-
Microbiology Spectrum Jul 2019Tuberculosis (TB) is a serious global public health challenge that results in significant morbidity and mortality worldwide. TB is caused by infection with the bacilli... (Review)
Review
Tuberculosis (TB) is a serious global public health challenge that results in significant morbidity and mortality worldwide. TB is caused by infection with the bacilli (), which has evolved a wide variety of strategies in order to thrive within its host. Understanding the complex interactions between and host immunity can inform the rational design of better TB vaccines and therapeutics. This chapter covers innate and adaptive immunity against infection, including insights on bacterial immune evasion and subversion garnered from animal models of infection and human studies. In addition, this chapter discusses the immunology of the TB granuloma, TB diagnostics, and TB comorbidities. Finally, this chapter provides a broad overview of the current TB vaccine pipeline.
Topics: Adaptive Immunity; Animals; Granuloma; Humans; Immune Evasion; Immunity, Innate; Mycobacterium tuberculosis; Tuberculosis
PubMed: 31298204
DOI: 10.1128/microbiolspec.GPP3-0022-2018 -
Microbiology Spectrum Jul 2019is the cause of tuberculosis (TB), a disease which continues to overwhelm health systems in endemic regions despite the existence of effective combination chemotherapy... (Review)
Review
is the cause of tuberculosis (TB), a disease which continues to overwhelm health systems in endemic regions despite the existence of effective combination chemotherapy and the widespread use of a neonatal anti-TB vaccine. For a professional pathogen, retains a surprisingly large proportion of the metabolic repertoire found in nonpathogenic mycobacteria with very different lifestyles. Moreover, evidence that additional functions were acquired during the early evolution of the complex suggests the organism has adapted (and augmented) the metabolic pathways of its environmental ancestor to persistence and propagation within its obligate human host. A better understanding of pathogenicity, however, requires the elucidation of metabolic functions under disease-relevant conditions, a challenge complicated by limited knowledge of the microenvironments occupied and nutrients accessed by bacilli during host infection, as well as the reliance in experimental mycobacteriology on a restricted number of experimental models with variable relevance to clinical disease. Here, we consider metabolism within the framework of an intimate host-pathogen coevolution. Focusing on recent advances in our understanding of mycobacterial metabolic function, we highlight unusual adaptations or departures from the better-characterized model intracellular pathogens. We also discuss the impact of these mycobacterial "innovations" on the susceptibility of to existing and experimental anti-TB drugs, as well as strategies for targeting metabolic pathways. Finally, we offer some perspectives on the key gaps in the current knowledge of fundamental mycobacterial metabolism and the lessons which might be learned from other systems.
Topics: Animals; Antitubercular Agents; Humans; Metabolic Networks and Pathways; Mycobacterium tuberculosis; Tuberculosis; Virulence
PubMed: 31350832
DOI: 10.1128/microbiolspec.GPP3-0067-2019 -
Trends in Microbiology Oct 2020Over a quarter of the world's population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Approximately 3.4% of new and 18%... (Review)
Review
Over a quarter of the world's population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Approximately 3.4% of new and 18% of recurrent cases of TB are multidrug-resistant (MDR) or rifampicin-resistant. Recent evidence has shown that certain drug-resistant strains of Mtb modulate host metabolic reprogramming, and therefore immune responses, during infection. However, it remains unclear how widespread these mechanisms are among circulating MDR Mtb strains and what impact drug-resistance-conferring mutations have on immunometabolism during TB. While few studies have directly addressed metabolic reprogramming in the context of drug-resistant Mtb infection, previous literature examining how drug-resistance mutations alter Mtb physiology and differences in the immune response to drug-resistant Mtb provides significant insights into how drug-resistant strains of Mtb differentially impact immunometabolism.
Topics: Animals; Antitubercular Agents; Bacterial Proteins; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis
PubMed: 32409147
DOI: 10.1016/j.tim.2020.04.010 -
Microbiological Research May 2021Mycobacterium tuberculosis complex (MTBC) refers to a group of mycobacteria encompassing nine members of closely related species that causes tuberculosis in animals and... (Review)
Review
Mycobacterium tuberculosis complex (MTBC) refers to a group of mycobacteria encompassing nine members of closely related species that causes tuberculosis in animals and humans. Among the nine members, Mycobacterium tuberculosis (M. tuberculosis) remains the main causative agent for human tuberculosis that results in high mortality and morbidity globally. In general, MTBC species are low in diversity but exhibit distinctive biological differences and phenotypes among different MTBC lineages. MTBC species are likely to have evolved from a common ancestor through insertions/deletions processes resulting in species speciation with different degrees of pathogenicity. The pathogenesis of human tuberculosis is complex and remains poorly understood. It involves multi-interactions or evolutionary co-options between host factors and bacterial determinants for survival of the MTBC. Granuloma formation as a protection or survival mechanism in hosts by MTBC remains controversial. Additionally, MTBC species are capable of modulating host immune response and have adopted several mechanisms to evade from host immune attack in order to survive in humans. On the other hand, current diagnostic tools for human tuberculosis are inadequate and have several shortcomings. Numerous studies have suggested the potential of host biomarkers in early diagnosis of tuberculosis, in disease differentiation and in treatment monitoring. "Multi-omics" approaches provide holistic views to dissect the association of MTBC species with humans and offer great advantages in host biomarkers discovery. Thus, in this review, we seek to understand how the genetic variations in MTBC lead to species speciation with different pathogenicity. Furthermore, we also discuss how the host and bacterial players contribute to the pathogenesis of human tuberculosis. Lastly, we provide an overview of the journey of "omics" approaches in host biomarkers discovery in human tuberculosis and provide some interesting insights on the challenges and directions of "omics" approaches in host biomarkers innovation and clinical implementation.
Topics: Animals; Biomarkers; Diagnostic Techniques and Procedures; Genetic Variation; Host-Pathogen Interactions; Humans; Mycobacterium tuberculosis; Phenotype; Tuberculosis
PubMed: 33549960
DOI: 10.1016/j.micres.2020.126674 -
Clinical Microbiology Reviews Dec 2020Successful treatment of tuberculosis (TB) can be hampered by populations that are temporarily able to survive antibiotic pressure in the absence of drug... (Review)
Review
Successful treatment of tuberculosis (TB) can be hampered by populations that are temporarily able to survive antibiotic pressure in the absence of drug resistance-conferring mutations, a phenomenon termed drug tolerance. We summarize findings on tolerance published in the past 20 years. Key responses to drug pressure are reduced growth rates, metabolic shifting, and the promotion of efflux pump activity. Metabolic shifts upon drug pressure mainly occur in 's lipid metabolism and redox homeostasis, with reduced tricarboxylic acid cycle activity in favor of lipid anabolism. Increased lipid anabolism plays a role in cell wall thickening, which reduces sensitivity to most TB drugs. In addition to these general mechanisms, drug-specific mechanisms have been described. Upon isoniazid exposure, reprograms several pathways associated with mycolic acid biosynthesis. Upon rifampicin exposure, upregulates the expression of its drug target Upon bedaquiline exposure, ATP synthesis is stimulated, and the transcription factors Rv0324 and Rv0880 are activated. A better understanding of 's responses to drug pressure will be important for the development of novel agents that prevent the development of drug tolerance following treatment initiation. Such agents could then contribute to novel TB treatment-shortening strategies.
Topics: Antitubercular Agents; Bacterial Proteins; Citric Acid Cycle; Drug Resistance, Multiple, Bacterial; Gene Expression Regulation, Bacterial; Humans; Lipid Metabolism; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Tuberculosis
PubMed: 33055230
DOI: 10.1128/CMR.00141-20 -
The Biochemical Journal Jul 2019Bacterial capsules have evolved to be at the forefront of the cell envelope, making them an essential element of bacterial biology. Efforts to understand the (Mtb)... (Review)
Review
Bacterial capsules have evolved to be at the forefront of the cell envelope, making them an essential element of bacterial biology. Efforts to understand the (Mtb) capsule began more than 60 years ago, but the relatively recent development of mycobacterial genetics combined with improved chemical and immunological tools have revealed a more refined view of capsule molecular composition. A glycogen-like α-glucan is the major constituent of the capsule, with lower amounts of arabinomannan and mannan, proteins and lipids. The major Mtb capsular components mediate interactions with phagocytes that favor bacterial survival. Vaccination approaches targeting the mycobacterial capsule have proven successful in controlling bacterial replication. Although the Mtb capsule is composed of polysaccharides of relatively low complexity, the concept of antigenic variability associated with this structure has been suggested by some studies. Understanding how Mtb shapes its envelope during its life cycle is key to developing anti-infective strategies targeting this structure at the host-pathogen interface.
Topics: Bacterial Capsules; Humans; Lipids; Mycobacterium tuberculosis; Polysaccharides, Bacterial; Tuberculosis Vaccines
PubMed: 31320388
DOI: 10.1042/BCJ20190324 -
Science (New York, N.Y.) Dec 2022The widespread use of antibiotics has placed bacterial pathogens under intense pressure to evolve new survival mechanisms. Genomic analysis of 51,229 ()clinical...
The widespread use of antibiotics has placed bacterial pathogens under intense pressure to evolve new survival mechanisms. Genomic analysis of 51,229 ()clinical isolates has identified an essential transcriptional regulator, , herein called for resilience regulator, as a frequent target of positive (adaptive) selection. mutants do not show canonical drug resistance or drug tolerance but instead shorten the post-antibiotic effect, meaning that they enable to resume growth after drug exposure substantially faster than wild-type strains. We refer to this phenotype as antibiotic resilience. ResR acts in a regulatory cascade with other transcription factors controlling cell growth and division, which are also under positive selection in clinical isolates of . Mutations of these genes are associated with treatment failure and the acquisition of canonical drug resistance.
Topics: Humans; Genomics; Treatment Failure; Tuberculosis; Mycobacterium tuberculosis; Drug Resistance, Bacterial; Tuberculosis, Multidrug-Resistant; Evolution, Molecular; Antibiotics, Antitubercular; Selection, Genetic; Bacterial Proteins; Transcription Factors
PubMed: 36480634
DOI: 10.1126/science.abq2787 -
MBio May 2021The global health burden of human tuberculosis (TB) and the widespread antibiotic resistance of its causative agent warrant new strategies for TB control. The...
The global health burden of human tuberculosis (TB) and the widespread antibiotic resistance of its causative agent warrant new strategies for TB control. The successful use of a bacteriophage cocktail to treat a infection suggests that phages could play a role in tuberculosis therapy. To assemble a phage cocktail with optimal therapeutic potential for tuberculosis, we have explored mycobacteriophage diversity to identify phages that demonstrate tuberculocidal activity and determined the phage infection profiles for a diverse set of strains spanning the major lineages of human-adapted strains of the complex. Using a combination of genome engineering and bacteriophage genetics, we have assembled a five-phage cocktail that minimizes the emergence of phage resistance and cross-resistance to multiple phages, and which efficiently kills the strains tested. Furthermore, these phages function without antagonizing antibiotic effectiveness, and infect both isoniazid-resistant and -sensitive strains. Tuberculosis kills 1.5 million people each year, and resistance to commonly used antibiotics contributes to treatment failures. The therapeutic potential of bacteriophages against offers prospects for shortening antibiotic regimens, provides new tools for treating multiple drug-resistant (MDR)-TB and extensively drug-resistant (XDR)-TB infections, and protects newly developed antibiotics against rapidly emerging resistance to them. Identifying a suitable suite of phages active against diverse isolates circumvents many of the barriers to initiating clinical evaluation of phages as part of the arsenal of antituberculosis therapeutics.
Topics: Antitubercular Agents; Humans; Mycobacteriophages; Mycobacterium smegmatis; Mycobacterium tuberculosis; Phage Therapy; Tuberculosis, Multidrug-Resistant
PubMed: 34016711
DOI: 10.1128/mBio.00973-21 -
Science (New York, N.Y.) Mar 2020has an unusual outer membrane that lacks canonical porin proteins for the transport of small solutes to the periplasm. We discovered that...
has an unusual outer membrane that lacks canonical porin proteins for the transport of small solutes to the periplasm. We discovered that 3,3--di(methylsulfonyl)propionamide (3bMP1) inhibits the growth of , and resistance to this compound is conferred by mutation within a member of the proline-proline-glutamate (PPE) family, PPE51. Deletion of PPE51 rendered cells unable to replicate on propionamide, glucose, or glycerol. Growth was restored upon loss of the mycobacterial cell wall component phthiocerol dimycocerosate. Mutants in other proline-glutamate (PE)/PPE clusters, responsive to magnesium and phosphate, also showed a phthiocerol dimycocerosate-dependent growth compromise upon limitation of the corresponding substrate. Phthiocerol dimycocerosate determined the low permeability of the mycobacterial outer membrane, and the PE/PPE proteins apparently act as solute-specific channels.
Topics: Amides; Bacterial Proteins; Biological Transport; Cell Membrane; Cell Membrane Permeability; Drug Resistance, Bacterial; Gene Deletion; Glucose; Glycerol; Lipids; Mycobacterium tuberculosis; Sulfhydryl Compounds
PubMed: 32139546
DOI: 10.1126/science.aav5912 -
Frontiers in Cellular and Infection... 2022
Topics: Humans; Mycobacterium tuberculosis; Tuberculosis, Lymph Node
PubMed: 36310862
DOI: 10.3389/fcimb.2022.1020267