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Printable Handouts
Navigable Slide Index
- Introduction
- Mycobacterium tuberculosis: the sobering facts
- The natural history of M. tuberculosis infection
- Immune control
- Controller vs. permissive phagocytes
- A fluorescent Mtb reporter strain for NO
- SSB-GFP fusion replication reporter
- Host cell heterogeneity impacts the bacterial burden
- Mtb is located in resident alveolar and recruited interstitial macrophages
- Expression of hspX-promoter-driven GFP (NO-mediated stress)
- Bacterial replication is higher in AM than in IM
- Impact of phagocyte populations of bacterial fitness
- The metabolic programming of the AM and IM lineages is markedly different
- Selective intoxication of IMs leads to expansion of the bacterial burden
- Impact of 2-DG & Etomoxir on bacterial growth inside macrophages in culture
- Mtb infection drives proliferation of uninfected, iNOS-ve macrophages
- Re-programming vs. pre-programming
- The metabolic state of the macrophages
- Metabolic flux experiment to demonstrate macrophage imprinting
- Profiling TB disease control and progression across species
- Dual RNA-seq of host and pathogen of in vivo infection
- Host cell and Mtb exhibit different transcriptional profiles
- Major cellular networks up-regulated in AMs and in IMs
- Differential host and bacterial responses to iron
- Mtb lives in a vacuole - where does the iron come from?
- Mycobacterial spp. modulate phagosome acidification to promote survival
- Transferrin cycles through the Mtb-containing vacuole
- EM autoradiography shows iron accumulation in Mtb
- Impact of immune status on iron acquisition & storage gene expression
- The impact of the host environment on drug action
- Screening in the host environment for 'smarter' antibiotics
- Summary of the hit compounds
- Carbon source influences compound activity in vitro
- New cholesterol-dependent inhibitors
- In vivo activity of an adenylate cyclase (rv1625c) active compound
- Host cell immune status impacts drug susceptibility
- A rational approach for identification of host-directed therapies
- Drugs and vaccines do not work independently
- Proposed workflow for analysis of metabolism of Mtb in vivo
- Co-incidence of HIV and TB infection in Sub-Saharan Africa
- How does HIV-1 impact human lung immunity?
- HIV-1 is preferentially located in the small alveolar macrophages
- HIV-1 does not trigger cell death in HIV-1-infected macrophages
- Regulatory lncRNAs are differentially induced by HIV-1
- lncRNA-SAF expression is upregulated in HIV-1-positive AMs from humans
- Down-regulation of lncRNA-SAF leads to cell death in infected macrophages
- Induction of cell death shuts down viral productivity
- Take-home messages
- Thank you for listening
Topics Covered
- Introduction to tuberculosis and immune control
- Macrophage subsets in the lung
- Transcriptional profiling of pathogen and host
- Immunometabolism in TB infection and disease control
- Novel drug screening platforms and new anti-TB drugs
- Investigation of the HIV-1/TB interplay
- Biology of HIV-1 infection of macrophages
Links
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Talk Citation
Russell, D. (2021, March 30). Understanding and combating tuberculosis [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved November 5, 2024, from https://doi.org/10.69645/HSET6435.Export Citation (RIS)
Publication History
Financial Disclosures
- There are no commercial/financial matters to disclose.
A selection of talks on Clinical Practice
Transcript
Please wait while the transcript is being prepared...
0:00
Hello, my name is David Russell.
I'm a professor in the department of microbiology and
immunology in the College of Veterinary Medicine at Cornell University.
I'm going to talk about tuberculosis today.
I've worked on TB for about 30 years.
In today's talk, what I want to emphasize is our more recent work on
understanding the biology of Mycobacterium tuberculosis within the context of its host,
looking at the in vivo biology of the interplay between the pathogen and the host.
0:35
I'm sorry about this slide
(it's a bit of a boring list),
but it will give you the background information that you need
to appreciate the significance of this infectious agent.
TB is the single greatest cause of death by infectious disease,
and there are approximately 1.2 million deaths per year.
It's estimated that about a quarter of
the human population is infected with this pathogen, and
there's a lifetime risk of developing disease that's between
5 and 10 percent over the course of your lifetime.
It's the single greatest cause of death in those individuals living with HIV.
We have no effective vaccine against tuberculosis.
Many people around the world are inoculated with BCG,
which is an attenuated form of a related species of Mycobacterium, and
this protects against the more severe forms of pediatric tuberculosis
but it doesn't protect adults against infection.
Effective chemotherapy is very long term,
you require 8 to 9 months of treatment with a combination of
at least three effective drugs, and there are many side-effects.
Not surprisingly there's considerable non-compliance, and this
leads to constant emergence of heritable drug resistance.
We lack any biomarkers that are either predictive of
disease progression or indicative of cure status,
so we don't know if the drug treatment is actually
working effectively to control or eradicate the disease.