Lecture 10. Slow Growing Mycobacteria; Mycobacteria tuberculosis Flashcards
What is tuberculosis?
An infectious, air borne disease, caused by Mycobacterium tuberculosis (Mtb)
The immune response can contain Mtb as latent form of disease whilst the active form it is contagious and causes disease symptoms
It is primarily a pulmonary disease (lungs) but can cause disease in most parts of the body
In many low and middle income countries TB is major cause of morbidity and mortality
How can tuberculosis be cured?
With prolonged multi-drug treatment regimes (increasing problems with drug resistance)
BCG vaccine offers some protection
How can other mycobacterium besides Mtb cause tuberculosis?
From the Mycobacterium tuberculosis complex (MTBC) including M. bovis (impacts cattle)
What is something to remember about Mtb?
There are multiple strains of Mtb that are different from the ancestral one
What is the history of tuberculosis?
Has been found in 9000 year old bones
Refereed to throughout written (E.g India 3300 years ago)
In 1600-1800s in Europe TB caused 25% of deaths
Overcrowded and substandard living or working conditions, poor nutrition
Which countries have a high burden of TB?
Found globally but particularly prevalent in sub-saharan Africa and Asia
What does TB co-infect with to cause more disease?
HIV (particularly sub-saharan Africa and parts of South America)
How is TB transmitted?
Primarily an airborne disease
Not highly infectious (3-10 people infected per infectious individual
Long period of infectiousness (without treatment) average >1yr
What determines TB disease progression?
The immune response
How does TB progress within most healthy people (>90%)?
The innate and adaptive immune systems allow most healthy people to control the growth of Mtb, although they harbour latent infection (it is not known whether host immune responses can eliminate infection)
What group of people develop acute TB either as primary progression or a reactivation?
Those with impaired T cell function
How does Mtb get into the phagosome?
M. tuberculosis is phagocytosed by antigen-presenting cells (APCs), including macrophages, monocytes and dendritic cells, and survives in phagosomes
Once in the phagosome, what does Mtb trigger?
Mtb ligands, including lipoproteins and glycolipids, are recognised in APCs by Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain (NOD) protein resulting in the secretion of inflammatory cytokines and chemokines.
Where do infected APCs migrate to and what does this cause?
Infected APCs migrate to regional lymphoid tissues, where adaptive immunity develops through antigen presentation to naive T cells
What happens within infected APC cells?
APCs process Mtb antigens by intravacuolar proteolysis to produce peptides that bind to major histocompatibility complex (MHC) class II molecules, which then translocate to the cell surface to mediate presentation of Mtb peptides to CD4+ T cells.
M. tuberculosis peptides are also presented by MHC class I molecules to CD8+ T cells and effector and memory T cells migrate back to sites of infection to control M. tuberculosis growth.
How do granulomas form in response to Mtb?
Granulomas develop through the secretion of tumour necrosis factor and other effector cytokines
What is the disease progression of TB?
Infection eliminated with innate immune response/acquired immune response
Latent TB infection brought upon by successful granuloma (fibrous coating encapsulates disease)
Subclinical TB disease
Active TB disease (granulomas bursting and mycobacteria being released)
What response does latent Mtb bring on?
Strong cell mediated respone
What response does active Mtb bring on?
Weak cell mediated response
What is the life cycle of Mtb?
Mtb bacilli, present in exhaled droplets or nuclei, are inhaled and phagocytosed by resident alveolar macrophages
Resulting proinflammatory response triggers the infected cells to invade the subtending epithelium
Leads to the recruitment of monocytes from the circulation, as well as extensive neovascularisation of the infection site
The macrophages form the granulomas along with epithelioid cells, multinucleate giant cells, and foamy cells filled with lipid droplets, a fibrous cuff of extracellular matrix material may form
Progression toward disease is characterised by the loss of vascularisation, increased necrosis, and the accumulation of caseum in the granuloma centre
What are the main symptoms of TB?
A bad cough that lasts 3 weeks or longer
Pain in the chest
Coughing up blood or sputum (phlegm from deep inside the lungs)
What are the other symptoms of TB disease?
Weakness or fatigue
Weight loss
No appetite
Chills
Fever
Sweating at night
How is TB diagnosed?
Physiology: night sweats, temperature, persistent cough, weight loss, fatigue
Smear test: microscopic visualisation of acid-fast bacilli in the sputum
X-ray of the chest to detect patches on the lungs
Cultivation sputum using highly growth sensitive systems such as the MGIT
Tuberculin skin test (Mantoux test) for hypersensitivity to antigens of Mtb
IFN-gamma release assay
T-SPOT.TB assay for activated TB-specific effector T cells (TB ELISpot)
Detection of Mtb specific antigens in the blood
Detection of specific genes using qPCR GeneXpert targets Mtb using rpoB, also will detect rifampicin resistance
What technique is the most commonly used technique to diagnose TB in low income countries and why?
Smear sputum microscopy, relatively fast, inexpensive and specific for tuberculosis
