Medical Abstracts

Keyword: tuberculosis

1. Nat Commun. 2019 Nov 29;10(1):5457. doi: 10.1038/s41467-019-13387-9.

Bridging the gap between efficacy trials and model-based impact evaluation for

new tuberculosis vaccines.

Tovar M(1)(2), Arregui S(1)(2), Marinova D(3)(4), Martín C(3)(4)(5), Sanz

J(6)(7)(8), Moreno Y(9)(10)(11).

Author information:

(1)Institute for Bio-computation and Physics of Complex Systems (BIFI),

University of Zaragoza, Zaragoza, Spain.

(2)Department of Theoretical Physics, Faculty of Sciences, University of

Zaragoza, Zaragoza, Spain.

(3)Microbiology Department, Faculty of Medicine, University of Zaragoza,

Zaragoza, Spain.

…

In Tuberculosis (TB), given the complexity of its transmission dynamics,

observations of reduced epidemiological risk associated with preventive

interventions can be difficult to translate into mechanistic interpretations.

Specifically, in clinical trials of vaccine efficacy, a readout of protection

against TB disease can be mapped to multiple dynamical mechanisms, an issue that

has been overlooked so far. Here, we describe this limitation and its effect on

model-based evaluations of vaccine impact. Furthermore, we propose a methodology

to analyze efficacy trials that circumvents it, leveraging a combination of

compartmental models and stochastic simulations. Using our approach, we can

disentangle the different possible mechanisms of action underlying vaccine

protection effects against TB, conditioned to trial design, size, and duration.

Our results unlock a deeper interpretation of the data emanating from efficacy

trials of TB vaccines, which renders them more interpretable in terms of

transmission models and translates into explicit recommendations for vaccine

developers.

DOI: 10.1038/s41467-019-13387-9

PMCID: PMC6884451

PMID: 31784512 [Indexed for MEDLINE]

2. Lancet Infect Dis. 2020 Feb;20(2):250-258. doi: 10.1016/S1473-3099(19)30568-7.

Epub 2019 Nov 26.

Drug-resistant tuberculosis in eastern Europe and central Asia: a time-series

analysis of routine surveillance data.

Dadu A(1), Hovhannesyan A(1), Ahmedov S(2), van der Werf MJ(3), Dara M(4).

Author information:

(1)WHO Regional Office for Europe, Copenhagen, Denmark.

(2)United States Agency for International Development, Washington DC, USA.

(3)European Centre for Disease Prevention and Control, Solna, Sweden.

(4)WHO Regional Office for Europe, Copenhagen, Denmark. Electronic address:

daram@who.int.

BACKGROUND: Among all WHO regions, the WHO European Region has the highest

proportion of drug-resistant tuberculosis among new and retreated cases. The 18

high-priority countries in eastern Europe and central Asia account for 85% of the

tuberculosis incidence and more than 90% of drug-resistant tuberculosis cases

emerging in the region. We aimed to analyse time-series trends in notification

rates of drug-resistant tuberculosis among new tuberculosis cases in the 18

high-priority countries in the WHO European Region.

METHODS: We used country data stored in WHO's global tuberculosis database. For

each country, we calculated annual notification rates per 100?000 population of

new tuberculosis cases and of drug-resistant tuberculosis among new cases

reported from Jan 1, 2000, to Dec 31, 2017. We computed annual percentage changes

of notification rates and identified time-points of significant change in trends

using the joinpoint regression method.

FINDINGS: All 17 countries with data (no data available from Turkmenistan) showed

a significant decline in new tuberculosis notification rates in the most recent

years since the last joinpoint if one was identified. Notification rates of

drug-resistant tuberculosis showed diverse trends, with substantial year-to-year

variation. In the most recent years, notification rates of drug-resistant

tuberculosis among new tuberculosis cases were decreasing in two countries

(Estonia and Latvia), increasing in eight countries (Azerbaijan, Kyrgyzstan,

Moldova [Republic of Moldova], Romania, Russia [Russian Federation], Tajikistan,

Ukraine, and Uzbekistan), and stable in seven countries (Armenia, Belarus,

Bulgaria, Georgia, Kazakhstan, Lithuania, and Turkey).

INTERPRETATION: Our findings suggest that countries in the WHO European Region

are more successful in controlling drug-susceptible tuberculosis than

drug-resistant forms, and as a result, the proportion of drug-resistant strains

among newly notified patients with tuberculosis is increasing in many settings.

Two countries showed that it is possible to decrease incidence of both

drug-susceptible and drug-resistant tuberculosis. If no additional efforts are

made in prevention and care of patients with drug-resistant tuberculosis, further

decline of the tuberculosis burden will be halted. Further studies are needed to

investigate the success stories and document the most effective interventions to

reach the target to end tuberculosis by 2030.

FUNDING: United States Agency for International Development.

Copyright © 2020 World Health Organization. Published by Elsevier Ltd. All rights

reserved. Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/S1473-3099(19)30568-7

PMID: 31784371

3. Lancet Infect Dis. 2020 Feb;20(2):e47-e53. doi: 10.1016/S1473-3099(19)30524-9.

Epub 2019 Nov 15.

Tuberculosis, HIV, and viral hepatitis diagnostics in eastern Europe and central

Asia: high time for integrated and people-centred services.

Dara M(1), Ehsani S(2), Mozalevskis A(2), Vovc E(2), Simões D(3), Avellon Calvo

A(4), Casabona I Barbarà J(5), Chokoshvili O(6), Felker I(7), Hoffner S(8),

Kalmambetova G(9), Noroc E(10), Shubladze N(11), Skrahina A(12), Tahirli R(13),

Tsertsvadze T(14), Drobniewski F(15).

Author information:

(1)Communicable Diseases Department, Division of Health Emergencies and

Communicable Diseases, Regional Office for Europe, World Health Organization,

Copenhagen, Denmark. Electronic address: daram@who.int.

(2)Joint Tuberculosis, HIV and Viral Hepatitis Programme, Regional Office for

Europe, World Health Organization, Copenhagen, Denmark.

(3)EPI Unit, Institute of Public Health, University of Porto, Porto, Portugal.

…

Globally, high rates (and in the WHO European region an increasing prevalence) of

co-infection with tuberculosis and HIV and HIV and hepatitis C virus exist. In

eastern European and central Asian countries, the tuberculosis, HIV, and viral

hepatitis programmes, including diagnostic services, are separate vertical

structures. In this Personal View, we consider underlying reasons for the poor

integration for these diseases, particularly in the WHO European region, and how

to address this with an initial focus on diagnostic services. In part, this low

integration has reflected different diagnostic development histories, global

funding sources, and sample types used for diagnosis (eg, typically sputum for

tuberculosis and blood for HIV and hepatitis C). Cooperation between services

improved as patients with tuberculosis needed routine testing for HIV and vice

versa, but financial, infection control, and logistical barriers remain.

Multidisease diagnostic platforms exist, but to be used optimally, appropriate

staff training and sensible understanding of different laboratory and infection

control risks needs rapid implementation. Technically these ideas are all

feasible. Poor coordination between these vertical systems remains unhelpful.

There is a need to increase political and operational integration of diagnostic

and treatment services and bring them closer to patients.

Copyright © 2020 World Health Organization. Published by Elsevier Ltd/Inc/BV. All

rights reserved. Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/S1473-3099(19)30524-9

PMID: 31740252

4. Am J Respir Crit Care Med. 2019 Nov 15;200(10):e93-e142. doi:

10.1164/rccm.201909-1874ST.

Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical

Practice Guideline.

Nahid P, Mase SR, Migliori GB, Sotgiu G, Bothamley GH, Brozek JL, …

Erratum in

Am J Respir Crit Care Med. 2020 Feb 15;201(4):500-501.

Background: The American Thoracic Society, U.S. Centers for Disease Control and

Prevention, European Respiratory Society, and Infectious Diseases Society of

America jointly sponsored this new practice guideline on the treatment of

drug-resistant tuberculosis (DR-TB). The document includes recommendations on the

treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but

rifampin-susceptible TB.Methods: Published systematic reviews, meta-analyses, and

a new individual patient data meta-analysis from 12,030 patients, in 50 studies,

across 25 countries with confirmed pulmonary rifampin-resistant TB were used for

this guideline. Meta-analytic approaches included propensity score matching to

reduce confounding. Each recommendation was discussed by an expert committee,

screened for conflicts of interest, according to the Grading of Recommendations,

Assessment, Development, and Evaluation (GRADE) methodology.Results: Twenty-one

Population, Intervention, Comparator, and Outcomes questions were addressed,

generating 25 GRADE-based recommendations. Certainty in the evidence was judged

to be very low, because the data came from observational studies with significant

loss to follow-up and imbalance in background regimens between comparator groups.

Good practices in the management of MDR-TB are described. On the basis of the

evidence review, a clinical strategy tool for building a treatment regimen for

MDR-TB is also provided.Conclusions: New recommendations are made for the choice

and number of drugs in a regimen, the duration of intensive and continuation

phases, and the role of injectable drugs for MDR-TB. On the basis of these

recommendations, an effective all-oral regimen for MDR-TB can be assembled.

Recommendations are also provided on the role of surgery in treatment of MDR-TB

and for treatment of contacts exposed to MDR-TB and treatment of

isoniazid-resistant TB.

DOI: 10.1164/rccm.201909-1874ST

PMCID: PMC6857485

PMID: 31729908

5. Sci Transl Med. 2019 Nov 13;11(518). pii: eaaw6635. doi:

10.1126/scitranslmed.aaw6635.

Targeting redox heterogeneity to counteract drug tolerance in replicating

Mycobacterium tuberculosis.

Mishra R(1)(2), Kohli S(1)(2), Malhotra N(3), Bandyopadhyay P(1)(2), Mehta

M(1)(2), Munshi M(1)(2), Adiga V(2), Ahuja VK(4), Shandil RK(4), Rajmani RS(2),

Seshasayee ASN(3), Singh A(5).

Author information:

(1)Department of Microbiology and Cell Biology, Indian Institute of Science,

Bangalore 560012, India.

(2)Centre for Infectious Disease Research, Indian Institute of Science, Bangalore

560012, India.

(3)National Centre for Biological Sciences (NCBS), Tata Institute of Fundamental

Research (TIFR), Bangalore 560065, India.

…

The capacity of Mycobacterium tuberculosis (Mtb) to tolerate multiple antibiotics

represents a major problem in tuberculosis (TB) management. Heterogeneity in Mtb

populations is one of the factors that drives antibiotic tolerance during

infection. However, the mechanisms underpinning this variation in bacterial

population remain poorly understood. Here, we show that phagosomal acidification

alters the redox physiology of Mtb to generate a population of replicating

bacteria that display drug tolerance during infection. RNA sequencing of this

redox-altered population revealed the involvement of iron-sulfur (Fe-S) cluster

biogenesis, hydrogen sulfide (H2S) gas, and drug efflux pumps in antibiotic

tolerance. The fraction of the pH- and redox-dependent tolerant population

increased when Mtb infected macrophages with actively replicating HIV-1,

suggesting that redox heterogeneity could contribute to high rates of TB therapy

failure during HIV-TB coinfection. Pharmacological inhibition of phagosomal

acidification by the antimalarial drug chloroquine (CQ) eradicated drug-tolerant

Mtb, ameliorated lung pathology, and reduced postchemotherapeutic relapse in in

vivo models. The pharmacological profile of CQ (C max and AUClast) exhibited no

major drug-drug interaction when coadministered with first line anti-TB drugs in

mice. Our data establish a link between phagosomal pH, redox metabolism, and drug

tolerance in replicating Mtb and suggest repositioning of CQ to shorten TB

therapy and achieve a relapse-free cure.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American

Association for the Advancement of Science. No claim to original U.S. Government

Works.

DOI: 10.1126/scitranslmed.aaw6635

PMID: 31723039

6. Autophagy. 2019 Nov 11:1-15. doi: 10.1080/15548627.2019.1687214. [Epub ahead of

print]

BAG2 ameliorates endoplasmic reticulum stress-induced cell apoptosis in

Mycobacterium tuberculosis-infected macrophages through selective autophagy.

Liang S(1)(2), Wang F(1)(2), Bao C(1)(2), Han J(1)(2), Guo Y(1)(2), Liu F(1)(2),

Zhang Y(1)(2).

Author information:

(1)College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi,

China.

(2)Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F

University, Yangling, Shaanxi, China.

BAG2 (BCL2 associated athanogene 2) is associated with cell fate determination in

response to various pathological conditions. However, the effects of BAG2 on M.

tuberculosis-induced endoplasmic reticulum (ER) stress remain elusive. Herein, we

report that M. tuberculosis infection of macrophages triggered ER stress and

downregulated BAG2 expression. Overexpression of BAG2 enhanced autophagic flux

and activated macroautophagy/autophagy targeted to the ER (reticulophagy). In

addition, through increasingly localizing SQSTM1 to the ER in BAG2-overexpressing

macrophages, we found that the autophagy receptor protein SQSTM1/p62

(sequestosome 1) is associated with the BAG2-induced reticulophagy. Our data also

confirmed that BAG2 could render cells resistant to M. tuberculosis-induced

cellular damage, and the anti-apoptotic effects of BAG2 in M.

tuberculosis-treated macrophages were partially abolished by the autophagic flux

inhibitor bafilomycin A1. Furthermore, the dissociation of BECN1 and BCL2

mediated by activation of mitogen-activated protein kinase (MAPK)/extracellular

signal-regulated kinase (ERK) was responsible for BAG2-activated autophagy. In

addition, XBP1 downstream of the ERN1/IRE1 signaling pathway was bound to the

Bag2 promoter region and transcriptionally inhibited BAG2 expression.

Collectively, these results indicated that BAG2 has anti-apoptotic effects on M.

tuberculosis-induced ER stress, which is dependent on the promotion of autophagic

flux and the induction of selective autophagy. We revealed a potential host

defense mechanism that links BAG2 to ER stress and autophagy during M.

tuberculosis infection.Abbreviations: ATF6: activating transcription factor 6;

BECN1: beclin 1; Baf A1: bafilomycin A1; CASP3: caspase 3; DDIT3/CHOP/GADD153:

DNA damage inducible transcript 3; DAPI: 4',6-diamidino-2-phenylindole;

EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER:

endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1;

HSPA5/GRP78/BiP: heat shock protein 5; MAP1LC3B/LC3B: microtubule associated

protein 1 light chain 3 beta; MAPK/ERK: mitogen-activated protein kinase;

SQSTM1/p62: sequestosome 1; UPR: unfolded protein response; XBP1: x-box binding

protein 1.

DOI: 10.1080/15548627.2019.1687214

PMID: 31711362

7. Lancet Infect Dis. 2019 Nov;19(11):1191-1201. doi: 10.1016/S1473-3099(19)30260-9.Epub 2019 Aug 27.

Effectiveness of pre-entry active tuberculosis and post-entry latent tuberculosis

screening in new entrants to the UK: a retrospective, population-based cohort

study.

Berrocal-Almanza LC(1), Harris R(2), Lalor MK(3), Muzyamba MC(4), Were J(4),

O'Connell AM(5), Mirza A(4), Kon OM(6), Lalvani A(7), Zenner D(8).

Author information:

(1)National Institute for Health Research Health Protection Research Unit in

Respiratory Infections, National Heart and Lung Institute, Imperial College

London, London, UK.

(2)Statistics, Modelling and Economics Department, National Infection Service,

Public Health England, London, UK.

(3)Tuberculosis Unit, TARGET, National Infection Service, Public Health England,

London, UK; Institute for Global Health, University College London, London, UK.

…

BACKGROUND: Evaluating interventions that might lead to a reduction in

tuberculosis in high-income countries with a low incidence of the disease is key

to accelerate progress towards its elimination. In such countries, migrants are

known to contribute a large proportion of tuberculosis cases to the burden. We

assessed the effectiveness of screening for active tuberculosis before entry to

the UK and for latent tuberculosis infection (LTBI) post-entry for reduction of

tuberculosis in new-entrant migrants to the UK. Additionally, we investigated the

effect of access to primary care on tuberculosis incidence in this population.

METHODS: We did a retrospective, population-based cohort study of migrants from

66 countries who were negative for active tuberculosis at pre-entry screening

between Jan 1, 2011, and Dec 31, 2014, and eligible for LTBI screening. We used

record linkage to track their first contact with primary care, uptake of LTBI

screening, and development of active tuberculosis in England, Wales, and Northern

Ireland. To assess the effectiveness of the pre-entry screening programme, we

identified a control group of migrants who were not screened for active

tuberculosis using the specific code for new entrants to the UK registering in

primary care within the National Health Service patient registration data system.

Our primary outcome was development of active tuberculosis notified to the

National Enhanced Tuberculosis Surveillance System.

FINDINGS: Our cohort comprised 224?234 migrants who were screened for active

tuberculosis before entry to the UK and a control group of 118?738 migrants who

were not. 103?990 (50%) migrants who were screened for active tuberculosis

registered in primary care; all individuals in the control group were registered

in primary care. 1828 tuberculosis cases were identified during the cohort time,

of which 31 were prevalent. There were 26 incident active tuberculosis cases in

migrants with no evidence of primary care registration, and 1771 cases in the

entire cohort of migrants who registered in primary care (n=222?728), giving an

incidence rate of 174 (95% CI 166-182) per 100?000 person-years. 672 (1%) of

103?990 migrants who were screened for active tuberculosis went on to develop

tuberculosis compared with 1099 (1%) of 118?738 not screened for active

tuberculosis (incidence rate ratio [IRR] 1·49, 95% CI 1·33-1·67; p<0·0001). 2451

(1%) of the 222?728 migrants registered in primary care were screened for LTBI,

of whom 421 (17%) tested positive and 1961 (80%) tested negative; none developed

active tuberculosis within the observed time period. Migrants settling in the

least deprived areas had a decreased risk of developing tuberculosis (IRR 0·74,

95% CI 0·62-0·89; p=0·002), and time from UK arrival to primary care registration

of 1 year or longer was associated with increased risk of active tuberculosis

(2·96, 2·59-3·38; p<0·0001).

INTERPRETATION: Pre-entry tuberculosis screening, early primary care

registration, and LTBI screening are strongly and independently associated with a

lower tuberculosis incidence in new-entrant migrants.

FUNDING: National Institute for Health Research (NIHR) Health Protection Research

Unit in Respiratory Infections and NIHR Imperial Biomedical Research Centre.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(19)30260-9

PMID: 31471131

8. Clin Infect Dis. 2019 Nov 27. pii: ciz1157. doi: 10.1093/cid/ciz1157. [Epub ahead

of print]

Clinical Characteristics of Active Tuberculosis Diagnosed after Starting

Treatment for Latent Tuberculosis Infection.

Flynn AG(1)(2), Aiona K(3), Haas MK(2)(3), Reves R(2), Belknap R(2)(3).

Author information:

(1)Duke University Medical Center Department of Family Medicine, Durham, NC, USA.

(2)University of Colorado School of Medicine, Aurora, CO USA.

(3)Denver Health and Hospital Authority, Denver, USA.

BACKGROUND: Efforts to expand treatment of latent tuberculosis infection (LTBI)

raise concerns for missed subclinical active tuberculosis (TB) and acquired

drug-resistance.

METHODS: We conducted a retrospective cohort review of patients who began LTBI

therapy between January 1, 2006 and December 31, 2017 at the Denver Metro TB

Clinic, Colorado, USA. Electronic databases and chart review were used for data

collection. Subsequent active TB diagnoses in this cohort were determined using

the state of Colorado TB database through June 30, 2018.

RESULTS: 8472 patients started LTBI treatment during the study period with 46%

prescribed nine months of isoniazid and 43% four months of rifampin. 24 (0.28%)

developed active TB, 10 during and 14 after LTBI therapy. Culture confirmation

was obtained for 13 (54%) and none had acquired drug-resistance. Patients

diagnosed during (n=10) versus after treatment (n=14) were less likely to be

culture-confirmed (30% versus 71%) and less likely to have pulmonary disease (20%

vs 57%).

CONCLUSIONS: Subclinical TB missed by symptom screening and chest radiography was

rare in our mostly HIV-negative cohort. Culture negative, extrapulmonary disease

was more common with TB diagnosed during than after LTBI treatment. We found no

evidence for acquired drug resistance in LTBI patients subsequently diagnosed

with active TB.

© The Author(s) 2019. Published by Oxford University Press for the Infectious

Diseases Society of America. All rights reserved. For permissions, e-mail:

journals.permissions@oup.com.

DOI: 10.1093/cid/ciz1157

PMID: 31773132

9. Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):25649-25658. doi:

10.1073/pnas.1910368116. Epub 2019 Nov 22.

The conical shape of DIM lipids promotes Mycobacterium tuberculosis infection of

macrophages.

Augenstreich J(1), Haanappel E(1), Ferré G(1), Czaplicki G(1), Jolibois F(2),

Destainville N(3), Guilhot C(1), Milon A(4), Astarie-Dequeker C(4), Chavent M(4).

Author information:

(1)Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse,

CNRS, Université Paul Sabatier, 31400 Toulouse, France.

(2)Laboratoire de Physique et Chimie des Nano-objets, Institut National des

Sciences Appliquées, Université de Toulouse, CNRS, Université Paul Sabatier,

F-31077 Toulouse, France.

(3)Laboratoire de Physique Théorique, Institut de Recherche sur les Systèmes

Atomiques et Moléculaires Complexes, Université de Toulouse, CNRS, Université

Paul Sabatier, 31062 Toulouse, France.

…

Phthiocerol dimycocerosate (DIM) is a major virulence factor of the pathogen

Mycobacterium tuberculosis (Mtb). While this lipid promotes the entry of Mtb into

macrophages, which occurs via phagocytosis, its molecular mechanism of action is

unknown. Here, we combined biophysical, cell biology, and modeling approaches to

reveal the molecular mechanism of DIM action on macrophage membranes leading to

the first step of Mtb infection. Matrix-assisted laser desorption ionization

time-of-flight (MALDI-TOF) mass spectrometry showed that DIM molecules are

transferred from the Mtb envelope to macrophage membranes during infection.

Multiscale molecular modeling and 31P-NMR experiments revealed that DIM adopts a

conical shape in membranes and aggregates in the stalks formed between 2 opposing

lipid bilayers. Infection of macrophages pretreated with lipids of various shapes

uncovered a general role for conical lipids in promoting phagocytosis. Taken

together, these results reveal how the molecular shape of a mycobacterial lipid

can modulate the biological response of macrophages.

DOI: 10.1073/pnas.1910368116

PMCID: PMC6926010 [Available on 2020-05-22]

PMID: 31757855

10. Brief Bioinform. 2019 Nov 13. pii: bbz127. doi: 10.1093/bib/bbz127. [Epub ahead

of print]

Decoding the similarities and specific differences between latent and active

tuberculosis infections based on consistently differential expression networks.

Sun J(1), Shi Q(1), Chen X(2)(3), Liu R(1).

Author information:

(1)Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics,

Huazhong Agricultural University, Wuhan 430070, China.

(2)State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural

University, Wuhan 430070, China.

(3)College of Veterinary Medicine, Huazhong Agricultural University, Wuhan

430070, China.

Although intensive efforts have been devoted to investigating latent tuberculosis

(LTB) and active tuberculosis (PTB) infections, the similarities and differences

in the host responses to these two closely associated stages remain elusive,

probably due to the difficulty in identifying informative genes related to LTB

using traditional methods. Herein, we developed a framework known as the

consistently differential expression network to identify tuberculosis

(TB)-related gene pairs by combining microarray profiles and protein-protein

interactions. We thus obtained 774 and 693 pairs corresponding to the PTB and LTB

stages, respectively. The PTB-specific genes showed higher expression values and

fold-changes than the LTB-specific genes. Furthermore, the PTB-related pairs

generally had higher expression correlations and would be more activated compared

to their LTB-related counterparts. The module analysis implied that the detected

gene pairs tended to cluster in the topological and functional modules.

Functional analysis indicated that the LTB- and PTB-specific genes were enriched

in different pathways and had remarkably different locations in the NF-κB

signaling pathway. Finally, we showed that the identified genes and gene pairs

had the potential to distinguish TB patients in different disease stages and

could be considered as drug targets for the specific treatment of patients with

LTB or PTB.

© The Author(s) 2019. Published by Oxford University Press. All rights reserved.

For Permissions, please email: journals.permissions@oup.com.

DOI: 10.1093/bib/bbz127

PMID: 31724702

11. Clin Infect Dis. 2019 Nov 12. pii: ciz1107. doi: 10.1093/cid/ciz1107. [Epub ahead

of print]

Clinical Outcomes among Patients with Drug-resistant Tuberculosis receiving

Bedaquiline or Delamanid Containing Regimens.

Kempker RR(1), Mikiashvili L(2), Zhao Y(3), Benkeser D(3), Barbakadze K(2),

Bablishvili N(2), Avaliani Z(2), Peloquin CA(4), Blumberg HM(1)(5), Kipiani M(2).

Author information:

(1)Department of Medicine, Division of Infectious Disease, Emory University

School of Medicine, Atlanta, Georgia, USA.

(2)National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia.

(3)Department of Biostatistics and Bioinformatics, Emory Rollins School of Public

Health.

…

BACKGROUND: Bedaquiline and delamanid are newly available drugs for treating

multidrug-resistant tuberculosis (MDR TB); however, there is limited data guiding

their use and no comparison studies.

METHODS: We conducted a prospective observational study among patients with MDR

TB in Georgia receiving a bedaquiline or delamanid-based treatment regimen.

Monthly sputum cultures, minimal inhibitory concentration testing, and adverse

event monitoring were performed. Primary outcomes were culture conversion rates

and clinical outcomes. Targeted maximum likelihood estimation (TMLE) and

superlearning were utilized to produce a covariate-adjusted proportion of

outcomes for each regimen.

RESULTS: Among 156 patients with MDR TB, 100 were enrolled and 95 were receiving

a bedaquiline (n=64) or delamanid (n=31) based regimen. Most were male (82%) and

the median age was 38 years. Rates of previous treatment (56%) and cavitary

disease (61%) were high. The most common companion drugs included linezolid,

clofazimine, cycloserine and a fluoroquinolone. Median effective drugs received

among patients on bedaquiline (4, IQR 4-4) and delamanid (4, IQR 3.5-5) based

regimens were similar. Rates of acquired drug resistance were significantly

higher among patients receiving delamanid versus bedaquiline (36% vs. 10%, p

<0.01). Adjusted rates of sputum culture conversion at two months (67 vs. 47%,

p=0.10) and six months (95 vs. 74%, p<0.01) and favorable clinical outcomes (96

vs. 72%, p<0.01) were higher among patients receiving bedaquiline versus

delamanid.

CONCLUSIONS: Among patients with MDR TB, bedaquiline-based regimens were

associated with higher rates of sputum culture conversion and favorable outcomes

and a lower rate of acquired drug resistance versus delamanid-based regimens.

© The Author(s) 2019. Published by Oxford University Press for the Infectious

Diseases Society of America. All rights reserved. For permissions, e-mail:

journals.permissions@oup.com.

DOI: 10.1093/cid/ciz1107

PMID: 31712809

12. J Immunol. 2019 Nov 15;203(10):2665-2678. doi: 10.4049/jimmunol.1801301. Epub

2019 Oct 16.

Mycobacterium tuberculosis LprE Suppresses TLR2-Dependent Cathelicidin and

Autophagy Expression to Enhance Bacterial Survival in Macrophages.

Padhi A(1), Pattnaik K(1), Biswas M(1), Jagadeb M(1), Behera A(1), Sonawane

A(2)(3).

Author information:

(1)School of Biotechnology, Kalinga Institute of Industrial Technology, Deemed to

Be University, Bhubaneswar, Odisha 751024, India; and.

(2)School of Biotechnology, Kalinga Institute of Industrial Technology, Deemed to

Be University, Bhubaneswar, Odisha 751024, India; and asonawane@iiti.ac.in.

(3)Discipline of Biosciences and Biomedical Engineering, Indian Institute of

Technology Indore, Simrol, Madhya Pradesh 453552, India.

Despite representing a very important class of virulence proteins, the role of

lipoproteins in the pathogenesis of Mycobacterium tuberculosis remains elusive.

In this study, we investigated the role of putative lipoprotein LprE in the

subversion of host immune responses using the M. tuberculosis CDC1551 LprE (LprE

Mtb ) mutant (Mtb?LprE). We show that deletion of LprE Mtb results in reduction

of M. tuberculosis virulence in human and mouse macrophages due to upregulation

of vitamin D3-responsive cathelicidin expression through the TLR2-dependent

p38-MAPK-CYP27B1-VDR signaling pathway. Conversely, episomal expression of LprE

Mtb in Mycobacterium smegmatis improved bacterial survival. Infection in

siTLR2-treated or tlr2-/- macrophages reduced the survival of LprE Mtb expressing

M. tuberculosis and M. smegmatis because of a surge in the expression of

cathelicidin. Infection with the LprE Mtb mutant also led to accumulation of

autophagy-related proteins (LC3, Atg-5, and Beclin-1) and augmented recruitment

of phagosomal (EEA1 and Rab7) and lysosomal (LAMP1) proteins, thereby resulting

in the reduction of the bacterial count in macrophages. The inhibition of

phago-lysosome fusion by LprE Mtb was found to be due to downregulation of IL-12

and IL-22 cytokines. Altogether, our data indicate that LprE Mtb is an important

virulence factor that plays a crucial role in mycobacterial pathogenesis in the

context of innate immunity.

Copyright © 2019 by The American Association of Immunologists, Inc.

DOI: 10.4049/jimmunol.1801301

PMID: 31619537

13. Eur Respir J. 2019 Nov 28;54(5). pii: 1900861. doi: 10.1183/13993003.00861-2019.

Print 2019 Nov.

Latent tuberculosis screening and treatment among asylum seekers: a mixed-methods

study.

Spruijt I(1)(2), Tesfay Haile D(2), Suurmond J(2), van den Hof S(3)(4), Koenders

M(5), Kouw P(6), van Noort N(7), Toumanian S(8), Cobelens F(9), Goosen S(10),

Erkens C(3).

Author information:

(1)KNCV Tuberculosis Foundation, The Hague, The Netherlands

ineke.spruijt@kncvtbc.org.

(2)Dept of Public Health, Amsterdam Public Health Research Institute, Amsterdam

University Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

(3)KNCV Tuberculosis Foundation, The Hague, The Netherlands.

…

INTRODUCTION: Evidence on conditions for implementation of latent tuberculosis

infection (LTBI) screening and treatment among asylum seekers is needed to inform

tuberculosis (TB) control policies. We used mixed-methods to evaluate the

implementation of an LTBI screening and treatment programme among asylum seekers

in the Netherlands.

METHODS: We offered voluntary LTBI screening to asylum seekers aged ≥12?years

living in asylum seeker centres from countries with a TB incidence >200 per

10?000 population. We calculated LTBI screening and treatment cascade coverage,

and assessed associated factors with Poisson regression using robust variance

estimators. We interviewed TB care staff (seven group interviews) and Eritrean

clients (21 group and 21 individual interviews) to identify programme enhancers

and barriers.

RESULTS: We screened 719 (63% of 1136) clients for LTBI. LTBI was diagnosed among

178 (25%) clients; 149 (84%) initiated LTBI treatment, of whom 129 (87%)

completed treatment. In-person TB and LTBI education, the use of professional

interpreters, and collaboration with partner organisations were enhancers for

LTBI screening uptake. Demand-driven LTBI treatment support by TB nurses enhanced

treatment completion. Factors complicating LTBI screening and treatment were

having to travel to public health services, language barriers and moving from

asylum seeker centres to the community during treatment.

CONCLUSION: LTBI screening and treatment of asylum seekers is feasible and

effective when high quality of care is provided, including culture-sensitive TB

education throughout the care cascade. Additionally, collaboration with partner

organisations, such as agencies responsible for reception and support of asylum

seekers, should be in place.

Copyright ©ERS 2019.

DOI: 10.1183/13993003.00861-2019

PMID: 31537698

14. FASEB J. 2019 Nov;33(11):12554-12564. doi: 10.1096/fj.201900487R. Epub 2019 Aug

26.

Mycobacterium tuberculosis induces connective tissue growth factor expression

through the TLR2-JNK-AP-1 pathway in human lung fibroblasts.

Lee HS(1), Hua HS(1), Wang CH(2)(3), Yu MC(3)(4)(5), Chen BC(4)(6), Lin CH(1).

Author information:

(1)Graduate Institute of Medical Sciences, Taipei Medical University, Taipei,

Taiwan.

(2)Department of Laboratory Medicine, Wanfang Hospital, Taipei Medical

University, Taipei, Taiwan.

(3)Pulmonary Research Center, Wanfang Hospital, Taipei Medical University,

Taipei, Taiwan.

…

Mycobacterium tuberculosis (M.tb) infection in lung causes pulmonary fibrosis,

which leads to the irreversible reduction of pulmonary function. Fibrotic protein

connective tissue growth factor (CTGF) expression has been confirmed to play a

crucial role in lung fibrosis. However, the underlying signal pathway and effect

of M.tb on CTGF expression in human lung fibroblasts are unclear. Our results

revaled that M.tb caused time- and concentration-dependent increases in CTGF

expression in human lung fibroblasts. A mechanistic investigation revealed that

M.tb induced CTGF expression through TLR2 but not TLR4. The promoter activity

assay indicated that M.tb-induced CTGF activity was mainly controlled by the

promoter region at -747 to -184 bp, which contained signal transducer and

activator of transcription 3 and activator protein 1 (AP-1) binding sites.

Moreover, curcumin (AP-1 inhibitor) restrained M.tb-induced CTGF expression. M.tb

also induced increases in AP-1 luciferase activity and DNA binding activity of

c-Jun and c-Fos on the CTGF promoter. Furthermore, the knockdown of c-Jun by

small interfering RNA attenuated M.tb-induced CTGF expression and AP-1 luciferase

activity. A JNK inhibitor (SP600125) and a JNK dominant-negative mutant

suppressed M.tb-induced CTGF expression. We also discovered that M.tb could

induce the phosphorylation of JNK and c-Jun. Furthermore, SP600125 inhibited

M.tb-induced c-Jun phosphorylation and AP-1- luciferase activity. M.tb-induced

fibronectin expression was inhibited by anti-CTGF antibody. These results

demonstrate that M.tb is activated through TLR2 to induce JNK activation, further

increasing the DNA binding activity of c-Jun and c-Fos and finally inducing CTGF

expression and extracellular matrix production.-Lee, H.-S., Hua, H.-S., Wang,

C.-H., Yu, M.-C., Chen, B.-C., Lin, C.-H. Mycobacterium tuberculosis induces

connective tissue growth factor expression through the TLR2-JNK-AP-1 pathway in

human lung fibroblasts.

DOI: 10.1096/fj.201900487R

PMCID: PMC6902670 [Available on 2020-08-26]

PMID: 31451010