scholarly journals Targeting Non-Replicating Mycobacterium tuberculosis and Latent Infection: Alternatives and Perspectives (Mini-Review)

2021 ◽  
Vol 22 (24) ◽  
pp. 13317
Author(s):  
Anna Egorova ◽  
Elena G. Salina ◽  
Vadim Makarov
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Small Molecules ◽  
Drug Targets ◽  
Latent Infection ◽  
Early Stage ◽  
Control Strategies ◽  
Latent Tuberculosis ◽  
Ltbi Treatment ◽  
Latent Tb ◽  
Current Guidelines

Latent tuberculosis infection (LTBI) represents a major challenge to curing TB disease. Current guidelines for LTBI management include only three older drugs and their combinations—isoniazid and rifamycins (rifampicin and rifapentine). These available control strategies have little impact on latent TB elimination, and new specific therapeutics are urgently needed. In the present mini-review, we highlight some of the alternatives that may potentially be included in LTBI treatment recommendations and a list of early-stage prospective small molecules that act on drug targets specific for Mycobacterium tuberculosis latency.

scholarly journals Cytokine Biosignature of Active and Latent Mycobacterium Tuberculosis Infection in Children

Pathogens ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 517
Author(s):  
Magdalena Druszczynska ◽  
Michal Seweryn ◽  
Sebastian Wawrocki ◽  
Magdalena Kowalewska-Pietrzak ◽  
Anna Pankowska ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Inflammatory Mediators ◽  
Latent Tuberculosis ◽  
Serum Levels ◽  
Diagnostic Tools ◽  
Mycobacterium Tuberculosis Infection ◽  
Only Children ◽  
Latent Tb ◽  
Ifn Γ ◽  
Multiplex Bead

None of the currently used diagnostic tools are efficient enough in diagnosing Mycobacterium tuberculosis (M.tb) infection in children. The study was aimed to identify cytokine biosignatures characterizing active and latent tuberculosis (TB) in children. Using a multiplex bead-based technology, we analyzed the levels of 53 Th17-related cytokines and inflammatory mediators in sera from 216 BCG-vaccinated children diagnosed with active TB (TB) or latent TB (LTBI) as well as uninfected controls (HC). Children with active TB, compared to HC children, showed reduced serum levels of IL-17A, MMP-2, OPN, PTX-3, and markedly elevated concentrations of APRIL/TNFSF13. IL-21, sCD40L, MMP-2, and IL-8 were significantly differentially expressed in the comparisons between groups: (1) HC versus TB and LTBI (jointly), and (2) TB versus LTBI. The panel consisting of APRIL/TNFSF13, sCD30/TNFRSF8, IFN-α2, IFN-γ, IL-2, sIL-6Rα, IL-8, IL-11, IL-29/IFN-λ1, LIGHT/TNFSF14, MMP-1, MMP-2, MMP-3, osteocalcin, osteopontin, TSLP, and TWEAK/TNFSF12 possessed a discriminatory potential for the differentiation between TB and LTBI children. Serum-based host biosignatures carry the potential to aid the diagnosis of childhood M.tb infections. The proposed panels of markers allow distinguishing not only children infected with M.tb from uninfected individuals but also children with active TB from those with latent TB.

scholarly journals Label-Free Comparative Proteomics of Differentially Expressed Mycobacterium tuberculosis Protein in Rifampicin-Related Drug-Resistant Strains

Pathogens ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 607
Author(s):  
Nadeem Ullah ◽  
Ling Hao ◽  
Jo-Lewis Banga Ndzouboukou ◽  
Shiyun Chen ◽  
Yaqi Wu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Control Strategies ◽  
Multidrug Resistant ◽  
Differentially Expressed ◽  
Effective Control ◽  
Drug Resistant ◽  
Differentially Expressed Proteins ◽  
Label Free ◽  
Candidate Target

Rifampicin (RIF) is one of the most important first-line anti-tuberculosis (TB) drugs, and more than 90% of RIF-resistant (RR) Mycobacterium tuberculosis clinical isolates belong to multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. In order to identify specific candidate target proteins as diagnostic markers or drug targets, differential protein expression between drug-sensitive (DS) and drug-resistant (DR) strains remains to be investigated. In the present study, a label-free, quantitative proteomics technique was performed to compare the proteome of DS, RR, MDR, and XDR clinical strains. We found iniC, Rv2141c, folB, and Rv2561 were up-regulated in both RR and MDR strains, while fadE9, espB, espL, esxK, and Rv3175 were down-regulated in the three DR strains when compared to the DS strain. In addition, lprF, mce2R, mce2B, and Rv2627c were specifically expressed in the three DR strains, and 41 proteins were not detected in the DS strain. Functional category showed that these differentially expressed proteins were mainly involved in the cell wall and cell processes. When compared to the RR strain, Rv2272, smtB, lpqB, icd1, and folK were up-regulated, while esxK, PPE19, Rv1534, rpmI, ureA, tpx, mpt64, frr, Rv3678c, esxB, esxA, and espL were down-regulated in both MDR and XDR strains. Additionally, nrp, PPE3, mntH, Rv1188, Rv1473, nadB, PPE36, and sseA were specifically expressed in both MDR and XDR strains, whereas 292 proteins were not identified when compared to the RR strain. When compared between MDR and XDR strains, 52 proteins were up-regulated, while 45 proteins were down-regulated in the XDR strain. 316 proteins were especially expressed in the XDR strain, while 92 proteins were especially detected in the MDR strain. Protein interaction networks further revealed the mechanism of their involvement in virulence and drug resistance. Therefore, these differentially expressed proteins are of great significance for exploring effective control strategies of DR-TB.

scholarly journals ID Learning Unit: Understanding Advances in the Treatment of Latent Tuberculosis Infection among People with HIV

2021 ◽  
Author(s):  
Nicky J Mehtani ◽  
Sarah Puryear ◽  
Paul Pham ◽  
Kelly E Dooley ◽  
Maunank Shah
Keyword(s):  
Antiretroviral Therapy ◽  
Drug Interactions ◽  
Latent Tuberculosis Infection ◽  
Modern Art ◽  
Latent Tuberculosis ◽  
Significant Heterogeneity ◽  
Preventative Therapy ◽  
Latent Tb ◽  
Latent Tb Infection ◽  
Current Guidelines

Abstract Tuberculosis remains the leading cause of death among people with HIV (PWH). The diagnosis of latent TB infection (LTBI) and treatment with TB preventative therapy (TPT) can reduce morbidity and mortality in this population. Historically, isoniazid has been recommended for TPT in PWH due to the absence of drug-drug interactions with most antiretroviral therapy (ART). However, newer rifamycin-based regimens are safer, shorter in duration, associated with improved adherence, and may be as or more effective than isoniazid TPT. Current guidelines have significant heterogeneity in their recommendations for TPT regimens and acceptability of drug interactions with modern ART. In this ID learning unit, we review common questions on diagnosis, treatment, and drug interactions related to the management of LTBI among PWH.

scholarly journals Prevention of Tuberculosis Reactivation

2021 ◽  
Vol 1 (8) ◽  
Author(s):  
Kendra Brett ◽  
Melissa Severn
Keyword(s):  
Latent Infection ◽  
Treatment Effectiveness ◽  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Ltbi Treatment ◽  
Reactivation Treatment ◽  
Increased Risk ◽  
Quality Guideline ◽  
Tuberculosis Reactivation ◽  
Tuberculosis Disease

It is not known if screening for latent tuberculosis infection (LTBI) is useful for reducing the risk of tuberculosis reactivation among people at risk (no evidence was found). In people with LTBI, providing treatment for the latent infection may be helpful for preventing the development of active tuberculosis disease. (In addition, LTBI treatments do not appear to increase the risk for hepatotoxicity.) Treatment effectiveness may depend on the specific LTBI treatment regimen used. For people at an increased risk for tuberculosis ― including those from areas with high rates of tuberculosis ― guidelines recommend screening and treatment for LTBI, as this may help prevent TB reactivation. Treatment is recommended for those who are 65 years old or younger and with a positive LTBI result (recommendation from 1 high-quality guideline).

Genetic models of latent tuberculosis in mice reveal differential influence of adaptive immunity

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
Hongwei Su ◽  
Kan Lin ◽  
Divya Tiwari ◽  
Claire Healy ◽  
Carolina Trujillo ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Mouse Model ◽  
Adaptive Immunity ◽  
High Frequency ◽  
Latent Infection ◽  
Latent Tuberculosis ◽  
Thioredoxin Reductase ◽  
Therapeutic Strategies ◽  
Biotin Protein Ligase

Studying latent Mycobacterium tuberculosis (Mtb) infection has been limited by the lack of a suitable mouse model. We discovered that transient depletion of biotin protein ligase (BPL) and thioredoxin reductase (TrxB2) results in latent infections during which Mtb cannot be detected but that relapse in a subset of mice. The immune requirements for Mtb control during latency, and the frequency of relapse, were strikingly different depending on how latency was established. TrxB2 depletion resulted in a latent infection that required adaptive immunity for control and reactivated with high frequency, whereas latent infection after BPL depletion was independent of adaptive immunity and rarely reactivated. We identified immune signatures of T cells indicative of relapse and demonstrated that BCG vaccination failed to protect mice from TB relapse. These reproducible genetic latency models allow investigation of the host immunological determinants that control the latent state and offer opportunities to evaluate therapeutic strategies in settings that mimic aspects of latency and TB relapse in humans.

scholarly journals Immune Response to Mycobacterial Infection: Lessons from Flow Cytometry

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Nikoletta Rovina ◽  
Marios Panagiotou ◽  
Konstantinos Pontikis ◽  
Magdalini Kyriakopoulou ◽  
Nikolaos G. Koulouris ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
Latent Tuberculosis ◽  
Mycobacterial Infection ◽  
Diagnostic Tools ◽  
Diagnostic Biomarkers ◽  
Reliable Diagnosis ◽  
Latent Tb ◽  
Two Stages

Detecting and treating active and latent tuberculosis are pivotal elements for effective infection control; yet, due to their significant inherent limitations, the diagnostic means for these two stages of tuberculosis (TB) to date remain suboptimal. This paper reviews the current diagnostic tools for mycobacterial infection and focuses on the application of flow cytometry as a promising method for rapid and reliable diagnosis of mycobacterial infection as well as discrimination between active and latent TB: it summarizes diagnostic biomarkers distinguishing the two states of infection and also features of the distinct immune response againstMycobacterium tuberculosis(Mtb) at certain stages of infection as revealed by flow cytometry to date.

scholarly journals Recent Progress in Diagnosis Methods for Latent Tuberculosis Infection and Its Clinical Applications

2015 ◽  
Vol 4 (3) ◽  
pp. 69-74
Author(s):  
Ling Zhou
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Recent Progress ◽  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Interferon Γ ◽  
Clinical Applications ◽  
Active Tuberculosis ◽  
Advantages And Disadvantages ◽  
Latent Tb ◽  
Latent Tb Infection

AbstractMost people with latentMycobacterium tuberculosisinfection can partly develop active tuberculosis (TB). Therefore, diagnosis of this condition bears significance in early TB prevention. To date, the main methods for diagnosis of latent TB infection (LTBI) include tuberculin skin test and interferon γ release test. These two methods feature their own advantages and disadvantages. Although new diagnostic markers continually emerge, no uniform diagnostic criteria are available for TB detection. This study summarizes several methods for diagnosis of LTBI and new related markers and their application value in clinical practice.

scholarly journals Accuracy of QuantiFERON-TB Gold Plus Test for Diagnosis of Mycobacterium tuberculosis Infection in Children

2020 ◽  
Vol 58 (6) ◽  
Author(s):  
Danilo Buonsenso ◽  
Giovanni Delogu ◽  
Clelia Perricone ◽  
Roberta Grossi ◽  
Angela Careddu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Latent Infection ◽  
Cross Sectional Study ◽  
Mycobacterium Tuberculosis Infection ◽  
Cross Sectional ◽  
Content Type ◽  
Latent Tb ◽  
Latent Tb Infection ◽  
Microbiological Analyses ◽  
Active Disease

ABSTRACT Compared to its predecessor QuantiFERON-TB Gold In Tube (QFT-IT), QuantiFERON-TB Gold Plus (QFT-Plus) contains an additional antigen tube (TB2), stimulating both CD4+ and CD8+ T cells. The ability to discriminate CD4+ and CD8+ responses is suggested to be useful in differentiating stages of Mycobacterium tuberculosis infection. While QFT-Plus has already been evaluated in adults, there are not enough data in children evaluated for suspected active tuberculosis (TB) or latent TB infection (LTBI). A prospective cross-sectional study was conducted among children aged 0 to 17 years who were evaluated for suspected active TB or screened for LTBI. All children underwent QFT-Plus and further clinical, radiological, and/or microbiological analyses according to clinical scenario. Of the 198 children enrolled, 43 (21.7%) were tested because of suspicion of active TB. A total of 12/43 (27.9%) were diagnosed with active TB, and among these, 10/12 (83.3%) had a positive QFT-Plus assay. Of the 155 children screened for LTBI, 18 (11.6%) had a positive QFT-Plus, and 5 (2.5%) had an indeterminate result. TB1 and TB2 quantitative responses were not able to discriminate active disease from latent infection. The percent agreement between TB1 and TB2 was 100%. QFT-Plus assay showed good sensitivity for active TB and was particularly useful for the evaluation of children with suspected LTBI, giving a low rate of indeterminate results in this group. More studies are needed to properly evaluate QFT-Plus ability in discriminating active disease from latent infection.

MiR-495 regulates cellular ROS levels by targeting sod2 to inhibit intracellular survival of Mycobacterium tuberculosis in macrophages

2021 ◽  
Author(s):  
Xuanxiu Ren ◽  
Wenqi Dong ◽  
Jiajia Feng ◽  
Pei Li ◽  
Yucheng Zheng ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Mycobacterium Tuberculosis ◽  
Human Health ◽  
Theoretical Basis ◽  
Drug Targets ◽  
Early Stage ◽  
Intracellular Survival ◽  
Laboratory Research ◽  
Bacillus Calmette Guerin ◽  
Major Infectious Disease

Mycobacterium tuberculosis is a chronic infectious disease pathogen. To date, tuberculosis is a major infectious disease that endangers human health. To better prevent and treat tuberculosis, it is important to study the pathogenesis of M. tb . Based on early-stage laboratory research results, in this study, we verified the upregulation of sod2 in Bacillus Calmette–Guérin ( BCG ) and H37Rv infection. By detecting BCG / H37Rv intracellular survival in sod2 -silenced and sod2 - overexpressing macrophages, sod2 was found to promote the intracellular survival of BCG / H37Rv. Then, miR-495 was determined to be downregulated by BCG / H37Rv . BCG / H37Rv can upregulate sod2 expression by miR-495 to promote the intracellular survival of BCG / H37Rv through a decline in ROS levels. This study provides a theoretical basis for developing new drug targets and treating tuberculosis.

scholarly journals Mycobacterium tuberculosisP-Type ATPases: Possible Targets for Drug or Vaccine Development

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Lorena Novoa-Aponte ◽  
Carlos Yesid Soto Ospina
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Vaccine Development ◽  
Ion Homeostasis ◽  
Toxic Substances ◽  
Human History ◽  
High Prevalence ◽  
Latent Tb ◽  
P Type ◽  
Structural Aspects

Tuberculosis (TB) has been the biggest killer in the human history; currently,Mycobacterium tuberculosis(Mtb) kills nearly 2 million people each year worldwide. The high prevalence of TB obligates the identification of new therapeutic targets and the development of anti-TB vaccines that can control multidrug resistance and latent TB infections. Membrane proteins have recently been suggested as key targets for bacterial viability. Current studies have shown that mycobacteria P-type ATPases may play critical roles in ion homeostasis and in the response of mycobacteria to toxic substances in the intraphagosomal environment. In this review, we bring together the genomic, transcriptomic, and structural aspects of the P-type ATPases that are relevant during active and latentMtbinfections, which can be useful in determining the potential of these ATPases as drug targets and in uncovering their possible roles in the development of new anti-TB attenuated vaccines.

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