2018年
No.23
Medical Abstracts
Keyword: tuberculosis
1. Nat Commun. 2018 Dec 6;9(1):5208. doi: 10.1038/s41467-018-07635-7.
Metabolite changes in blood predict the onset of tuberculosis.
Weiner J 3rd(1), Maertzdorf J(1), Sutherland JS(2), Duffy FJ(3), Thompson E(3),
Suliman S(4), McEwen G(1)(5), Thiel B(6), Parida SK(1)(7), Zyla J(1), Hanekom
WA(4), Mohney RP(8), Boom WH(6), Mayanja-Kizza H(9), Howe R(10), Dockrell HM(11),
Ottenhoff THM(12), Scriba TJ(4), Zak DE(3), Walzl G(13), Kaufmann SHE(14); GC6-74
consortium.
Author information:
(1)Max Planck Institute for Infection Biology, 10117, Berlin, Germany.
(2)Vaccines & Immunity Theme, Medical Research Council Unit The Gambia at the
London School of Hygiene and Tropical Medicine, P. O. Box 273, Banjul, The
Gambia.
(3)The Center for Infectious Disease Research, Seattle, WA 98145-5005, USA.
…
New biomarkers of tuberculosis (TB) risk and disease are critical for the
urgently needed control of the ongoing TB pandemic. In a prospective multisite
study across Subsaharan Africa, we analyzed metabolic profiles in serum and
plasma from HIV-negative, TB-exposed individuals who either progressed to TB 3-24
months post-exposure (progressors) or remained healthy (controls). We generated a
trans-African metabolic biosignature for TB, which identifies future progressors
both on blinded test samples and in external data sets and shows a performance of
69% sensitivity at 75% specificity in samples within 5 months of diagnosis. These
prognostic metabolic signatures are consistent with development of subclinical
disease prior to manifestation of active TB. Metabolic changes associated with
pre-symptomatic disease are observed as early as 12 months prior to TB diagnosis,
thus enabling timely interventions to prevent disease progression and
transmission.
DOI: 10.1038/s41467-018-07635-7
PMCID: PMC6283869
PMID: 30523338 [Indexed for MEDLINE]
2. Lancet Infect Dis. 2018 Dec;18(12):1329-1349. doi: 10.1016/ S1473-3099(18) 30625-X.
Global, regional, and national burden of tuberculosis, 1990-2016: results from
the Global Burden of Diseases, Injuries, and Risk Factors 2016 Study.
GBD Tuberculosis Collaborators.
Collaborators: Kyu HH, Maddison ER, Henry NJ, Ledesma JR, Wiens KE, Reiner R Jr,
Biehl MH, Shields C, Osgood-Zimmerman A, Ross JM, Carter A, Frank TD, Wang H,
Srinivasan V, Agarwal SK, Alahdab F, Alene KA, Ali BA, Alvis-Guzman N, Andrews
JR, Antonio CAT, Atique S, Atre SR, Awasthi A, Ayele HT, Badali H, Badawi A,
Barac A, Bedi N, Behzadifar M, Behzadifar M, Bekele BB, Belay SA, Bensenor IM,
Butt ZA, Carvalho F, Cercy K, Christopher DJ, Daba AK, Dandona L, Dandona R,
Daryani A, Demeke FM, Deribe K, Dharmaratne SD, Doku DT, Dubey M, Edessa D,
…
BACKGROUND: Although a preventable and treatable disease, tuberculosis causes
more than a million deaths each year. As countries work towards achieving the
Sustainable Development Goal (SDG) target to end the tuberculosis epidemic by
2030, robust assessments of the levels and trends of the burden of tuberculosis
are crucial to inform policy and programme decision making. We assessed the
levels and trends in the fatal and non-fatal burden of tuberculosis by drug
resistance and HIV status for 195 countries and territories from 1990 to 2016.
METHODS: We analysed 15?943 site-years of vital registration data, 1710
site-years of verbal autopsy data, 764 site-years of sample-based vital
registration data, and 361 site-years of mortality surveillance data to estimate
mortality due to tuberculosis using the Cause of Death Ensemble model. We
analysed all available data sources, including annual case notifications,
prevalence surveys, population-based tuberculin surveys, and estimated
tuberculosis cause-specific mortality to generate internally consistent estimates
of incidence, prevalence, and mortality using DisMod-MR 2.1, a Bayesian
meta-regression tool. We assessed how the burden of tuberculosis differed from
the burden predicted by the Socio-demographic Index (SDI), a composite indicator
of income per capita, average years of schooling, and total fertility rate.
FINDINGS: Globally in 2016, among HIV-negative individuals, the number of
incident cases of tuberculosis was 9·02 million (95% uncertainty interval [UI]
8·05-10·16) and the number of tuberculosis deaths was 1·21 million (1·16-1·27).
Among HIV-positive individuals, the number of incident cases was 1·40 million
(1·01-1·89) and the number of tuberculosis deaths was 0·24 million (0·16-0·31).
Globally, among HIV-negative individuals the age-standardised incidence of
tuberculosis decreased annually at a slower rate (-1·3% [-1·5 to -1·2]) than
mortality did (-4·5% [-5·0 to -4·1]) from 2006 to 2016. Among HIV-positive
individuals during the same period, the rate of change in annualised
age-standardised incidence was -4·0% (-4·5 to -3·7) and mortality was -8·9% (-9·5 to -8·4). Several regions had higher rates of age-standardised incidence and
mortality than expected on the basis of their SDI levels in 2016. For
drug-susceptible tuberculosis, the highest observed-to-expected ratios were in
southern sub-Saharan Africa (13·7 for incidence and 14·9 for mortality), and the
lowest ratios were in high-income North America (0·4 for incidence) and Oceania
(0·3 for mortality). For multidrug-resistant tuberculosis, eastern Europe had the
highest observed-to-expected ratios (67·3 for incidence and 73·0 for mortality),
and high-income North America had the lowest ratios (0·4 for incidence and 0·5
for mortality).
INTERPRETATION: If current trends in tuberculosis incidence continue, few
countries are likely to meet the SDG target to end the tuberculosis epidemic by
2030. Progress needs to be accelerated by improving the quality of and access to
tuberculosis diagnosis and care, by developing new tools, scaling up
interventions to prevent risk factors for tuberculosis, and integrating control
programmes for tuberculosis and HIV.
FUNDING: Bill & Melinda Gates Foundation.
Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access
article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights
reserved.
DOI: 10.1016/S1473-3099(18)30625-X
PMCID: PMC6250050
PMID: 30507459
3. Biosens Bioelectron. 2019 Mar 1;128:76-82. doi: 10.1016/j.bios.2018.11.045. Epub
2018 Dec 7.
E-DNA detection of rpoB gene resistance in Mycobacterium tuberculosis in real
samples using Fe3O4/polypyrrole nanocomposite.
Haddaoui M(1), Sola C(2), Raouafi N(3), Korri-Youssoufi H(4).
Author information:
(1)Univ. Paris Sud, Université Paris-Saclay, LCBB, Institut de Chimie Moléculaire
et des Matériaux d'Orsay(UMR -CNRS 8182), Bât 420, 2 Rue du Doyen Georges Poitou,
91400 Orsay, France; Université de Tunis El Manar, Faculté des Sciences,
Laboratoire de Chimie Analytique et Electrochimie (LR99ES15), Campus
universitaire de Tunis El Manar, 2092 Tunis El-Manar, Tunisia.
(2)Institute of Integrative Cell Biology(I2BC), CEA, ?CNRS, Univ. Paris-Sud,
Université Paris-Saclay, 91198, Gif-sur-Yvette, France.
(3)Université de Tunis El Manar, Faculté des Sciences, Laboratoire de Chimie
Analytique et Electrochimie (LR99ES15), Campus universitaire de Tunis El Manar,
2092 Tunis El-Manar, Tunisia. Electronic address: noureddine.raouafi@fst.utm.tn.
(4)Univ. Paris Sud, Université Paris-Saclay, LCBB, Institut de Chimie Moléculaire
et des Matériaux d'Orsay(UMR -CNRS 8182), Bât 420, 2 Rue du Doyen Georges Poitou,
91400 Orsay, France. Electronic address: hafsa.korri-youssoufi@u-psud.fr.
In this work, we achieved the selective detection of wild and mutated rpoB gene
in M. tuberculosis using an electrochemical DNA (E-DNA) sensor based on
polypyrrole/Fe3O4 nanocomposite bearing redox naphthoquinone tag on PAMAM
(spaNQ/PAMAM/PPy/Fe3O4). The hybridization between a given probe and the
complementary DNA target induced a large decrease in the naphthoquinone redox
signal as measured by SWV and no cross-hybridization with single nucleotide
mismatch DNA target occurred. Thanks to the catalytic properties of iron oxide
nanoparticles combined with conducting properties of polypyrrole platform, we
demonstrated that the transducing system allowed the detection of 1 fM of DNA
target in a 50-µL drop corresponding to 3?×?104 copies of DNA. The sensor was
able to detect the rpoB gene in PCR-amplified samples of genomic DNA and could
also discriminate between the wild type rpoB gene and a single nucleotide mutated
rpoB gene that provides resistance? to rifampicin. Furthermore, the sensor could
selectively detect the wild and mutant DNA in genomic samples without PCR
amplification.
Copyright © 2018. Published by Elsevier B.V.
DOI: 10.1016/j.bios.2018.11.045
PMID: 30640123
4. J Infect Dis. 2018 Dec 28. doi: 10.1093/infdis/jiy587. [Epub ahead of print]
Minocycline Immunomodulates via Sonic Hedgehog Signaling and Apoptosis and Has
Direct Potency Against Drug-Resistant Tuberculosis.
Deshpande D(1), Pasipanodya JG(1), Srivastava S(1), Martin KR(1), Athale S(1),
van Zyl J(1), Antiabong J(1), Koeuth T(1), Lee PS(1), Dheda K(2), Gumbo T(1)(2).
Author information:
(1)Center for Infectious Diseases Research and Experimental Therapeutics, Baylor
Research Institute, Dallas, Texas.
(2)Division of Pulmonology, Centre for Lung Infection and Immunity, University of
Cape Town Lung Institute, South Africa.
Drug-resistant tuberculosis represents a global emergency, requiring new drugs.
We found that minocycline was highly potent in laboratory strains of
Mycobacterium tuberculosis and that 30 drug-susceptible and multidrug/extensively
drug-resistant clinical strains were susceptible to clinically achievable
concentrations. In the hollow fiber system model, lung concentration-time
profiles of 7 mg/kg/day human-equivalent minocycline dose achieved bacterial kill
rates equivalent to those of first-line antituberculosis agents. Minocycline
killed extracellular bacilli directly. Minocycline also killed intracellular
bacilli indirectly, via concentration-dependent granzyme A-driven apoptosis.
Moreover, minocycline demonstrated dose-dependent antiinflammatory activity and
downregulation of extracellular matrix-based remodeling pathways and, thus, could
protect patients from tuberculosis immunopathology. In RNA sequencing of
repetitive samples from the hollow fiber system and in independent protein
abundance experiments, minocycline demonstrated dose-dependent inhibition of
sonic hedgehog-patched-gli signaling. These findings have implications for
improved lung remodeling and for dual immunomodulation and direct microbial
kill-based treatment shortening regimens for drug-susceptible and drug-resistant
latent and active M. tuberculosis infection.
DOI: 10.1093/infdis/jiy587
PMID: 30597040
5. J Infect Dis. 2018 Dec 21. doi: 10.1093/infdis/jiy712. [Epub ahead of print]
Remembering the Host in Tuberculosis Drug Development.
Frank DJ(1), Horne DJ(2), Dutta NK(3), Shaku MT(4), Madensein R(5), Hawn TR(2),
Steyn AJC(6)(7), Karakousis PC(3), Kana BD(4)(8), Meintjes G(9)(10), Laughon
B(11)(12), Tanvir Z(12)(13).
Author information:
(1)Division of AIDS, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Bethesda, Maryland.
(2)University of Washington School of Medicine, Seattle, WA, USA.
(3)Center for Tuberculosis Research and Center for Systems Approaches to
Infectious Diseases, Department of Medicine, Johns Hopkins University School of
Medicine.
…
New therapeutics to augment current approaches and shorten treatment duration are
of critical importance for combating tuberculosis (TB), especially those with
novel mechanisms of action to counter the emergence of drug-resistant TB.
Host-directed therapy (HDT) offers a novel strategy with mechanisms that include
activating immune defense mechanisms or ameliorating tissue damage. These and
related concepts will be discussed along with issues that emerged from the
workshop organized by the Stop TB Working Group on New Drugs, held at the Gordon
Research Conference for Tuberculosis Drug Development in Lucca, Italy in June
2017, titled "Strategic Discussion on Repurposing Drugs & Host Directed Therapies
for TB." In this review, we will highlight recent data regarding drugs, pathways,
and concepts that are important for successful development of HDTs for TB.
DOI: 10.1093/infdis/jiy712
PMID: 30590592
6. Cell Death Dis. 2018 Dec 21;10(1):11. doi: 10.1038/s41419-018-1240-3.
CCR4-dependent reduction in the number and suppressor function of CD4+Foxp3+
cells augments IFN-γ-mediated pulmonary inflammation and aggravates tuberculosis
pathogenesis.
Bertolini TB(1), Piñeros AR(1), Prado RQ(1), Gembre AF(1), Ramalho LNZ(2),
Alves-Filho JC(3), Bonato VLD(4).
Author information:
(1)Department of Biochemistry and Immunology, Ribeirao Preto Medical School,
University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.
(2)Department of Pathology, Ribeirao Preto Medical School, University of Sao
Paulo, Ribeirao Preto, Sao Paulo, Brazil.
(3)Department of Pharmacology, Ribeirao Preto Medical School, University of Sao
Paulo, Ribeirao Preto, Sao Paulo, Brazil.
(4)Department of Biochemistry and Immunology, Ribeirao Preto Medical School,
University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. vlbonato@fmrp.usp.br.
Chronic pulmonary inflammation marked predominantly by CD4+IFN-γ+ cells is the
hallmark of tuberculosis pathogenesis in immunocompetent adults, who are
substantially affected by this disease. Moreover, CD4+Foxp3+ cell-mediated
suppression contributes to infection susceptibility. We addressed the role of
CD4+Foxp3+ cells in tuberculosis pathogenesis, because this aspect has not been
addressed during chronic infection. We targeted CCR4, which induces the influx of
CD4+Foxp3+ cells into the lungs. CCR4-/- mice exhibited a lower frequency of
CD4+Foxp3+ cells at 15, 30, and 70 days of infection than their wild-type
counterparts. However, only at 70 days of infection was an exacerbated
IFN-γ-mediated immune response associated with apparent tuberculosis pathogenesis
and susceptibility. In addition, CCR4-/- mice exhibited a decrease in the
suppressor function of CD4+Foxp3+ cells. Adoptive transfer of Foxp3+ cells into
infected CCR4-/- mice restored pulmonary inflammation and bacterial load to
levels observed in wild-type mice. Our findings suggest that CD4+Foxp3+ cells
play a time-dependent role in tuberculosis and highlight that CCR4 plays a
critical role in the balance of IFN-γ-mediated inflammation by regulating the
influx and function of CD4+Foxp3+ cells. Our findings are translationally
relevant, as CD4+Foxp3+ cells or CCR4 could be a target for immunotherapy,
considering the heterogeneity of tuberculosis in immunocompetent adults.
DOI: 10.1038/s41419-018-1240-3
PMCID: PMC6315058
PMID: 30584243
7. PLoS Pathog. 2018 Dec 20;14(12):e1007491. doi: 10.1371/journal.ppat.1007491.
eCollection 2018 Dec.
EspL is essential for virulence and stabilizes EspE, EspF and EspH levels in
Mycobacterium tuberculosis.
Sala C(1), Odermatt NT(1), Soler-Arnedo P(1), Gülen MF(1), von Schultz S(1),
Benjak A(1), Cole ST(1).
Author information:
(1)Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne,
Switzerland.
The ESX-1, type VII, secretion system represents the major virulence determinant
of Mycobacterium tuberculosis, one of the most successful intracellular
pathogens. Here, by combining genetic and high-throughput approaches, we show
that EspL, a protein of 115 amino acids, is essential for mediating
ESX-1-dependent virulence and for stabilization of EspE, EspF and EspH protein
levels. Indeed, an espL knock-out mutant was unable to replicate intracellularly,
secrete ESX-1 substrates or stimulate innate cytokine production. Moreover,
proteomic studies detected greatly reduced amounts of EspE, EspF and EspH in the
espL mutant as compared to the wild type strain, suggesting a role for EspL as a
chaperone. The latter conclusion was further supported by discovering that EspL
interacts with EspD, which was previously demonstrated to stabilize the ESX-1
substrates and effector proteins, EspA and EspC. Loss of EspL also leads to
downregulation in M. tuberculosis of WhiB6, a redox-sensitive transcriptional
activator of ESX-1 genes. Overall, our data highlight the importance of a so-far
overlooked, though conserved, component of the ESX-1 secretion system and begin
to delineate the role played by EspE, EspF and EspH in virulence and
host-pathogen interaction.
DOI: 10.1371/journal.ppat.1007491
PMCID: PMC6319747
PMID: 30571761
Conflict of interest statement: The authors have declared that no competing
interests exist.
8. J Immunol. 2019 Jan 15;202(2):421-427. doi: 10.4049/jimmunol.1800840. Epub 2018
Dec 17.
HBHA-Induced Polycytotoxic CD4+ T Lymphocytes Are Associated with the Control of
Mycobacterium tuberculosis Infection in Humans.
Aerts L(1), Selis E(1), Corbière V(1), Smits K(1), Van Praet A(1), Dauby N(2),
Petit E(3)(4)(5)(6), Singh M(7), Locht C(3)(4)(5)(6), Dirix V(1), Mascart
F(8)(9).
Author information:
(1)Laboratoire de Vaccinologie et d'Immunologie Mucosale, Université Libre de
Bruxelles, 1070 Brussels, Belgium.
(2)Département de Maladies Infectieuses, Centre Hospitalier Universitaire
Saint-Pierre, Université Libre de Bruxelles, 1000 Brussels, Belgium.
(3)INSERM, U1019, F-59019 Lille, France.
(4)CNRS, UMR8204, F-59019 Lille, France.
…
Heparin-binding hemagglutinin (HBHA), a surface protein of Mycobacterium
tuberculosis, is an attractive vaccine candidate and marker of protective
immunity against tuberculosis, although the mechanisms underlying this protective
immunity are not fully understood. Comparisons of the immune responses of
latently M. tuberculosis-infected (LTBI) subjects to those of patients with
active tuberculosis (aTB) may help to identify surrogate markers of protection,
as LTBI subjects are most often lifelong protected against the disease. HBHA was
shown to induce strong Th1 responses and cytotoxic CD8+ responses in LTBI
subjects, but additional mechanisms of control of M. tuberculosis infection
remain to be identified. In this study, using HBHA-induced blast formation as a
readout of specific T lymphocyte activation, we report the presence in M.
tuberculosis-infected subjects of HBHA-induced CD4+ T cell blasts that
degranulate, as measured by surface capture of CD107a. This suggests the
induction by HBHA of a CD4+ T cell subset with cytolytic function, and as nearly
half of these cells also contained IFN-γ, they had both Th1 and cytotoxic
characteristics. We further identified a CD4+ T lymphocyte subset producing IFN-γ
together with a combination of mediators of cytotoxicity, i.e., perforin,
granzymes, and granulysin, and we called them polycytotoxic CD4+ T lymphocytes.
Interestingly, whereas purified protein derivative induced such cells in both
LTBI subjects and patients with aTB, HBHA-specific polycytotoxic CD4+ T
lymphocytes were detected in LTBI subjects and not in patients with pulmonary
aTB. To our knowledge, we thus identified a new HBHA-induced CD4+ T cell subset
that may contribute to the control of M. tuberculosis infection.
Copyright © 2019 by The American Association of Immunologists, Inc.
DOI: 10.4049/jimmunol.1800840
PMID: 30559320
9. Am J Transplant. 2018 Dec 17. doi: 10.1111/ajt.15220. [Epub ahead of print]
Influence of epidemiology, immunosuppressive regimens, clinical presentation, and
treatment on kidney transplant outcomes of patients diagnosed with tuberculosis:
A retrospective cohort analysis.
Viana LA(1), Cristelli MP(1), Santos DW(1), Tavares MG(1), Dantas MTC(1), Felipe
CR(1), Silva HT(1), Pestana JM(1).
Author information:
(1)Hospital do Rim, Universidade Federal de São Paulo (UNIFESP), São Paulo,
Brazil.
Tuberculosis (TB) mortality is high among kidney transplant (KT) recipients.
Although local epidemiology is an important factor, diagnostic/therapeutic
challenges and immunosuppressive therapy (ISS) may influence outcomes. We
analyzed the cumulative incidence (CumI) of TB in KT recipients receiving a
variety of ISS with long-term follow-up. Our retrospective single-center cohort
study included all KT procedures performed between January 1, 1998, and August
31, 2014, with follow-up until August 31, 2014. Induction therapy was based on
perceived immunological risk; maintenance ISS included prednisone and calcineurin
inhibitor (CNI) plus azathioprine (AZA), and mycophenolic acid (MPA) or
mechanistic target of rapamycin inhibitor (mTORi). Thirty-four patients received
belatacept/MPA. KT was performed on 11 453 patients and followed for 1989 (IQR
932 to 3632) days. Among these, 152 patients were diagnosed with TB (CumI 1.32%).
Median time from KT to TB was 18.8 (IQR 7.2 to 60) months, with 59% of patients
diagnosed after the first year. Unadjusted analysis revealed an increasing
confidence interval (CI) of TB (0.94% CNI/AZA vs 1.6% CNI/MPA [HR = 1.62, 95% CI
= 1.13 to 2.34, P = .009] vs 2.85% CNI/mTORi [HR = 2.45, 95% CI = 1.49 to 4.32,
P < .001] vs 14.7% belatacept/MPA [HR = 13.14, 95% CI = 5.27 to 32.79,
P < .001]). Thirty-seven (24%) patients died, and 39 (25.6%) patients experienced
graft loss. Cytomegalovirus infection (P = .02) and definitive ISS
discontinuation (P < .001) were associated with death. Rejection (P = .018) and
ISS discontinuation (P = .005) occurred with graft loss. TB occurred at any time
after KT and was influenced by ISS.
© 2018 The American Society of Transplantation and the American Society of
Transplant Surgeons.
DOI: 10.1111/ajt.15220
PMID: 30556285
10. J Infect Dis. 2018 Dec 12. doi: 10.1093/infdis/jiy709. [Epub ahead of print]
The role of glutamine metabolism for host defense against Mycobacterium
tuberculosis infection.
Koeken VACM(1), Lachmandas E(1), Riza A(2), Matzaraki V(3), Li Y(3), Kumar
V(1)(3), Oosting M(1), Joosten LAB(1), Netea MG(1)(2), van Crevel R(1).
Author information:
(1)Radboud university medical center, Department of Internal Medicine and Radboud
Center of Infectious Diseases, Nijmegen, the Netherlands.
(2)Human Genomics Laboratory, Craiova University of Medicine and Pharmacy,
Craiova, Romania.
(3)University of Groningen, University Medical Center Groningen, department of
Genetics, Groningen, the Netherlands.
Background: Rewiring cellular metabolism is important for activation of immune
cells during host defense against Mycobacterium tuberculosis. Glutamine has been
implicated as an immunomodulatory nutrient, but its role in response to M.
tuberculosis is unknown.
Methods: We assessed expression of glutamine pathway genes in M. tuberculosis
infected macrophages and blood transcriptomics from individuals with latent or
active tuberculosis. Subsequently, we studied the effect of blocking
glutaminolysis on M. tuberculosis-induced cytokines. Finally, we examined whether
polymorphisms in genes involved in the glutamine pathway influence M.
tuberculosis-induced cytokines in a cohort of 500 individuals.
Results: Glutamine pathway genes were differentially expressed in infected
macrophages and patients with active tuberculosis. Human peripheral blood
mononuclear cells stimulated with M. tuberculosis displayed decreased cytokine
responses (IL-1β, IFN-γ, and IL-17) when medium was devoid of glutamine. Specific
inhibitors of the glutamine pathway led to decreased cytokine responses,
especially T-cell cytokines (IFN-γ, IL-17, and IL-22). Finally, genetic
polymorphisms in glutamine metabolism genes (including GLS2, SLC1A5, and SLC7A5)
influenced ex-vivo cytokine responses to M. tuberculosis, especially for T-cell
cytokines.
Conclusions: Cellular glutamine metabolism is implicated in effective host
responses against M. tuberculosis. Targeting immunometabolism may represent new
strategies for TB prevention and/or treatment.
DOI: 10.1093/infdis/jiy709
PMID: 30541099
11. Eur Respir J. 2018 Dec 20;52(6). pii: 1801528. doi: 10.1183/13993003.01528-2018.
Print 2018 Dec.
High treatment success rate for multidrug-resistant and extensively
drug-resistant tuberculosis using a bedaquiline-containing treatment regimen.
Ndjeka N(1), Schnippel K(2), Master I(3), Meintjes G(4)(5), Maartens G(6), Romero
R(7), Padanilam X(8), Enwerem M(9), Chotoo S(3), Singh N(3), Hughes J(10),
Variava E(11)(12), Ferreira H(11), Te Riele J(13), Ismail N(14)(15)(16), Mohr
E(17), Bantubani N(18), Conradie F(19).
Author information:
(1)National TB Programme, National Dept of Health, Pretoria, South Africa.
(2)Health Economics Unit, School of Public Health and Family Medicine, University
of Cape Town, Cape Town, South Africa.
(3)King Dinuzulu Hospital Complex, Kwazulu Natal Dept of Health, Durban, South
Africa.
…
South African patients with rifampicin-resistant tuberculosis (TB) and resistance
to fluoroquinolones and/or injectable drugs (extensively drug-resistant (XDR) and
preXDR-TB) were granted access to bedaquiline through a clinical access programme
with strict inclusion and exclusion criteria.PreXDR-TB and XDR-TB patients were
treated with 24?weeks of bedaquiline within an optimised, individualised
background regimen that could include levofloxacin, linezolid and clofazimine as
needed. 200 patients were enrolled: 87 (43.9%) had XDR-TB, 99 (49.3%) were female
and the median age was 34?years (interquartile range (IQR) 27-42). 134 (67.0%)
were living with HIV; the median CD4+ count was 281 cells·μL-1 (IQR 130-467) and
all were on antiretroviral therapy.16 out of 200 patients (8.0%) did not complete
6?months of bedaquiline: eight were lost to follow-up, six died, one stopped
owing to side effects and one was diagnosed with drug-sensitive TB. 146 out of
200 patients (73.0%) had favourable outcomes: 139 (69.5%) were cured and seven
(3.5%) completed treatment. 25 patients (12.5%) died, 20 (10.0%) were lost from
treatment and nine (4.5%) had treatment failure. 22 adverse events were
attributed to bedaquiline, including a QT interval corrected using the Fridericia
formula (QTcF) >500?ms (n=5), QTcF increase >50?ms from baseline (n=11) and
paroxysmal atrial flutter (n=1).Bedaquiline added to an optimised background
regimen was associated with a high rate of successful treatment outcomes for this
preXDR-TB and XDR-TB cohort.
Copyright ©ERS 2018.
DOI: 10.1183/13993003.01528-2018
PMID: 30361246
12. Eur Respir J. 2018 Dec 20;52(6). pii: 1801470. doi: 10.1183/13993003.01470-2018.
Print 2018 Dec.
Short-course regimens of rifapentine plus isoniazid to treat latent tuberculosis
infection in older Chinese patients: a randomised controlled study.
Gao L(1)(2)(2), Zhang H(1)(2), Xin H(1)(2), Liu J(3)(2), Pan S(4)(2), Li X(1),
Guan L(3), Shen F(3), Liu Z(4), Wang D(4), Guan X(3), Yan J(4), Li H(1), Feng
B(1), Cao X(1), Chen Y(3), Cui W(3), Zhang Z(5), Ma Y(5), Chen X(5), Zhou X(5),
Jin Q(1)(2); LATENTTB-NSTM study team.
Author information:
(1)MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen
Biology and Center for Tuberculosis, Chinese Academy of Medical Sciences and
Peking Union Medical College, Beijing, China.
(2)These authors contributed equally to this work.
(3)The Sixth People's Hospital of Zhengzhou, Zhengzhou, China.
(4)Center for Diseases Control and Prevention of Zhongmu, Zhongmu, China.
(5)Beijing Chest Hospital, Capital Medical University, Beijing Key Laboratory for
Drug Resistant Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor
Research Institute, Beijing, China.
Latent tuberculosis infection (LTBI) management is now a critical component of
the World Health Organization's End TB Strategy.In this randomised controlled
trial (Chinese Clinical Trial Registry identifier ChiCTR-IOR-15007202), two
short-course regimens with rifapentine plus isoniazid (a 3-month once-weekly
regimen and a 2-month twice-weekly regimen) were initially designed to be
evaluated for rural residents aged 50-69 years with LTBI in China.Due to the
increasingly rapid growth and unexpected high frequency of adverse effects, the
treatments were terminated early (after 8?weeks for the once-weekly regimen and
after 6?weeks for the twice-weekly regimen). In the modified intention-to-treat
analysis on the completed doses, the cumulative rate of active disease during
2?years of follow-up was 1.21% (14 out of 1155) in the untreated controls, 0.78%
(10 out of 1284) in the group that received the 8-week once-weekly regimen and
0.46% (six out of 1299) in the group that received the 6-week twice-weekly
regimen. The risk of active disease was decreased, with an adjusted hazard ratio
of 0.63 (95% CI 0.27-1.43) and 0.41 (95% CI 0.15-1.09) for the treatments,
respectively. No significant difference was found in the occurrence of
hepatotoxicity (1.02% (13 out of 1279) versus 1.17% (15 out of 1279);
p=0.704).The short regimens tested must be used with caution among the elderly
because of the high rates of adverse effects. Further work is necessary to test
the ultrashort regimens in younger people with LTBI.
Copyright ©ERS 2018.
DOI: 10.1183/13993003.01470-2018
PMID: 30361241
13. Mol Ther. 2018 Dec 5;26(12):2863-2874. doi: 10.1016/j.ymthe.2018.08.023. Epub
2018 Sep 1.
Recombinant BCG Overexpressing phoP-phoR Confers Enhanced Protection against
Tuberculosis.
Ahn SK(1), Tran V(1), Leung A(1), Ng M(1), Li M(1), Liu J(2).
Author information:
(1)Department of Molecular Genetics, Faculty of Medicine, University of Toronto,
Toronto, ON M5G 1M1, Canada.
(2)Department of Molecular Genetics, Faculty of Medicine, University of Toronto,
Toronto, ON M5G 1M1, Canada. Electronic address: jun.liu@utoronto.ca.
The live tuberculosis vaccine Mycobacterium bovis BCG (Bacille Calmette-Guérin)
comprises a number of genetically distinct substrains. In BCG-Prague, phoP of the
PhoP-PhoR two-component system is a pseudogene due to a single insertion
mutation. We hypothesized that this mutation partially accounts for the low
immunogenicity of BCG-Prague observed in the 1970s. In this study, we showed that
complementation with the M. bovis allele of phoP restored BCG-Prague's
immunogenicity. Furthermore, we showed that overexpression of the M. bovis allele
of phoP-phoR in BCG-Japan, a strain already containing a copy of phoP-phoR,
further enhanced immunogenicity and protective efficacy. Vaccination of C57BL/6
mice with the recombinant strain rBCG-Japan/PhoPR induced higher levels of
interferon-γ (IFN-γ) production by CD4+ T cells than that with the parental BCG.
Guinea pigs vaccinated with rBCG-Japan/PhoPR were better protected against
challenge with Mycobacterium tuberculosis than those immunized with the parental
BCG, showing significantly longer survival time, reduced bacterial burdens, and
less severe pathology. Taken together, our study has identified a genetic
modification that could be generally applied to generate new recombinant BCG
vaccines.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ymthe.2018.08.023
PMCID: PMC6277425 [Available on 2019-12-05]
PMID: 30274790
14. Biosens Bioelectron. 2018 Dec 15;121:111-117. doi: 10.1016/j.bios.2018.08.068.
Epub 2018 Aug 28.
Gold-copper nanoshell dot-blot immunoassay for naked-eye sensitive detection of
tuberculosis specific CFP-10 antigen.
Phan LMT(1), Rafique R(1), Baek SH(1), Nguyen TP(1), Park KY(1), Kim EB(1), Kim
JG(1), Park JP(2), Kailasa SK(3), Kim HJ(4), Chung C(5), Shim TS(6), Park TJ(7).
Author information:
(1)Department of Chemistry, Institute of Interdisciplinary Convergence Research,
Research Institute of Halal Industrialization Technology, Chung-Ang University,
84 Heukseok-ro, Donjak-gu, Seoul 06974, Republic of Korea.
(2)Department of Pharmaceutical Engineering, Daegu Haany University, Gyeongsan
38610, Republic of Korea.
(3)Department of Chemistry, Institute of Interdisciplinary Convergence Research,
Research Institute of Halal Industrialization Technology, Chung-Ang University,
84 Heukseok-ro, Donjak-gu, Seoul 06974, Republic of Korea; Department of Applied
Chemistry, S. V. National Institute of Technology, Surat 395007, Gujarat, India.
…
Herein, a straightforward and highly specific dot-blot immunoassay was
successfully developed for the detection of Mycobacterium tuberculosis antigen
(10?kDa culture filtrate protein, CFP-10) via the formation of copper nanoshell
on the gold nanoparticles (AuNPs) surface. The principle of dot-blot immunoassay
was based on the reduction of Cu2+ ion on the GBP-CFP10G2-AuNPs conjugates, which
has gold binding and antigen binding affinities, simultaneously, favouring to
appear red dot that can be observed with naked-eye. The dot intensity is
proportional to the concentration of tuberculosis antigen CFP-10, which offers a
detection limit of 7.6?pg/mL. The analytical performance of
GBP-CFP10G2-AuNPs-copper nanoshell dot-blot was superior than that of
conventional silver nanoshell. This method was successfully applied to identify
the CFP-10 antigen in the clinical urine sample with high sensitivity,
specificity, and minimized sample preparation steps. This method exhibits great
application potential in the field of nanomedical science for highly reliable
point-of-care detection of CFP-10 antigen in real samples to early diagnosis of
tuberculosis.
Copyright © 2018 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bios.2018.08.068
PMID: 30205244 [Indexed for MEDLINE]
15. Clin Pharmacol Ther. 2018 Dec;104(6):1208-1218. doi: 10.1002/cpt.1102. Epub 2018 Jun 19.
Forecasting Clinical Dose-Response From Preclinical Studies in Tuberculosis
Research: Translational Predictions With Rifampicin.
Wicha SG(1)(2), Clewe O(1), Svensson RJ(1), Gillespie SH(3), Hu Y(4), Coates
ARM(4), Simonsson USH(1).
Author information:
(1)Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
(2)Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg,
Hamburg, Germany.
(3)School of Medicine, University of St Andrews, St Andrews, UK.
(4)Institute for Infection and Immunity, St George's University of London,
London, UK.
A crucial step for accelerating tuberculosis drug development is bridging the gap
between preclinical and clinical trials. In this study, we developed a
preclinical model-informed translational approach to predict drug effects across
preclinical systems and early clinical trials using the in vitro-based Multistate
Tuberculosis Pharmacometric (MTP) model using rifampicin as an example. The MTP
model predicted rifampicin biomarker response observed in 1) a hollow-fiber
infection model, 2) a murine study to determine pharmacokinetic/pharmacodynamic
indices, and 3) several clinical phase IIa early bactericidal activity (EBA)
studies. In addition, we predicted rifampicin biomarker response at high doses of
up to 50 mg/kg, leading to an increased median EBA0-2 days (90% prediction
interval) of 0.513 log CFU/mL/day (0.310; 0.701) compared to the standard dose of
10 mg/kg of 0.181 log/CFU/mL/day (0.076; 0.483). These results suggest that the
translational approach could assist in the selection of drugs and doses in
early-phase clinical tuberculosis trials.
© 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley
Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and
Therapeutics.
DOI: 10.1002/cpt.1102
PMCID: PMC6282494
PMID: 29700814
16. Tuberculosis (Edinb). 2018 Dec;113:242-248. doi: 10.1016/j.tube.2018.11.001. Epub 2018 Nov 3.
Multicentre laboratory validation of the nitrate reductase assay using liquid
medium for the rapid detection of multidrug-resistant and extensively
drug-resistant Mycobacterium tuberculosis.
Huang Z(1), Du J(2), Deng Z(1), Luo Q(1), Xiong G(3), Wang Y(4), Zhang X(5), Li
J(6).
Author information:
(1)Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang
University, Nanchang, Jiangxi, China.
(2)Department of Clinical Laboratory, First Teaching Hospital of Tianjin
University of TCM, Tianjin, China.
(3)Province Tuberculosis Reference Laboratory, Jiangxi Chest Hospital, Nanchang,
Jiangxi, China.
…
To perform a multicentre study evaluating the performance of the nitrate
reductase assay (NRA) using liquid medium for the detection of
multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis and
to establish the MICs and critical concentrations of rifampicin, isoniazid,
ofloxacin, amikacin, kanamycin and capreomycin. The study was carried out in
three phases. Phase I determined the MIC of each drug. Phase II established the
critical concentration of each drug. Phase III validated critical concentrations
for the six drugs tested by the NRA using liquid medium compared with the agar
proportion method or MGIT 960 system at each site. The critical concentrations
for the six drugs used in the NRA are as follows: rifampicin, 1?mg/L; isoniazid,
0.2?mg/L; ofloxacin, 2?mg/L; amikacin, 2?mg/L; kanamycin, 5?mg/L; capreomycin,
2.5?mg/L. Phase III: Excellent agreement was obtained for all drugs tested at the
majority of sites. The accuracy was 97%-100% for rifampicin, 96.8%-99.2% for
isoniazid, 98%-100% for ofloxacin, 96.8%-98.5% for amikacin, 96.4%-99.5% for
kanamycin and 96.8%-100% for capreomycin. Results for NRA using liquid medium
were obtained in a median time of 7 days. NRA performed in liquid medium offers a
rapid, economical and feasible method for detection of M. tuberculosis resistance
to first- and second-line drugs in resource-limited settings.
Copyright © 2018 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tube.2018.11.001
PMID: 30514509
17. Tuberculosis (Edinb). 2018 Dec;113:231-238. doi: 10.1016/j.tube.2018.10.008. Epub 2018 Oct 30.
A novel derivative of the fungal antimicrobial peptide plectasin is active
against Mycobacterium tuberculosis.
Tenland E(1), Krishnan N(2), Rönnholm A(1), Kalsum S(3), Puthia M(4), Mörgelin
M(5), Davoudi M(4), Otrocka M(6), Alaridah N(1), Glegola-Madejska I(2), Sturegård
E(7), Schmidtchen A(4), Lerm M(3), Robertson BD(2), Godaly G(8).
Author information:
(1)Department of Microbiology, Immunology and Glycobiology, Institution of
Laboratory Medicine, Lund University, Lund, Sweden.
(2)MRC Centre for Molecular Bacteriology and Infection, Department of Medicine,
Imperial College London, UK.
(3)Department of Clinical and Experimental Medicine, Faculty Medicine and Health
Sciences, Linköping, Sweden.
…
Tuberculosis has been reaffirmed as the infectious disease causing most deaths in
the world. Co-infection with HIV and the increase in multi-drug resistant
Mycobacterium tuberculosis strains complicate treatment and increases mortality
rates, making the development of new drugs an urgent priority. In this study we
have identified a promising candidate by screening antimicrobial peptides for
their capacity to inhibit mycobacterial growth. This non-toxic peptide, NZX, is
capable of inhibiting both clinical strains of M. tuberculosis and an MDR strain
at therapeutic concentrations. The therapeutic potential of NZX is further
supported in vivo where NZX significantly lowered the bacterial load with only
five days of treatment, comparable to rifampicin treatment over the same period.
NZX possesses intracellular inhibitory capacity and co-localizes with
intracellular bacteria in infected murine lungs. In conclusion, the data
presented strongly supports the therapeutic potential of NZX in future anti-TB
treatment.
Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.tube.2018.10.008
PMCID: PMC6289163
PMID: 30514507
