scholarly journals Sterilizing immunity: New opportunities for rational TB vaccine design

2021 ◽  
Vol 218 (7) ◽  
Author(s):  
Alan Sher ◽  
Joanne L. Flynn
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Animal Models ◽  
Vaccine Design ◽  
High Level ◽  
Sterilizing Immunity ◽  
Induced Immunity ◽  
Effector Mechanisms

Recent studies have revealed situations of high-level naturally acquired and vaccine-induced immunity against Mycobacterium tuberculosis in animal models along with examples of significantly protective immunization in humans. These discoveries offer immunologists new opportunities to define effector mechanisms that when triggered by appropriately engineered vaccines could end TB’s deadly reign.

scholarly journals Mutations in fbiD (Rv2983) as a Novel Determinant of Resistance to Pretomanid and Delamanid in Mycobacterium tuberculosis

2020 ◽  
Vol 65 (1) ◽  
pp. e01948-20
Author(s):  
Dalin Rifat ◽  
Si-Yang Li ◽  
Thomas Ioerger ◽  
Keshav Shah ◽  
Jean-Philippe Lanoix ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clinical Evidence ◽  
Clinical Samples ◽  
Loss Of Function ◽  
Wild Type ◽  
Content Type ◽  
Solid Media ◽  
High Level ◽  
Level Resistance

ABSTRACTThe nitroimidazole prodrugs delamanid and pretomanid comprise one of only two new antimicrobial classes approved to treat tuberculosis (TB) in 50 years. Prior in vitro studies suggest a relatively low barrier to nitroimidazole resistance in Mycobacterium tuberculosis, but clinical evidence is limited to date. We selected pretomanid-resistant M. tuberculosis mutants in two mouse models of TB using a range of pretomanid doses. The frequency of spontaneous resistance was approximately 10−5 CFU. Whole-genome sequencing of 161 resistant isolates from 47 mice revealed 99 unique mutations, of which 91% occurred in 1 of 5 genes previously associated with nitroimidazole activation and resistance, namely, fbiC (56%), fbiA (15%), ddn (12%), fgd (4%), and fbiB (4%). Nearly all mutations were unique to a single mouse and not previously identified. The remaining 9% of resistant mutants harbored mutations in Rv2983 (fbiD), a gene not previously associated with nitroimidazole resistance but recently shown to be a guanylyltransferase necessary for cofactor F420 synthesis. Most mutants exhibited high-level resistance to pretomanid and delamanid, although Rv2983 and fbiB mutants exhibited high-level pretomanid resistance but relatively small changes in delamanid susceptibility. Complementing an Rv2983 mutant with wild-type Rv2983 restored susceptibility to pretomanid and delamanid. By quantifying intracellular F420 and its precursor Fo in overexpressing and loss-of-function mutants, we provide further evidence that Rv2983 is necessary for F420 biosynthesis. Finally, Rv2983 mutants and other F420H2-deficient mutants displayed hypersusceptibility to some antibiotics and to concentrations of malachite green found in solid media used to isolate and propagate mycobacteria from clinical samples.

scholarly journals Allelic Exchange and Mutant Selection Demonstrate that Common Clinical embCAB Gene Mutations Only Modestly Increase Resistance to Ethambutol in Mycobacterium tuberculosis

2009 ◽  
Vol 54 (1) ◽  
pp. 103-108 ◽  
Author(s):  
Hassan Safi ◽  
Robert D. Fleischmann ◽  
Scott N. Peterson ◽  
Marcus B. Jones ◽  
Behnam Jarrahi ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
In Vitro Selection ◽  
Gene Mutations ◽  
Wild Type ◽  
Mutant Selection ◽  
Preferential Growth ◽  
Allelic Exchange ◽  
High Level ◽  
Isogenic Mutants

ABSTRACT Mutations within codon 306 of the Mycobacterium tuberculosis embB gene modestly increase ethambutol (EMB) MICs. To identify other causes of EMB resistance and to identify causes of high-level resistance, we generated EMB-resistant M. tuberculosis isolates in vitro and performed allelic exchange studies of embB codon 406 (embB406) and embB497 mutations. In vitro selection produced mutations already identified clinically in embB306, embB397, embB497, embB1024, and embC13, which result in EMB MICs of 8 or 14 μg/ml, 5 μg/ml, 12 μg/ml, 3 μg/ml, and 4 μg/ml, respectively, and mutations at embB320, embB324, and embB445, which have not been identified in clinical M. tuberculosis isolates and which result in EMB MICs of 8 μg/ml, 8 μg/ml, and 2 to 8 μg/ml, respectively. To definitively identify the effect of the common clinical embB497 and embB406 mutations on EMB susceptibility, we created a series of isogenic mutants, exchanging the wild-type embB497 CAG codon in EMB-susceptible M. tuberculosis strain 210 for the embB497 CGG codon and the wild-type embB406 GGC codon for either the embB406 GCC, embB406 TGC, embB406 TCC, or embB406 GAC codon. These new mutants showed 6-fold and 3- to 3.5-fold increases in the EMB MICs, respectively. In contrast to the embB306 mutants, the isogenic embB497 and embB406 mutants did not have preferential growth in the presence of isoniazid or rifampin (rifampicin) at their MICs. These results demonstrate that individual embCAB mutations confer low to moderate increases in EMB MICs. Discrepancies between the EMB MICs of laboratory mutants and clinical M. tuberculosis strains with identical mutations suggest that clinical EMB resistance is multigenic and that high-level EMB resistance requires mutations in currently unknown loci.

scholarly journals Monkey Models of Tuberculosis: Lessons Learned

2014 ◽  
Vol 83 (3) ◽  
pp. 852-862 ◽  
Author(s):  
Juliet C. Peña ◽  
Wen-Zhe Ho
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Animal Models ◽  
Nonhuman Primates ◽  
Lessons Learned ◽  
Preclinical Testing ◽  
Content Type ◽  
Cynomolgus Macaques ◽  
Drug Regimens

The use of animal models has been invaluable for studying the pathogenesis ofMycobacterium tuberculosisinfection, as well as for testing the efficacy of vaccines and drug regimens for tuberculosis. Among the applied animal models, nonhuman primates, particularly macaques, share the greatest anatomical and physiological similarities with humans. As such, macaque models have been used for investigating tuberculosis pathogenesis and preclinical testing of drugs and vaccines. This review focuses on published major studies which illustrate how the rhesus and cynomolgus macaques have enriched and may continue to advance the field of global tuberculosis research.

scholarly journals The Antibody Response to Plasmodium falciparum: Cues for Vaccine Design and the Discovery of Receptor-Based Antibodies

2019 ◽  
Vol 37 (1) ◽  
pp. 225-246 ◽  
Author(s):  
Joshua Tan ◽  
Luca Piccoli ◽  
Antonio Lanzavecchia
Keyword(s):  
Public Health ◽  
Plasmodium Falciparum ◽  
Immune System ◽  
Antibody Response ◽  
Public Health Problem ◽  
Vaccine Design ◽  
Immunoglobulin Genes ◽  
And Control ◽  
Sterilizing Immunity

Plasmodium falciparum remains a serious public health problem and a continuous challenge for the immune system due to the complexity and diversity of the pathogen. Recent advances from several laboratories in the characterization of the antibody response to the parasite have led to the identification of critical targets for protection and revealed a new mechanism of diversification based on the insertion of host receptors into immunoglobulin genes, leading to the production of receptor-based antibodies. These advances have opened new possibilities for vaccine design and passive antibody therapies to provide sterilizing immunity and control blood-stage parasites.

Association of ubiA mutations and high-level of ethambutol resistance among Mycobacterium tuberculosis Thai clinical isolates

Tuberculosis ◽  
2019 ◽  
Vol 114 ◽  
pp. 42-46 ◽  
Author(s):  
Orawan Tulyaprawat ◽  
Angkana Chaiprasert ◽  
Piriyaporn Chongtrakool ◽  
Kamol Suwannakarn ◽  
Popchai Ngamskulrungroj
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clinical Isolates ◽  
High Level

scholarly journals Rv3131, a gene encoding nitroreductase, is essential for metronidazole activation in Mycobacterium tuberculosis under hypoxic condition

2020 ◽  
Author(s):  
Wenzhu Dong ◽  
Jin Shi ◽  
Ping Chu ◽  
Rongmei Liu ◽  
Shu’an Wen ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Anaerobic Bacteria ◽  
Aerobic Condition ◽  
Hypoxic Condition ◽  
Significant Inhibition ◽  
Wild Type ◽  
Minimal Inhibitory Concentrations ◽  
High Level ◽  
Nitroreductase Activity

Abstract ObjectivesThe impressive potency of metronidazole (MTZ) against anaerobic bacteria indicates the potential for killing anaerobic Mtb. However, how MTZ is activated in Mtb still remains unknown. We aimed to characterize the endogenous nitroreductase responsible for MTZ activation in anaerobic Mtb.MethodsThe minimal inhibitory concentrations (MICs) of Mtb isolates against MTZ were determined by microplate Alamar Blue assay. Intracellular anti-TB activities of MTZ and pyrazinamide (PZA) were tested in THP-1 cells infected by Mycobacterium tuberculosis (Mtb) H37Rv with a multiplicity of infection (MOI) of 10. The nitroreductase activity of purified wild-type Rv3131 and mutants were measured under anaerobic conditions generated by glucose oxidase/catalase system. Two-tailed unpaired Student’s t test was used to compare the difference between various groups.Results180 Mtb isolates (81.8%, 180/220) had MIC values higher than 16 μg/mL, and 40 had MIC values of 16 μg/mL, demonstrating high-level resistance to MTZ under aerobic condition. The number of viable bacteria in macrophages treated with MTZ was dramatically decreased by 71.3% after 5-day MTZ treatment, indicating significant inhibition of MTZ against anaerobic Mtb. In vitro biochemical analysis demonstrated that Rv3131 exhibited the NADPH oxidase activity under anaerobic condition. The substitutions of Cys75Ser and Cys279Ser could maintain 41.7% and 71.1% of enzyme activity compared to wild-type protein, respectively.ConclusionsOur data demonstrate that MTZ has more potent efficacy against intracellular Mtb than PZA. Rv3131 is identified as a nitroreductase enzyme in the activation of MTZ, and Cys75 of Rv3131 is the major active residue for nitroreductase activity.

scholarly journals Lessons from Bacillus Calmette-Guérin: Harnessing Trained Immunity for Vaccine Development

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2109
Author(s):  
Samuel T. Pasco ◽  
Juan Anguita
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Vaccine Development ◽  
Vaccine Design ◽  
Innate Immune ◽  
Bacillus Calmette Guerin ◽  
Adaptive Immune Responses ◽  
Trained Immunity ◽  
Adaptive Immune ◽  
Potential Methods

Vaccine design traditionally focuses on inducing adaptive immune responses against a sole target pathogen. Considering that many microbes evade innate immune mechanisms to initiate infection, and in light of the discovery of epigenetically mediated innate immune training, the paradigm of vaccine design has the potential to change. The Bacillus Calmette-Guérin (BCG) vaccine induces some level of protection against Mycobacterium tuberculosis (Mtb) while stimulating trained immunity that correlates with lower mortality and increased protection against unrelated pathogens. This review will explore BCG-induced trained immunity, including the required pathways to establish this phenotype. Additionally, potential methods to improve or expand BCG trained immunity effects through alternative vaccine delivery and formulation methods will be discussed. Finally, advances in new anti-Mtb vaccines, other antimicrobial uses for BCG, and “innate memory-based vaccines” will be examined.

scholarly journals Vaccine Design Informed by Virus-Induced Immunity

2020 ◽  
Vol 33 (4) ◽  
pp. 342-350 ◽  
Author(s):  
Rhiannon R. Penkert ◽  
Jane S. Hankins ◽  
Neal S. Young ◽  
Julia L. Hurwitz
Keyword(s):  
Vaccine Design ◽  
Induced Immunity

scholarly journals Mutations ingyrAandgyrBamong Fluoroquinolone- and Multidrug-Resistant Mycobacterium tuberculosis Isolates

2016 ◽  
Vol 60 (4) ◽  
pp. 2090-2096 ◽  
Author(s):  
Jung-Yien Chien ◽  
Wei-Yih Chiu ◽  
Shun-Tien Chien ◽  
Chia-Jung Chiang ◽  
Chong-Jen Yu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
East Asian ◽  
Multidrug Resistant ◽  
Molecular Techniques ◽  
Content Type ◽  
Low Level ◽  
High Prevalence ◽  
Mdr Tb ◽  
High Level

ABSTRACTIn order to correlate the mutations inside the entiregyrAandgyrBgenes with the level of resistance to ofloxacin (OFX) and moxifloxacin (MFX) in isolates of multidrug-resistantMycobacterium tuberculosis(MDR-TB), a total of 111 isolates were categorized into OFX-susceptible (MIC, ≤2 μg/ml) and low-level (MIC, 4 to 8 μg/ml) and high-level (MIC, ≥16 μg/ml) OFX-resistant isolates and MFX-susceptible (MIC, ≤0.5 μg/ml) and low-level (MIC, 1 to 2 μg/ml) and high-level (MIC, ≥4 μg/ml) MFX-resistant isolates. Resistance-associated mutations inside thegyrAgene were found in 30.2% of OFX-susceptible and 72.5% and 72.2% of low-level and high-level OFX-resistant isolates and in 28.6% of MFX-susceptible and 58.1% and 83.9% of low-level and high-level MFX-resistant isolates. Compared with OFX-susceptible isolates, low-level and high-level OFX-resistant isolates had a significantly higher prevalence of mutations atgyrAcodons 88 to 94 (17.0%, 65.0%, and 72.2%, respectively;P< 0.001) and a higher prevalence of thegyrBG512R mutation (0.0%, 2.5%, and 16.7%, respectively;P= 0.006). Similarly, compared with MFX-susceptible isolates, low-level and high-level MFX-resistant isolates had a significantly higher prevalence of mutations atgyrAcodons 88 to 94 (14.3%, 51.6%, and 80.6%, respectively;P< 0.001) as well as a higher prevalence of thegyrBG512R mutation (0.0%, 0.0%, and 12.9%, respectively;P= 0.011). D94G and D94N mutations ingyrAand the G512R mutation ingyrBwere correlated with high-level MFX resistance, while the D94A mutation was associated with low-level MFX resistance. The prevalence of mutations atgyrAcodons 88 to 94 and thegyrBG512R mutation were higher among fluoroquinolone (FQ)-susceptible East Asian (Beijing) and Indo-Oceanic strains than they were among Euro-American strains, implying that molecular techniques to detect FQ resistance may be less specific in areas with a high prevalence of East Asian (Beijing) and Indo-Oceanic strains.

scholarly journals Mycobacterium tuberculosis and the host response

2005 ◽  
Vol 201 (11) ◽  
pp. 1693-1697 ◽  
Author(s):  
Stefan H.E. Kaufmann ◽  
Stewart T. Cole ◽  
Valerie Mizrahi ◽  
Eric Rubin ◽  
Carl Nathan
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Animal Models ◽  
Immune Responses ◽  
Host Response ◽  
Morbidity And Mortality ◽  
Infected Host ◽  
International Meeting ◽  
New Techniques

Mycobacterium tuberculosis remains a leading cause of morbidity and mortality worldwide. Advances reported at a recent international meeting highlight insights and controversies in the genetics of M. tuberculosis and the infected host, the nature of protective immune responses, adaptation of the bacillus to host-imposed stresses, animal models, and new techniques.

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