Pinto, Rachel
%A Aguilo, Juan I
%A Takatsu, Kiyoshi
%A Martin, Carlos
%A Britton, Warwick J
%A Triccas, James A
%T Protective immunity afforded by attenuated, PhoP-deficient Mycobacterium tuberculosis is associated with sustained generation of CD4(+)  T-cell memory.
%B European Journal of Immunology
%D 2012
%C Germany
%I Wiley - VCH Verlag GmbH & Co. KGaA
%V 42
%N 2
%P 385-392
%@ 0014-2980
%X Definition of protective immunity induced by effective vaccines is important for the design of new pathogen control strategies. Inactivation of the PhoP response-regulator in Mycobacterium tuberculosis results in a highly attenuated strain that demonstrates impressive protective efficacy in pre-clinical models of tuberculosis. In this report we demonstrate that the protection afforded by the M. tuberculosis phoP mutant strain is associated with the long-term maintenance of CD4(+) T-cell memory. Immunization of mice with SO2 resulted in enhanced expansion of M. tuberculosis-specific CD4(+) T cells compared with vaccination with the BCG vaccine, with an increased frequency of these cells persisting at extended time-points after vaccination. Strikingly, vaccination with SO2 resulted in sustained generation of CD4(+) T cells displaying a central memory phenotype, a property not shared by BCG. Further, SO2 vaccination markedly improved the generation of polyfunctional cytokine-secreting CD4(+) T cells compared with BCG vaccination. The improved generation of functionally competent memory T cells by SO2 correlated with augmented recall responses in SO2-vaccinated animals after challenge with virulent M. tuberculosis. This study defines a mechanism for the protective effect of the SO2 vaccine and suggests that deletion of defined virulence networks may provide vaccine strains with potent immuno-stimulatory properties.
%Z FOR Codes: 110704 110801


%0 Journal Article
%~ PubMed
%A Gracey, D
%A Garsia, R
%A Britton, W
%A McKenzie, P
%T Rapid recovery of renal function after pulse steroid therapy in a human immunodeficiency virus-infected patient with glomerulonephritis.
%B Internal Medicine Journal
%D 2012
%C Australia, United Kingdom, Netherlands, United States
%I Wiley-Blackwell Publishing Asia
%V 42
%N 12
%P 1363-1365
%@ 1445-5994
%X 
%Z FOR Codes: 110312 110309


%0 Journal Article
%~ PubMed
%A Manos-Turvey, Alexandra
%A Cergol, Katie M
%A Salam, Noeris K
%A Bulloch, Esther M M
%A Chi, Gamma
%A Pang, Angel
%A Britton, Warwick J
%A West, Nicholas P
%A Baker, Edward N
%A Lott, J Shaun
%A Payne, Richard J
%T Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site.
%B Organic & Biomolecular Chemistry
%D 2012
%C United Kingdom
%I RSC Publications
%V 10
%N 46
%P 9223-9236
%@ 1477-0539
%X 
%Z FOR Codes: 110801 30401


%0 Journal Article
%~ PubMed
%A Kao, Fan F
%A Mahmuda, Sultana
%A Pinto, Rachel
%A Triccas, James A
%A West, Nicholas P
%A Britton, Warwick J
%T The Secreted Lipoprotein, MPT83, of Mycobacterium tuberculosis Is Recognized during Human Tuberculosis and Stimulates Protective Immunity in Mice.
%B PLoS One
%D 2012
%C United States
%I Public Library of Science
%V 7
%N 5
%P e34991
%@ 1932-6203
%X The long-term control of tuberculosis (TB) will require the development of more effective anti-TB vaccines, as the only licensed vaccine, Mycobacterium bovis bacille Calmette-Gu??rin (BCG), has limited protective efficacy against infectious pulmonary TB. Subunit vaccines have an improved safety profile over live, attenuated vaccines, such as BCG, and may be used in immuno-compromised individuals. MPT83 (Rv2873) is a secreted mycobacterial lipoprotein expressed on the surface of Mycobacterium tuberculosis. In this study, we examined whether recombinant MPT83 is recognized during human and murine M. tuberculosis infection. We assessed the immunogenicity and protective efficacy of MPT83 as a protein vaccine, with monophosphyl lipid A (MPLA) in dimethyl-dioctadecyl ammonium bromide (DDA) as adjuvant, or as a DNA vaccine in C57BL/6 mice and mapped the T cell epitopes with peptide scanning. We demonstrated that rMPT83 was recognised by strong proliferative and Interferon (IFN)-??-secreting T cell responses in peripheral blood mononuclear cells (PBMC) from patients with active TB, but not from healthy, tuberculin skin test-negative control subjects. MPT83 also stimulated strong IFN-?? T cell responses during experimental murine M. tuberculosis infection. Immunization with either rMPT83 in MPLA/DDA or DNA-MPT83 stimulated antigen-specific T cell responses, and we identified MPT83(127-135) (PTNAAFDKL) as the dominant H-2(b)-restricted CD8(+) T cell epitope within MPT83. Further, immunization of C57BL/6 mice with rMPT83/MPLA/DDA or DNA-MPT83 stimulated significant levels of protection in the lungs and spleens against aerosol challenge with M. tuberculosis. Interestingly, immunization with rMPT83 in MPLA/DDA primed for stronger IFN-?? T cell responses to the whole protein following challenge, while DNA-MPT83 primed for stronger CD8(+) T cell responses to MPT83(127-135). Therefore MPT83 is a protective T cell antigen commonly recognized during human M. tuberculosis infection and should be considered for inclusion in future TB subunit vaccines.
%Z FOR Codes: 110801 110704


%0 Journal Article
%~ PubMed
%A Ritz, Nicole
%A Dutta, Binita
%A Donath, Susan
%A Casalaz, Dan
%A Connell, Tom G
%A Tebruegge, Marc
%A Robins-Browne, Roy
%A Hanekom, Willem A
%A Britton, Warwick J
%A Curtis, Nigel
%T The influence of bacille Calmette-Guerin vaccine strain on the immune response against tuberculosis: a randomized trial.
%B American Journal of Respiratory and Critical Care Medicine
%D 2012
%C United States
%I American Thoracic Society
%V 185
%N 2
%P 213-222
%@ 1073-449X
%X Approximately 100 million doses of bacille Calmette-Guérin (BCG) vaccine are given each year to protect against tuberculosis (TB). More than 20 genetically distinct BCG vaccine strains are in use worldwide. Previous studies suggest that BCG vaccine strain influences the immune response and protection against TB. Current data on which BCG vaccine strain induces the optimal immune response in humans are insufficient.
%Z FOR Codes: 110704 110801


%0 Journal Article
%~ PubMed
%A West, Nicholas P
%A Thomson, Scott A
%A Triccas, James A
%A Medveczky, C Jill
%A Ramshaw, Ian A
%A Britton, Warwick J
%T Delivery of a multivalent scrambled antigen vaccine induces broad spectrum immunity and protection against tuberculosis.
%B Vaccine
%D 2011
%C United Kingdom
%I Elsevier Ltd
%V 29
%N 44
%P 7759-7765
%@ 0264-410X
%X The development of effective anti-Tuberculosis (TB) vaccines is an important step towards improved control of TB in high burden countries. Subunit vaccines are advantageous in terms of safety, particularly in the context of high rates of HIV co-infection, but they must contain sufficient Mycobacterium tuberculosis antigens to stimulate immunity in genetically diverse human populations. We have used a novel approach to develop a synthetic scrambled antigen vaccine (TB-SAVINE), comprised of overlapping, recombined peptides from four M. tuberculosis proteins, Ag85B, ESAT-6, PstS3 and Mpt83, each of which is immunogenic and protective against experimental TB. This polyvalent TB-SAVINE construct stimulated CD4 and CD8T cell responses against the individual proteins and M. tuberculosis in C57BL/6 and Balb/c mice, when delivered as DNA, Fowl Pox Virus or Vaccinia Virus vaccines. In addition, the DNA-TBS vaccine induced protective immunity against pulmonary M. tuberculosis infection in C57BL/6 mice. Co-immunization of Balb/c mice with virally expressed TBS and HIV1-SAVINE vaccine stimulated strong T cell responses to both the M. tuberculosis and HIV proteins, indicating no effects of antigenic competition. Further development of this TB-SAVINE vaccine expressing components from multiple M. tuberculosis proteins may prove an effective vaccine candidate against TB, which could potentially form part of a safe, combined preventative strategy together with HIV immunisations.
%Z FOR Codes: 110704 60502


%0 Journal Article
%~ PubMed
%A West, Nicholas P
%A Cergol, Katie M
%A Xue, Millie
%A Randall, Elizabeth J
%A Britton, Warwick J
%A Payne, Richard J
%T Inhibitors of an essential mycobacterial cell wall lipase (Rv3802c) as tuberculosis drug leads.
%B Chemical Communications
%D 2011
%C United Kingdom
%I Royal Society of Chemistry
%V 47
%N 18
%P 5166-5168
%@ 1364-548X
%X The first targeted inhibitors of an essential M. tuberculosis cell wall lipase, Rv3802c, are described. Lead compounds exhibited nanomolar inhibition of the enzyme, and encouraging antibacterial activity against M. tuberculosis in vitro, supporting Rv3802c as a novel TB drug target.
%Z FOR Codes: 30499 110802


%0 Journal Article
%~ PubMed
%A Fox, Gregory J
%A Britton, Warwick J
%T Learning from the genetics of enteric tuberculosis.
%B Journal of Gastroenterology and Hepatology
%D 2011
%C Australia, Japan, Hong Kong
%I Wiley-Blackwell Publishing Asia
%V 26
%N 7
%P 1086-1088
%@ 0815-9319
%X See article in J. Gastroenterol. Hepatol. 2011; 26: 1145-1150.
%Z FOR Codes: 110801 110307 60406


%0 Journal Article
%~ PubMed
%A Tran, Anh Thu
%A Cergol, Katie M
%A West, Nicholas P
%A Randall, Elizabeth J
%A Britton, Warwick J
%A Bokhari, Syed Ali Imran
%A Ibrahim, Musadiq
%A Lapthorn, Adrian J
%A Payne, Richard J
%T Synthesis and evaluation of potent ene-yne inhibitors of type II dehydroquinases as tuberculosis drug leads.
%B ChemMedChem
%D 2011
%C Germany
%I Wiley - VCH Verlag GmbH & Co. KGaA
%V 6
%N 2
%P 262-265
%@ 1860-7179
%X 
%Z FOR Codes: 30401 60502 110801 30401 60502 110801


%0 Journal Article
%~ PubMed
%A Wozniak, Teresa M
%A Saunders, Bernadette M
%A Ryan, Anthony A
%A Britton, Warwick J
%T BCG-specific Th17 cells confer partial protection against Mycobacterium tuberculosis infection in the absence of IFN-{gamma}.
%B Infection and immunity
%D 2010
%C United States
%I American Society of Microbiology
%V 78
%N 10
%P 4187-94
%@ 0019-9567
%X Protective immunity against tuberculosis (TB) requires the integrated response of a network of lymphocytes. Both gamma interferon (IFN-??)- and interleukin 17 (IL-17)-secreting CD4(+) T cells have been identified in subjects with latent TB infection and during experimental Mycobacterium tuberculosis infection, but the contribution of Th17 cells to protective immunity is unclear. To examine their protective effects in vivo, we transferred mycobacterium-specific IL-17- and IFN-??-secreting CD4(+) T cells isolated from M. tuberculosis BCG-immunized IL-12p40(-/-) and IFN-??(-/-) or wild-type mice, respectively, into M. tuberculosis-infected IL-12p40(-/-) or RAG(-/-) mice. In the absence of IL-12 and IL-23, neither IL-17-secreting (Th17) nor IFN-??-secreting (Th1) BCG-specific T cells expanded or provided protection against M. tuberculosis. In RAG(-/-) recipients with an intact IL-12/IL-23 axis, both Th17 and Th1 cells were activated and induced significant protection against M. tuberculosis. The reduction in the bacterial load following transfer of IFN-??(-/-) Th17 cells was associated with significant prolongation of survival compared to recipients of na??ve IFN-??(-/-) T cells. This effect was at the cost of an increased inflammatory infiltrate characterized by an excess of neutrophils. Therefore, Th17 cells can provide IFN-??-independent protection against M. tuberculosis, and this effect may contribute to the early control of M. tuberculosis infection.
%Z FOR Codes: 1107


%0 Journal Article
%~ PubMed
%A Shanahan, Erin R
%A Pinto, Rachel
%A Triccas, James A
%A Britton, Warwick J
%A West, Nicholas P
%T Cutinase-like protein-6 of Mycobacterium tuberculosis is recognised in tuberculosis patients and protects mice against pulmonary infection as a single and fusion protein vaccine.
%B Vaccine
%D 2010
%C United Kingdom
%I Elsevier Ltd
%V 28
%N 5
%P 1341-6
%@ 0264-410X
%X Infection with Mycobacterium tuberculosis continues to be a leading cause of death in many regions of the world, and control of this disease is hampered by the lack of a safe and effective vaccine. Secreted proteins of M. tuberculosis are an important group of antigens for subunit vaccines which target this infection. We have tested three secreted members of the cutinase-like protein (CULP) family of M. tuberculosis for their potential as protein vaccine antigens. Culp6 elicited a strong T lymphocyte response in M. tuberculosis infected mice, and importantly, in tuberculosis (TB) patients tested. Culp1, Culp2 and Culp6 when delivered as protein vaccines to mice, induced potent IFN-gamma responses which in turn translated into a significant level of protection against aerosol M. tuberculosis infection. A Culp1-6 fusion protein provided an increased level of protection against infection compared to Culp1 or Culp6 alone. The data presented here may indicate that the cell wall-associated, putatively essential protein Culp6, shown here for the first time to be recognised in TB patients, is an attractive candidate for inclusion in future subunit vaccines.
%Z FOR Codes: 110701 60501


%0 Journal Article
%~ PubMed
%A Spratt, Joanne M
%A Britton, Warwick J
%A Triccas, James A
%T In vivo persistence and protective efficacy of the bacille Calmette Guerin vaccine overexpressing the HspX latency antigen.
%B Bioengineered bugs
%D 2010
%C United States
%I Landes Bioscience
%V 1
%N 1
%P 61-65
%@ 1949-1026
%X New strategies to control infection with Mycobacterium tuberculosis, the causative agent of tuberculosis, are urgently required, particularly in areas where acquired immunodeficiencies are prevalent. In this report we have determined if modification of the current tuberculosis vaccine, Mycobacterium bovis BCG, to constitutively express the mycobacterial HspX latency antigen altered its protective effect against challenge with virulent M. tuberculosis. Overexpression of M. tuberculosis HspX in BCG caused reduced growth in aerated cultures compared to control BCG, but growth under limited oxygen availability was not markedly altered. Upon infection of mice, BCG:HspX displayed tissue-specific attenuation compared to control BCG, with reduced growth within the lung and liver but not the spleen. Both BCG:HspX and control BCG protected mice against aerosol M. tuberculosis challenge to a similar extent, however, immunodeficient mice infected with BCG:HspX survived significantly longer than mice infected with the control BCG strain. Therefore, altering the in vivo persistence of BCG by overexpression of HspX may be one important step towards developing a new tuberculosis vaccine with an improved safety profile and suitable protective efficacy against M. tuberculosis infection.
%Z FOR Codes: 1108


%0 Journal Article
%~ PubMed
%A Musicki, Korana
%A Briscoe, Helen
%A Britton, Warwick J
%A Saunders, Bernadette M
%T LIGHT contributes to early but not late control of Mycobacterium tuberculosis infection.
%B International immunology
%D 2010
%C United Kingdom,Japan
%I Oxford University Press
%V 22
%N 5
%P 353-8
%@ 1460-2377
%X The TNF superfamily member, LIGHT, contributes to optimal T-cell activation in vitro through co-stimulation of dendritic cell cytokine production; however, its role in T-cell-mediated control of intracellular bacterial infections is unknown. Protective immunity against Listeria monocytogenes and Mycobacterium tuberculosis infection requires both antigen-specific CD4(+) and CD8(+) T cells. Using LIGHT-deficient mice we determined that LIGHT was necessary for optimal re-stimulation of anti-listerial CD8(+) T cells in vitro. By contrast, LIGHT(-/-) mice infected with L. monocytogenes generated equivalent T-cell responses and controlled the infection as effectively as normal C57BL/6 mice. Following M. tuberculosis infection, LIGHT(-/-) mice showed a significant increase in bacterial replication in the lungs at 4 weeks, but by 6 weeks had controlled the infection. Analysis of T-cell responses in vivo revealed that LIGHT was dispensable for the activation of primary T-cell responses and the production of IL-12 and IFN-gamma. In addition, LIGHT was not required for the induction of memory T-cell responses to anti-mycobacterial DNA or BCG vaccines and for subsequent protection against tuberculosis challenge. Therefore, LIGHT contributes to the optimal co-stimulation of anti-listerial CD8(+) T-cell responses in vitro and to the early control of M. tuberculosis infection; however, other mechanisms compensate for LIGHT deficiency in the control of these pathogens in vivo.
%Z FOR Codes: 110704 60501


%0 Journal Article
%~ PubMed
%A Nambiar, Jonathan K
%A Ryan, Anthony A
%A Kong, Carlyn
%A Britton, Warwick J
%A Triccas, James A
%T Modulation of pulmonary dendritic cell function by vaccine-encoded GM-CSF enhances protective immunity against Mycobacterium tuberculosis infection.
%B European Journal of Immunology
%D 2010
%C Germany
%I Wiley - VCH Verlag GmbH & Co. KGaA
%V 40
%N 1
%P 153-161
%@ 0014-2980
%X The rational design of new vaccines engineered to target key components of the host immune response is crucial to aid control of important infectious diseases such as tuberculosis. In this report we determined whether modifying the function of pulmonary antigen presenting cells (APC) could improve protection against infection with Mycobacterium tuberculosis. Targeted delivery to the lung of the cytokine GM-CSF, expressed by the Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine strain, increased pulmonary dendritic cell numbers and secretion of the immunoregulatory cytokine IL-12, compared with parental BCG immunization. This impact on APC number by BCG:GM-CSF resulted in accelerated priming of antigen-specific CD4(+) T cells in the mediastinal lymph nodes and increased migration of activated CD4(+) T cells into the lung. Intranasal administration of BCG:GM-CSF resulted in significantly increased protection against M. tuberculosis infection compared to mice vaccinated with BCG alone. BCG:GM-CSF exhibited an improved safety profile, as immunodeficient RAG1(-/-) mice vaccinated intranasally with BCG:GM-CSF survived significantly longer than control BCG-vaccinated mice. These data demonstrate that manipulating immune cells in the lung by BCG-based delivery of GM-CSF can assist the development of protective mucosal immunity against pulmonary bacterial infection.
%Z FOR Codes: 60502


%0 Book Section
%A Britton, Warwick
%A Saunders, Bernadette
%T Pathology and Pathogenesis of Bacterial Infections
%B Immunology of Infectious Diseases
%D 2010
%C United States
%I ASM Press
%V 
%N 
%P 260-265
%@ 9781555815141
%E Kaufmann, Stefan H. E.
%E Rouse, Barry
%E Sacks, David
%X 
%Z FOR Codes: 110316 60501


%0 Journal Article
%A Tran, Anh Thu
%A Cergol, Katie M
%A Britton, Warwick
%A Bokhari, Syed Ali Imran
%A Ibrahim, Musadiq
%A Lapthorne, Adrian L
%A Payne, Richard J
%T Rapid assembly of potent type II dehydroquinase inhibitors via ‘‘Click’’chemistry
%B MedChemComm
%D 2010
%C United Kingdom
%I Royal Society of Chemistry
%V 1
%N 4
%P 271-275
%@ 2040-2503
%X 
%Z FOR Codes: 30401 30401


%0 Journal Article
%~ PubMed
%A Crellin, Paul K
%A Vivian, Julian P
%A Scoble, Judith
%A Chow, Frances M
%A West, Nicholas P
%A Brammananth, Rajini
%A Proellocks, Nicholas I
%A Shahine, Adam
%A Le Nours, Jerome
%A Wilce, Matthew C J
%A Britton, Warwick J
%A Coppel, Ross L
%A Rossjohn, Jamie
%A Beddoe, Travis
%T Tetrahydrolipstatin inhibition, functional analyses, and three-dimensional structure of a lipase essential for mycobacterial viability.
%B The Journal of Biological Chemistry
%D 2010
%C United States
%I American Society for Biochemistry and Molecular Bi
%V 285
%N 39
%P 30050-30060
%@ 1083-351X
%X The highly complex and unique mycobacterial cell wall is critical to the survival of Mycobacteria in host cells. However, the biosynthetic pathways responsible for its synthesis are, in general, incompletely characterized. Rv3802c from Mycobacterium tuberculosis is a partially characterized phospholipase/thioesterase encoded within a genetic cluster dedicated to the synthesis of core structures of the mycobacterial cell wall, including mycolic acids and arabinogalactan. Enzymatic assays performed with purified recombinant proteins Rv3802c and its close homologs from Mycobacterium smegmatis (MSMEG_6394) and Corynebacterium glutamicum (NCgl2775) show that they all have significant lipase activities that are inhibited by tetrahydrolipstatin, an anti-obesity drug that coincidently inhibits mycobacterial cell wall biosynthesis. The crystal structure of MSMEG_6394, solved to 2.9 ? resolution, revealed an ?/? hydrolase fold and a catalytic triad typically present in esterases and lipases. Furthermore, we demonstrate direct evidence of gene essentiality in M. smegmatis and show the structural consequences of loss of MSMEG_6394 function on the cellular integrity of the organism. These findings, combined with the predicted essentiality of Rv3802c in M. tuberculosis, indicate that the Rv3802c family performs a fundamental and indispensable lipase-associated function in mycobacteria.
%Z FOR Codes: 60106 60501


%0 Journal Article
%~ PubMed
%A Ryan, Anthony A
%A Nambiar, Jonathan K
%A Wozniak, Teresa M
%A Roediger, Ben
%A Shklovskaya, Elena
%A Britton, Warwick J
%A Fazekas de St Groth, Barbara
%A Triccas, James A
%T Antigen load governs the differential priming of CD8 T cells in response to the bacille Calmette Guerin vaccine or Mycobacterium tuberculosis infection.
%B Journal of Immunology
%D 2009
%C United States
%I American Association of Immunologists
%V 182
%N 11
%P 7172-7177
%@ 1550-6606
%X One reason proposed for the failure of Mycobacterium bovis bacille Calmette Guérin (BCG) vaccination to adequately control the spread of tuberculosis is a limited ability of the vaccine to induce effective CD8 T cell responses. However, the relative capacity of the BCG vaccine and virulent Mycobacterium tuberculosis to induce activation of CD8 T cells, and the factors that govern the initial priming of these cells after mycobacterial infection, are poorly characterized. Using a TCR transgenic CD8 T cell transfer model, we demonstrate significant activation of Ag-specific CD8 T cells by BCG, but responses were delayed and of reduced magnitude compared with those following infection with M. tuberculosis. The degree of CD8 T cell activation was critically dependent on the level of antigenic stimulation, as modifying the infectious dose to achieve comparable numbers of BCG or M. tuberculosis in draining lymph nodes led to the same pattern of CD8 T cell responses to both strains. Factors specific to M. tuberculosis infection did not influence the priming of CD8 T cells, as codelivery of M. tuberculosis with BCG did not alter the magnitude of BCG-induced T cell activation. Following transfer to RAG-1(-/-) recipients, BCG and M. tuberculosis-induced CD8 T cells conferred equivalent levels of protection against M. tuberculosis infection. These findings demonstrate that BCG is able to prime functional CD8 T cells, and suggest that effective delivery of Ag to sites of T cell activation by vaccines may be a key requirement for optimal CD8 T cell responses to control mycobacterial infection.
%Z FOR Codes: 110704 60501


%0 Journal Article
%~ PubMed
%A West, Nicholas P
%A Chow, Frances M E
%A Randall, Elizabeth J
%A Wu, Jing
%A Chen, Jian
%A Ribeiro, Jose M C
%A Britton, Warwick J
%T Cutinase-like proteins of Mycobacterium tuberculosis: characterization of their variable enzymatic functions and active site identification.
%B FASEB journal : official publication of the Federation of American Societies for Experimental Biology
%D 2009
%C United States
%I Federation of American Societies for Experimental
%V 23
%N 0
%P 1694-704
%@ 1530-6860
%X Discovery and characterization of novel secreted enzymes of Mycobacterium tuberculosis are important for understanding the pathogenesis of one of the most important human bacterial pathogens. The proteome of M. tuberculosis contains over 400 potentially secreted proteins, the majority of which are uncharacterized. A family of seven cutinase-like proteins (CULPs) was identified by bioinformatic analysis, expressed and purified from Escherichia coli, and characterized in terms of their enzymatic activities. These studies revealed a functional diversity of enzyme classes based on differential preferences for substrate chain length. One member, Culp1, exhibited strong esterase activity, 40-fold higher than that of Culp6, which had strong activity as a lipase. Another, Culp4, performed moderately as an esterase and weakly as a lipase. Culp6 lipase activity was optimal above pH 7.0, and fully maintained to pH 8.5. None of the CULP members exhibited cutinase activity. Site-directed mutagenesis of each residue of the putative catalytic triad in Culp6 confirmed that each was essential for activity toward all fatty acid chain lengths of nitrophenyl esters and lipolytic function. Culp1 and Culp2 were present only in culture supernatants of M. tuberculosis, while Culp6, which is putatively essential for mycobacterial growth, was retained in the cell wall, suggesting the proteins play distinct roles in mycobacterial biology.
%Z FOR Codes: 110801 110802


%0 Journal Article
%~ PubMed
%A Maddocks, Susan
%A Scandurra, Gabriella M
%A Nourse, Craig
%A Bye, Chris
%A Williams, Rohan B
%A Slobedman, Barry
%A Cunningham, Anthony L
%A Britton, Warwick J
%T Gene expression in HIV-1/Mycobacterium tuberculosis co-infected macrophages is dominated by M. tuberculosis.
%B Tuberculosis (Edinburgh, Scotland)
%D 2009
%C United Kingdom
%I Churchill Livingstone
%V 89
%N 4
%P 285-93
%@ 1873-281X
%X The resurgence of tuberculosis worldwide has closely mirrored the HIV pandemic. In regions like sub-Saharan Africa, a large proportion of individuals are co-infected with Mycobacterium tuberculosis and HIV. Macrophages are the reservoir host cells for both pathogens, however the interactions between both pathogens in co-infected cells remain poorly understood. Thus, the global gene responses of primary human macrophages following productive co-infection with highly purified HIV and M. tuberculosis were analyzed using cDNA microarrays. A broad range of genes was up-regulated in response to co-infection or M. tuberculosis infection of primary macrophages, including those encoding pro-inflammatory chemokines and cytokines, their receptors, signalling associated genes, type I IFN signalling genes and genes of the tryptophan degradation pathway. Real-time RT-PCR analysis confirmed up-regulation of a wide variety of genes including indoleamine 2,3 dioxygenase and Sp110 in M. tuberculosis and co-infected samples. Downstream analysis confirmed significant elevation of the chemokines CCL3, CCL4 and CCL8 in M. tuberculosis and co-infected culture supernatants. In contrast, the changes seen in gene expression following HIV infection alone were fewer in number and significantly less in magnitude. Thus, the effects of M. tuberculosis infection on global gene expression dominated the effects of HIV-1 in co-infected primary human macrophages.
%Z FOR Codes: 60501 110707 60506


%0 Journal Article
%~ PubMed
%A Hagge, Deanna A
%A Saunders, Bernadette M
%A Ebenezer, Gigi J
%A Ray, Nashone A
%A Marks, Vilma T
%A Britton, Warwick J
%A Krahenbuhl, James L
%A Adams, Linda B
%T Lymphotoxin-alpha and TNF have essential but independent roles in the evolution of the granulomatous response in experimental leprosy.
%B The American Journal of Pathology
%D 2009
%C United States
%I American Society for Investigative Pathology
%V 174
%N 4
%P 1379-1389
%@ 0002-9440
%X Recent studies identified an association between genetic variants in the lymphotoxin-alpha (LTalpha) gene and leprosy. To study the influence of LTalpha on the control of experimental leprosy, both low- and high-dose Mycobacterium leprae foot pad (FP) infections were evaluated in LTalpha-deficient chimeric (cLTalpha(-/-)) and control chimeric (cB6) mice. Cellular responses to low-dose infection in cLTalpha(-/-) mice were dramatically different, with reduced accumulation of CD4(+) and CD8(+) lymphocytes and macrophages and failure to form granulomas. Growth of M. leprae was contained for 6 months, but augmented late in infection. In contrast, tumor necrosis factor knockout and tumor necrosis factor receptor 1 knockout FPs exhibited extensive inflammatory infiltration with an increase in M. leprae growth throughout infection. Following high-dose infection, cB6 FP induration peaked at 4 weeks and was maintained for 12 weeks. Induration was not sustained in cLTalpha(-/-) FPs that contained few lymphocytes and no granulomas. There was a reduction in the expression levels of inflammatory cytokines, chemokines, and chemokine receptors, including nitric oxide synthase 2, vascular cell adhesion molecule, and intercellular cell adhesion molecule. Furthermore, cLTalpha(-/-) popliteal lymph nodes contained a higher proportion of naïve CD44(lo)CD62L(hi) T cells than cB6 mice, suggestive of reduced T cell activation. Therefore, both LTalpha and tumor necrosis factor are essential for the regulation of the granuloma, but they have distinctive roles in the recruitment of lymphocytes and maintenance of the granulomatous response during chronic M. leprae infection.
%Z FOR Codes: 110704 60501


%0 Journal Article
%~ PubMed
%A Weir, Rosemary E
%A Fine, Paul E M
%A Floyd, Sian
%A Stenson, Sally
%A Stanley, Carolynne
%A Branson, Keith
%A Britton, Warwick J
%A Huygen, Kris
%A Singh, Mahavir
%A Black, Gillian
%A Dockrell, Hazel M
%T Comparison of IFN-gamma responses to mycobacterial antigens as markers of response to BCG vaccination.
%B Tuberculosis (Edinburgh, Scotland)
%D 2008
%C United Kingdom
%I Churchill Livingstone
%V 88
%N 1
%P 31-38
%@ 1472-9792
%X An increase in interferon-gamma (IFN-gamma) production to Mycobacterium tuberculosis purified protein derivative (Mtb PPD), as measured in the cultured diluted whole blood assay, is one indicator of a protective immune response to BCG vaccine. We have explored the potential for this assay to be improved by measuring IFN-gamma responses to more defined antigens of M. tuberculosis (short-term and mid-term culture filtrates, ESAT-6, 38 kDa), Mycobacterium bovis (MPB70), M. bovis BCG (Antigen 85) and Mycobacterium leprae (35 kDa), in UK teenagers before and 1 year after BCG vaccination (or no vaccination as controls). There was a significant increase in response to the culture filtrates post-vaccination, but this was no greater than that to Mtb PPD. Many teenagers responded to the purified antigens, in particular to Antigen 85, prior to vaccination, and BCG vaccination could only augment this pre-existing response to a limited extent; prior exposure to environmental mycobacteria can thus induce cross-reactive responses to antigens which complicate interpretation of in vitro assays of vaccine response. In contrast, ESAT-6 was recognised by only one teenager prior to vaccination, and, as expected, responses were not boosted by BCG. We therefore conclude that Mtb PPD is the antigen preparation of choice for assessing the immunogenicity of BCG vaccination.
%Z FOR Codes: 110799


%0 Book Section
%A O'Garra, Anne
%A Britton, Warwick
%T Cytokines in Tuberculosis
%B Handbook of Tuberculosis: Immunology and Cell Biology
%D 2008
%C Germany
%I Wiley - VCH Verlag GmbH & Co. KGaA
%V 
%N 
%P 185-225
%@ 978-3-527-31887-2
%E Kaufmann, Stefan HE
%E Britton, Warwick
%X 
%Z FOR Codes: 110704 110203


%0 Book
%A Kaufmann, Stefan HE
%A Britton, Warwick
%T Handbook of Tuberculosis: Immunology and Cell Biology
%B 
%D 2008
%C Germany
%I Wiley - VCH Verlag GmbH & Co. KGaA
%V 
%N 
%P 
%@ 978-3-527-31887-2
%X 
%Z FOR Codes: 110203 110701


%0 Journal Article
%~ PubMed
%A West, Nicholas P
%A Wozniak, Teresa M
%A Valenzuela, Jesus
%A Feng, Carl G
%A Sher, Alan
%A Ribeiro, Jose M C
%A Britton, Warwick J
%T Immunological diversity within a family of cutinase-like proteins of Mycobacterium tuberculosis.
%B Vaccine
%D 2008
%C United Kingdom
%I Elsevier
%V 26
%N 31
%P 3853-9
%@ 0264-410X
%X Secreted proteins of Mycobacterium tuberculosis play key roles in the assembly of the mycobacterial cell wall, with many being major targets of the host immune response. To date, meaningful characterization of a significant proportion of this important group of proteins is lacking. Among the group of putatively secreted proteins of M. tuberculosis are 7 cutinase-like proteins (CLP), not previously characterized in terms of their immunogenicity or vaccine protective efficacy. Although the CLP vary in the degree of homology with one another, they all share a similar active catalytic triad, closely homologous to that of the cutinase of Fusarium solani. By construction of DNA vaccines of all 7 CLP, and expression and purification of soluble, recombinant CLP, this study addresses the immunological responses to these proteins. Clp1, 2, 3 and 6 were found to elicit significant IFN-gamma secretion in DNA immunized mice, with the antigens also demonstrating specificity in terms of CLP-generated T cell IFN-gamma release, with minimal cross reactivity of humoral responses. Finally, following delivery of DNA vaccines, Clp1, 2 and 6, conferred a moderate yet reproducible and significant level of protection in a murine aerosol model of M. tuberculosis infection.
%Z FOR Codes: 110799


%0 Journal Article
%~ PubMed
%A Ritz, Nicole
%A Hanekom, Willem A
%A Robins-Browne, Roy
%A Britton, Warwick J
%A Curtis, Nigel
%T Influence of BCG vaccine strain on the immune response and protection against tuberculosis.
%B FEMS microbiology reviews
%D 2008
%C Netherlands
%I Wiley-Blackwell
%V 32
%N 5
%P 821-841
%@ 0168-6445
%X The Bacille Calmette-Guérin (BCG) vaccine has been used for more than 80 years to protect against tuberculosis. Worldwide, over 90% of children are immunized with BCG, making it the most commonly administered vaccine, with more than 120 million doses used each year. Although new tuberculosis vaccines are under investigation, BCG will remain the cornerstone of the strategy to fight the worsening tuberculosis pandemic for the foreseeable future. The recent delineation of genetic differences between BCG vaccine strains has renewed interest in the influence of the vaccine strain on the protective efficacy against tuberculosis. This review critically examines the data from animal and human studies comparing BCG vaccine strains. Although there is good evidence to support the notion that the induced immune response and protection afforded against tuberculosis differs between BCG vaccine strains, currently, there are insufficient data to favour or recommend one particular strain. Identifying BCG strains with superior protection would have a dramatic effect on tuberculosis control at a population level: a small increment in protection provided by BCG immunization will prevent large numbers of cases of severe tuberculosis and deaths, particularly in children.
%Z FOR Codes: 110799


%0 Book Section
%A Britton, Warwick
%A Triccas, James
%T The constituents of the cell envelope and their impact on the host immune system
%B The Mycobacterial Cell Envelope
%D 2008
%C United States
%I ASM Press
%V 
%N 
%P 249-270
%@ 9781555814687
%E Daffé, Mamadou
%E Reyrat, Jean-Marc
%X 
%Z FOR Codes: 110801


%0 Journal Article
%~ PubMed
%A Almqvist, C
%A Li, Q
%A Britton, W J
%A Kemp, A S
%A Xuan, W
%A Tovey, E R
%A Marks, G B
%A , for the CAPS team
%T Early predictors for developing allergic disease and asthma: examining separate steps in the 'allergic march'.
%B Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
%D 2007
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 37
%N 9
%P 1296-1302
%@ 0954-7894
%X Background Sensitization and symptoms of allergic disease are strongly correlated, but little is known about the early clinical precursors of the development of allergen sensitization in childhood. The aim of this study was to identify these predictors, and to examine separately the effect of early sensitization on subsequent wheeze, asthma, rhinitis and eczema. Methods In the Childhood Asthma Prevention Study, children with a family history of asthma were assessed for allergen sensitization, total serum IgE, wheeze, asthma, eczema and rhinitis at ages 18 months and 5 years. To examine predictors, at 18 months, for subsequent sensitization, children who were non-sensitized at 18 months and had data on sensitization at 5 years were investigated, n=375. To examine the predictors, at age 18 months, of subsequent onset of symptoms, children who did not have wheeze, asthma, eczema or rhinitis at 18 months were followed-up at 5 years, n=177. Results Among children who were non-sensitized at age 18 months, the presence of eczema [adjusted relative risk (aRR), 1.67, 95% confidence interval (CI) 1.20-2.33], but not wheeze, asthma or rhinitis, was an independent predictor of the onset of sensitization by age 5 years. Among children who were asymptomatic at age 18 months, sensitization to any allergen at 18 months was an independent predictor for the presence of wheeze (aRR 2.41, 95% CI 1.28-4.55), asthma (aRR 4.66, 95% CI 1.88-11.54) and rhinitis (aRR 1.77, 95% CI 1.08-2.90), but not for the development of eczema (aRR 0.78, 95% CI 0.23-2.64) at 5 years. Conclusion In non-sensitized children, eczema, but not wheeze, asthma or rhinitis is a predictor for subsequent development of sensitization. This suggests that early childhood eczema, rather than wheeze and rhinitis, may promote subsequent allergen sensitization and raises the possibility that early management of eczema may reduce the prevalence of sensitization in children.
%Z FOR Codes: 110203


%0 Journal Article
%~ PubMed
%A Triccas, James A
%A Shklovskaya, Elena
%A Spratt, Joanne
%A Ryan, Anthony A
%A Palindera, Umaimainthan
%A de St Groth, Barbara Fazekas
%A Britton, Warwick J
%T Effects of DNA- and BCG-based delivery of Flt3 ligand on protective immunity to Mycobacterium tuberculosis.
%B Infection and immunity
%D 2007
%C Customer Relations M
%I Elsevier Sci Ireland Ltd
%V 75
%N 11
%P 5368-75
%@ 1098-5522
%X The control of intracellular pathogens such as Mycobacterium tuberculosis is dependent on the activation and maintenance of pathogen-reactive T cells. Dendritic cells (DCs) are the major antigen-presenting cells initiating antimycobacterial T-cell responses in vivo. To investigate if immunization strategies that aim to optimize DC function can improve protective immunity against virulent mycobacterial infection, we exploited the ability of the hematopoietic growth factor Fms-like tyrosine kinase 3 ligand (Flt3L) to expand the number of DCs in vivo. A DNA fusion of the genes encoding murine Flt3L and M. tuberculosis antigen 85B stimulated enhanced gamma interferon (IFN-gamma) release by T cells and provided better protection against virulent M. tuberculosis than DNA encoding the single components. Vaccination of mice with a recombinant Mycobacterium bovis BCG strain secreting Flt3L (BCG:Flt3L) led to early expansion of DCs compared to immunization with BCG alone, and this effect was associated with increased stimulation of BCG-reactive IFN-gamma-secreting T cells. BCG and BCG:Flt3L provided similar protective efficacies against low-dose aerosol M. tuberculosis; however, immunization of immunodeficient mice revealed that BCG:Flt3L was markedly less virulent than conventional BCG. These results demonstrate the potential of in vivo targeting of DCs to improve antimycobacterial vaccine efficacy.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Weber-Chrysochoou, Christina
%A Crisafulli, Daniel
%A Almqvist, Catarina
%A Li, Qiang
%A Kemp, Andrew S
%A Britton, Warwick J
%A Marks, Guy B
%A , for the Childhood Asthma Prevention Study Investigators
%T IL-5 T-cell responses to house dust mite are associated with the development of allergen-specific IgE responses and asthma in the first 5 years of life.
%B The Journal of allergy and clinical immunology
%D 2007
%C United States
%I Mosby, Inc.
%V 120
%N 2
%P 286-92
%@ 0091-6749
%X BACKGROUND: Allergen-specific T(H)2-like cytokine responses are considered to be important in sensitization and allergic diseases. OBJECTIVE: To examine the profile of house dust mite (HDM) stimulated T-cell cytokines and their relationship to allergic disease in children over the period of the first 5 years of life. METHODS: Subjects with a family history of asthma who were enrolled antenatally in the Childhood Asthma Prevention Study and had skin prick tests, clinical evaluation for asthma and eczema, and in vitro assessment of lymphocyte cytokine responses to HDM extract performed at ages 18 months (n = 281), 3 years (n = 349), and 5 years (n = 370). IL-13 at 3 and 5 years and IL-5, IL-10, and IFN- gamma at 18 months, 3 years, and 5 years were measured by ELISA. RESULTS: House dust mite-specific cytokine responses increased with age for all cytokines except IFN-gamma. HDM-specific IL-5 responses at 3 years and 5 years were significantly positively related to skin prick test positivity at 5 years. IL-5 responses at 5 years were also significantly related to asthma at 5 years. Other HDM-specific cytokine responses were not related to asthma or eczema at 5 years. Responses were not altered by a HDM avoidance intervention. CONCLUSION: IL-5 responses to HDM, the dominant local inhalant allergen, are related to the expression of clinical illness at age 5 years. CLINICAL IMPLICATIONS: The T-cell response to HDM, as reflected in IL-5 production, is acquired over the first years of life and may play a role in the expression of allergic airways disease.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Ryan, Anthony A
%A Wozniak, Teresa M
%A Shklovskaya, Elena
%A O'Donnell, Michael A
%A Fazekas de St Groth, Barbara
%A Britton, Warwick J
%A Triccas, James A
%T Improved protection against disseminated tuberculosis by Mycobacterium bovis bacillus Calmette-Guerin secreting murine GM-CSF is associated with expansion and activation of APCs.
%B Journal of immunology
%D 2007
%C United States
%I American Association of Immunologists
%V 179
%N 12
%P 8418-8424
%@ 0022-1767
%X Modulating the host-immune response by the use of recombinant vaccines is a potential strategy to improve protection against microbial pathogens. In this study, we sought to determine whether secretion of murine GM-CSF by the bacillus Calmette-Guérin (BCG) vaccine influenced protective immunity against Mycobacterium tuberculosis. BCG-derived GM-CSF stimulated the in vitro generation of functional APCs from murine bone marrow precursors, as demonstrated by the infection-induced secretion of IL-12 by differentiated APCs, and the ability of these cells to present Ag to mycobacterium-specific T cells. Mice vaccinated with BCG-secreting murine GM-CSF (BCG:GM-CSF) showed increased numbers of CD11c+MHCII+ and CD11c-CD11b+F480+ cells compared with those vaccinated with control BCG, and this effect was most apparent in the draining lymph nodes at 7 and 14 days postvaccination. Vaccination with BCG:GM-CSF also resulted in enhanced expression of costimulatory molecules on migratory dendritic cells in the draining lymph nodes. The increased APC number was associated with an increase in the frequency of anti-mycobacterial IFN-gamma-secreting T cells generated after BCG:GM-CSF vaccination compared with vaccination with control BCG, and this effect was sustained up to 17 wk in the spleens of immunized mice. Vaccination with BCG:GM-CSF resulted in an approximately 10-fold increase in protection against disseminated M. tuberculosis infection compared with control BCG. This study demonstrates the potential of BCG-secreting immunostimulatory molecules as vaccines to protect against tuberculosis and suggests BCG:GM-CSF merits further appraisal as a candidate to control M. tuberculosis infection in humans.
%Z FOR Codes: 110801 110704


%0 Journal Article
%~ PubMed
%A Scandurra, G M
%A Britton, W J
%A Triccas, J A
%T Inactivation of the Mycobacterium tuberculosis fadB4 gene results in increased virulence in host cell and mice.
%B Microbes and infection / Institut Pasteur
%D 2007
%C France
%I Elsevier France
%V 10
%N 0
%P 38-44
%@ 1286-4579
%X The genome of Mycobacterium tuberculosis encodes many proteins involved in fatty acid metabolism, a subset of which are required for virulence. The Mycobacterium tuberculosis fadB4 gene, which shares strong similarity with oxidoreductases and fatty acid synthases, is up-regulated during infection of macrophages and is predicted to protect the bacterium from the hostile environment of the host cell. In order to determine if fadB4 plays a role in the virulence of M. tuberculosis, we constructed a M. tuberculosis mutant in which the fadB4 had been disrupted (DeltafadB4). Surprisingly, DeltafadB4, grew more rapidly in host cells compared to wild-type M. tuberculosis or the DeltafadB4 or the gene-disrupted strain complemented with fadB4. In addition, macrophages infected with DeltafadB4 displayed reduced secretion of the cytokine TNF-alpha, suggesting a role for the FadB4 protein in influencing the pro-inflammatory host response to M. tuberculosis. After infection of mice, DeltafadB4 demonstrated an increased replication at early time-points post-infection compared to the growth of wild-type M. tuberculosis. This increased capacity of DeltafadB4 to replicate in vivo was reflected in the decreased time to death of immuno-deficient RAG-1(-/-) mice infected with M. tuberculosis lacking the fadB4 gene. Therefore fadB4 is part of the family of genes whose expression serves to regulate the virulence of M. tuberculosis within the host.
%Z FOR Codes: 110801 110704


%0 Journal Article
%~ PubMed
%A Saunders, Bernadette M
%A Britton, Warwick J
%T Life and death in the granuloma: immunopathology of tuberculosis.
%B Immunology and cell biology
%D 2007
%C UK, Australia
%I Nature Publishing Group
%V 85
%N 
%P 103-11
%@ 1440-1711
%X During tuberculosis (TB) infection, the granuloma provides the microenvironment in which antigen-specific T cells colocate with and activate infected macrophages to inhibit the growth of Mycobacterium tuberculosis. Although the granuloma is the site for mycobacterial killing, virulent mycobacteria have developed a variety of mechanisms to resist this macrophage-mediated killing. These surviving mycobacteria become dormant, however, if host cellular immunity or the signals maintaining granuloma structure wane, or if mycobacteria resume replication, leading to reactivation of TB. This balance of life and death applies not only to the mycobacterium but also to the host macrophages that may undergo apoptosis or necrosis, leading to the characteristic caseous necrosis within the granuloma, and the potential spread of TB infection. The immunological factors controlling the development and maintenance of the granuloma will be reviewed.
%Z FOR Codes:


%0 Book Section
%~ PubMed
%A Britton, W J
%A Fernando, S L
%A Saunders, B M
%A Sluyter, R
%A Wiley, J S
%T The genetic control of susceptibility to Mycobacterium tuberculosis.
%B Decoding the Genomic Control of Immune Reactions
%D 2007
%C United Kingdom
%I John Wiley & Sons
%V 
%N 
%P 79-89
%@ 978-0-470-02755-4
%X Mycobacterium tuberculosis is one of the most successful human pathogens, surviv ing in latent foci of infection in one third of humanity, yet causing lung necrosis in sufficient individuals to ensure its transmission. Each stage of the host response to M. tuberculosis is under genetic control, including the initial encounter with mycobacteria by macrophages, epithelial cells and dendritic cells in the lung, induction of the inductive T cell response, and killing by activated macrophages within granulomas. Although environmental factors are important determinants of progression to disease, there is a genetic component underlying susceptibility to tuberculosis (TB), the basis of which may vary in different populations. Recent studies using a variety of methods have defined a number of susceptibility alleles for the development of active TB. Many of these influence macrophage responses to mycobacteria. We have studied the influence of loss of function polymorphisms in the human P2X7 gene on the capacity of macrophages to kill M. tuberculosis. Activation of the P2X7 receptor, an ATP-gated Ca2+ channel, leads to the formation of pores, the activation of phospholipase D, and the induction of apoptosis with death of the infecting mycobacteria. Macrophages from subjects who are heterozygote, homozygote or compound heterozygote for these polymorphisms fail to undergo apoptosis and show partial or complete inhibition of mycobacterial killing. One of these non-functioning polymorphisms was significantly associated with increased susceptibility to TB disease, particularly extrapulmonary disease, in two unrelated cohorts of TB patients. Insights into the genetic regulation of susceptibility to human TB may identify novel methods for controlling latent M. tuberculosis and reducing the burden of tuberculosis.
%Z FOR Codes: 110704