Please enable JavaScript.

Coggle requires JavaScript to display documents.

TB (Cliff (immune response in blood 2015), Warner (metabolism 2015), Bruch…

- - - - Making new treatment/diagnostics hard
    - - Absent in latent infection (asymptomatic)
        
        Over expression of interferon-inducible genes, myeloid genes and inflammatory genes
        
        Type I or II interferon stimulation
        
        Type 1 interferon may be preventing protective responses when switching from latent to active infection.
        
        Blood cell genes (myeloid)
        
        Activate the inflammation pathways
        
        Down regulation of lymphocytic functional gene expression.
  - - - If TB is inside you, latent or not, this will be a positive result.
        
        We can do better
        
        Blood transcriptomic signatures
        
        Active vs latent results
        
        Better treatment and drug testing results
        
        CurrentlyMostly early bactericidal assays and 2-month sputum conversion
      - Or nucleic acid amplification testing
  - - - Including immune responses
        
        Even specific diseases
        
        Depends on immune/pathogen pathways and transciption programs
        
        Has been successful in TB identification
        
        Can also indicate severity or treatment response
  - - - Really help with infant and AIDS/HIV patients
    - - Downregulation of T-cell genes due to diminished CD4 effectors and memory cells
        
        Signal apoptosis or migration to infection
      - Also FC(gamma) receptor 1B (FCGRIB) and innate immune-related genes, Toll-like receptors to microbe patterns, and IFN signalling.
        
        All indicate resistance/ susceptibility to TB
        
        FCGR 1 signaling and transcriptional activity are the hallmark
        
        Support improved diagnosis
        
        Insights to functional immune and inflammatory networks in TB pathogenesis
      - Whole blood transcriptomics can indicate cell populations
        
        Mostly activated CD4 and CD8 (noted with + superscript) gene expression differences
        
        Also myeloid cell inflammation and TREM1 signaling
        
        From increased inflammatory monocyte numbers and purified monocyte gene expression
  - - - Respiratory disorder that also effects IFN-induced genes
    - - Increased inflammatory signature
        
        Transcript classifiers specific to TB have been found
        
        Padiatric HIV+ still needs work
  - - - Diagnostic accuracy and to validate new transcript classifiers
        
        Dominant algorithm of transcript classifiers consisting of 12-100 genes
        
        All blood transriptome producers
        
        Critical for smear/culture negatives & children
    - - May be detecting early switch to active
  - - - Shorter treatment for decreased drug resistance in TB
        
        Problem: no cheap or easy way to monitor drug efficacy
        
        Will require many independent studies
        
        And lots of money
        
        Currently mostly using sputum analysis and bacterial assays
        
        Easy false negatives for HIV+ & kids
        
        Diabetics = easy relapse
        
        Need host biomarkers that show treatment efficacy
        
        Can be done for individual granulomas
        
        1 more item...
    - - Other molecules direct from the infection site
        
        Plasma & serum proteins
        
        Active vs. latent
        
        Treatment efficacy shifts
        
        Maybe cytokines?
        
        Post-transcription and post-translation regulation/degradation have caused controversial responses
        
        Metabolic profiling
        
        Kynurenine from tryptophan is higher in serum of actively infected
        
        Required enzyme is induced by phagocytic cells and is released from lung granulomas
        
        Also higher cortisol and lower lysophosphatidilocholines
        
        By inhibition of phospholipase
        
        1 more item...
        
        MicroRNA-223
        
        Deletion in mice significantly increase acute infection overall
        
        A chemoattractant to immune stimulating cytokines
    - - Gone by 12 months
      - Diminished B/T cell levels require closer to 12 months for most to be signif
        
        Successful treatment show changes in other genes after 1 week
        
        Different pathways for different stages of treatment
        
        Inflammatory genes
  - - - Type I IFN signatures indicate the switch to active
        
        Supported by radiographic events
        
        Decreased after treatment
        
        Elevation also reported with mycobacterial leprosy
        
        Balance of types I and II IFNs indicate resistance to leprosy
        
        Increases in type I IFNs have been linked to suppression of immune related cytokines
        
        Also blocks type II IFNS from activating machrophages
        
        Creating an imbalance in IFNS
      - Interleukin alpha & beta have been shown to inhibit type I IFN induction in macrophages
    - - Blood transcriptomics is critical to monitoring TB progression
        
        Shown from many independent cohorts from around the world
        
        Supports/Boosts diagnostics and treatment planning
        
        Thus, reducing tranmission
        
        Requires a set of discriminant classifiers that are easy for PCR testing
        
        More cohorts for similar testing/acting diseases would improve the accuracy of these test
        
        RNA sequencing or microarray of genome expression profile in the future
      - Better bioinformatic tools would help discover more pathways of suscepibility, co-infection, and comorbidities
    - - What is part of the immune response and what signals active infection?
- - - - Some new insights from developments in fields/tools like metabolomics
        
        New mechanism of action reviews
        
        labeling of metabolic intermediates and NMR
      - For obligate pathogens, metabolism would have to underpin physiology and pathogenicity
        
        Research has generally focused on clarifying metabolic capacity in defines growth media and environmental conditions
        
        Not in vivo, yet
  - - - Lodge in alveolar sacs and undergo endophagocytosis by phagocytes
        
        Immune to phagosomal acidification and blocks lysozomal fusion
        
        The phagocyte becomes deactivated while the mycobacterium proliferates
        
        Immune system activation can slow this replication and triggers granuloma formation
        
        The bacteria is effectively dormant
        
        They can also occupy other cell types and spread to other organs
        
        1 more item...
    - - Immune responses induce oxygen limitations
        
        Metabolism must exist to maintain an energized membrane when growth is limited
        
        Produces future generations with decreased pathogenic ability
        
        Bacillary number is irrelevant to infection outcome
        
        Metabolism is instead dedicated to moaximize biomass even during stress response
        
        Pathology is not mediated by bacterial toxins, but by the reactions of the host to mycobacterial antigens
        
        Primate pulmonary lesion analysis reports that lesion population maxs out around 200000 bacilli/lesion
        
        1 more item...
  - - - Phototrohpic synthesis of amino acids, vitamins, and cofactors
      - Extensive genetic abilities in fatty acid metabilism
        
        Primary carbon source
        
        Can assimilate host lipids
        
        incorporated into propionyl-CoA catabolism
        
        Propionyl-CoA is toxic to M.TB, unwanted byproduct of lipid assimilation
        
        These byproducts can be used in virulence factors
        
        Requires B12
      - EMP & PPP glycolysis and a funtional tricarboxylic acid cycle
        
        Has alpha-ketoglutarate (AKG), requiring AKG dehydrogenase and glutamate synthase
        
        AKG can be used to monitor anabolism/catabolism balance
        
        M. tubersulosis uses GarA to control these enzymes
        
        GarA is also easily phosphorylated and interacts with multiple kinases
        
        It should be investigated as a core metabolic regulator
      - Able to use host CO2 for carbon source (succinyl-CoA)
        
        Can run multiple Carbon catabolizations in compartmentalized vesicles
        
        Contributions from each catabolic process to overall growth in general is unknown
      - Able to assimilate alanine, glatmate/mine, and asparagine/asparate from hosts
  - - - Mass secretion of succinate in fermentive respiration
        
        Replication with high extracellular lipids resulted insuccinate and glycine
        
        Therefore, succinate effectively powers membrane potential, ATP synthesis and TCA intermediates
  - - - Disrupting macrophages with ketone body synthesis
        
        Additionally causes autophagy in infected phagocytes
      - Disrupts host lipid metabolism so granulomas are mostly comprised of lipids
      - Macrophages produce itaconic acid which inhibits isocitrate lyase (used to break propionyl-CoA)
        
        Also caused by immunoresponsive gene I
    - - Immune activation involves an up-regulation of a tryptophan catabolic enzyme
        
        An effort to starve invading pathogens
        
        If a drug could target mycobacterial typtophan synthetic enzymes...
        
        bacteriocidal in vitro, growth inhibitor in vivo
    - - certain metabolic functions are under direct negative selection
      - Also selective gains and losses in metabolic functions to play into decreasing host immune activation
  - - - Amino acid auxotrophs: live-attenuated (reduced in strength) vaccines
        
        Double auxotrophic mutants (inactive deletions of B5 & lysine/leucine biosynth paths) fail to cause disease
      - Can be used as probes of the host (shock)
        
        The bacilli cannot transport amino acids into infected macrophages
        
        Or host cells are just hiding select amino acids
        
        TB requires host-derived aspartate
        
        deletion of aspartate transporters caused decreases in growth adn pathogenicity in vivo
        
        Implying the host environment changes with infection and per the infector
        
        There is usually another enzyme in mycobacteria to make up for these selective defiencies
        
        We need to better map mechanisms for essntial nutrient, cofactor, and trace element uptake
        
        Also highlights protein conservation abilities of obligate pathogens
- - - - Especially TB
        
        Proteome has been explored, but most breakthroughs have come from phenotypic screenings.
        
        This review covers 3 case studies for new drug therapies
        
        Serine/theonine-protein kinase B & G
        
        Long time interest
        
        1 & 2?
        
        TB DNA gyrase
        
        Old, but proven, target of fluroqionolones
        
        Rationale of what remains to be done
        
        New paths opened by recent methodology, strucural biology, and technique improvements
  - - - For drugs or targets
      - Monetarily and temporally costly
        
        Trial and error
      - Drug design can rely on what is already know
        
        Structure-based drug design
        
        Looking at known targets in 3D and optimize molecules to bind with it.
        
        First used on HIV then glaucoma
        
        Targets usually gleamed via X-ray crystalography, NMR, or (new!) cryo-electron microscopy (cryo-EM)
        
        Cryo-EM has higher resolution for single molecules
        
        The leader of the "resolution revolution"
        
        Weh unhelpful, silico structure predictions based on homologous proteins for trial and error
        
        Helping future elucidation
        
        Much trial and error for antibiotics
  - - - Protein kinases promote this phosphorylation signal transduction
        
        Why it has been a marker for diseases (cancer, where it goes wild) and pharma targets
    - - Therefore bacteria have a two component singal system
      - One gene coding for Ser/Thr phosphatase (pstP) was in an operon with pknA & B (ptpA & B)
        
        Making Tyr phosphatases
      - All but PknG & K are integral proteins
        
        Same topology as N-terminal catalytic domain of Hanks motifs
        
        Sensing domain
        
        Believed to be active in kinase activation via oligomerization state control
        
        "Back-to-back dimerization to promote active kinase conformation," but not PknB & D.
        
        PknB -> peptidoglycan synthesis control
        
        Most inhibition worked on micromolar and submicromolar levels, but not the mycobacterium
        
        1 more item...
        
        A bi-lobed Pkn with a separating fold
  - - - Then, it has to get through the cell walls
        
        And act on latent as well as active infection
        
        Different metabolic needs
        
        Usually triggers drug resistance
        
        Cocktails of drugs, not individual
        
        Must take into account the bioavailibility and pharmacokinetic properties of each component and their associations
        
        1 more item...
        
        "metabolic plasticity"
    - - That damn cell wall
        
        mycobacterial DNA gyrase is the key, but we can't access the hole on the lock
      - Major redundancy among kinases
        
        Also poor substrate specificity
        
        Require a cocktail for multiple inhibitions
      - Activation mechanisms need more work
        
        Pkn B & G are still theoretical
        
        Metabolic plasticity is still being investigated
        
        In vitro testing is likely to fail on a massive, in vivo trial
        
        We need more phenotypic screening
  - - - Eukaryotes have 2 pairs, meaning ours are specific and different
        
        Obvious target
        
        Fluoroquinolones
        
        Drug resistant strains have emerged
        
        They're working on it
        
        ATP and DNA binding sites
        
        1 more item...
- - - - Kinases specific for stages of infection remain unresolved
      - Drug cocktails required in a guess and check method
        
        Mechanisms of action need better elucidation
        
        Really complicated to make sure they all play well together and still work
        
        Then we have to worry about host toxicity
  - - - Decrease immune response to nonviral infection
        
        Block interferon II from activating phagocytes
    - - Children & HIV+ give false absent
      - decrease transmission, improve treatment assessment
      - 10-20% of positive results from new test are still latent
        
        Possibly due to early switch to active
  - - - It can gain carbon and nitrogen from multiple sources in any host cell
      - It can alter its metabolic activity to hide from host immunity
      - Lesion populations remain just below detectible levels
      - It can use succinate during hypoxic conditions
      - Phototrophy for carbohydrate, lipid, and amino acid synthesis
      - Will decrease pathogenicity to continue proliferation