An overview of tuberculosis: infection, immune response and preventive strategies Flashcards
Other names for tuberculosis
TB Consumption Wasting disease Koch’s disease White plague Phthisis Scrofula
how many ppl have been infected with TB? 2006 report
2 billion infected, i.e. 1 in 3 of global population
how many people die from TB annually? 2006 report
1.8 million deaths annually, 98% in low-income countries
how many people are exposed to TB? 2006 report
2 billion is exposed to TB (doesn’t mean ill, but exposed and carry pathogen)
endemic area of TB? (2006 WHO report)
Subsaharan africa = endemic area. South america some parts, former soviet union also.
what pathogen causes TB?
Mycobacterium tuberculosis
describe Mycobacterium tuberculosis
- rod-like
- slow growing
- gram positive
- can be stained by acid fast stain test
how is TB transmitted?
aerosol (coughing, sneezing), typically with few bacilli (don’t need large infectious dose)
enters cell body through resp route, either nose or mouth. Goes to lung.
typically, infects and survives in lung macrophages
what does TB start as?
lung disease
TB risk factors?
household sharing and crowded public areas
in most people what happens?
In most people, bacteria are eliminated by phagocytic cells in the lungs. However, in some individuals (5-10 %), not all bacteria are eliminated and some survive and begin to divide.
what % of infections result in TB?
only 10%, hence why 2 billion exposed, but not ill.
What is ‘normal’ outcome of interaction?
Host: 90% of infections do not result in disease - therefore, disease is anomaly
Bacteria: infection without disease is dead end - therefore, disease is a necessity to get to next host.
Best case scenario, infect many but have disease in minority. Only small proportion will transmit.
when happens once TB is in the body?
Granulomas are formed from infiltrating cells surrounding the infected cells and serve the purpose of containing the spread of infection.
They also provide a milieu for cell-cell interactions that may facilitate bacterial removal.
Inhale droplets from cough / sneeze from infected person.
Cough will create visible droplets as well as fine aerosol which you can’t see.
Remain in air for prolonged period of time, several hours. Likely source of new infection. (The visible droplets unlikely source of new infection)
TB initially forms granuloma in lungs which can be seen in a chest X-ray.
Host cells grouping around to isolate bacteria, limit spread. And possible eradicate it.
Sometimes the immune response works. If it fails, lesions breaks and liquefies spreads to other part of lung.
Course of M. tuberculosis infection
- primary
- latent
- reactivated
Latent TB
1/3 world’s population infected
BCG largely ineffective
Preventive drug treatment possible but not practical
Reactivation many years later
Risk factors for reactivation
Malnutrition Immunodeficiencies - HIV IS A BIG FACTOR Immunosuppression Old age Poor health HIV
can latent TB and active TB be treated in the same way?
can treat latent TB like active. However, it’s not practical / economical bc don’t always know who has latent TB and not all latent TB progresses to active TB.
can BCG prevent TB onset?
BCG can’t prevent onset of latent infection.
How does HIV impact your chances of getting TB?
TB = 10% chance of infection
HIV shifts the balance. Risk increases 4 folds for active TB.
The difference between latent TB infection and active TB Disease
Latent
- does not feel sick
- usually +ve skin test
- normal chest x-ray and test
- has symptoms
Active
- symptoms: bad cough lasting 3 weeks, chest pain, coughing blood/sputum, weight loss, no appetite, chills, fever, sweating at night
- may spread TB to others
- usually +ve skin test
- abnormal chest x-ray
hallmark of active TB?
Cough with blood = hallmark of active TB. Also bacteria in sputum (this is one diagnosis method)
tests for TB?
Chest x-ray
Sputum cultures
Interferon (IFN)-gamma blood test. This type of test looks for an immune response to proteins produced by M. tuberculosis.
Rarely, biopsy of the affected tissue (typically lungs, pleura, or lymph nodes)
Tuberculin skin test
explain the tuberculin skin test further
TST = mantoux test.
Inject small amount of non-pathogenic TB under skin.
Leave for several days.
Reaction wider than 1cm diameter = already exposed.
A bit smaller = BCG vaccine.
If nothing – not vaccinated, not exposed to TB.
Cavitary pulmonary TB
the presence of a gas-filled space surrounded by a discrete cavity wall in the lung parenchyma on a chest X-rays
Lung tissue = damaged by TB disease.
It’s not bacterium that causes this, its immunopathology, the inflammatory response destroys healthy lung tissue.
Milliary TB (spread through the lungs)
This is disseminated all around lung rather than cavity.
Produces grainy X-ray, tiny granuloma, affects most of lungs.
Its case of failed granulomas.
Lung function can be irreversibly lost in this severe form.
Treatment of TB
In past no proven treatment. No antibiotics. Would send them to sanitorium High up in mountain, air is clean. Isolated there, lot of rest. Hope them to get better by themeselves. Away from others so don’t spread. Helped to a point, but was just managing disease (clean air) not treating disease.
Drugs for Tuberculosis
1943 - Streptomycin – worked v well but resistance to streptomycin = rapid occurred spurring need for new treatment.
1952 - Isoniazid
1954 - Pyrazinamide
1955 - Cycloserine
1962 - Ethambutol
1963 - Rifampin (also known as rifampicin)
Most drugs act only on dividing bacilli
High relapse rate due to poor compliance
Treatment: within 4 weeks = dramatic decrease (more than 98%). Remaining 4-6 months, its to eliminate very small proportion of bacteria in lungs. As slow growing and not dividing (so must wait for division).
Problem with TB treatment?
Treatment takes a while, 6-9 months. Most drugs act on dividing bacteria. E.g. cell wall synthesis. Therefore TB drugs = slow, because TB = slow growing organism.
E coli division = 20-30mins in contrast TB division: 15-20hrs.
Poor compliance due to treatment length, danger of relapse. If returns, will be resistant to surviving drug.
Directly observed treatment strategy (DOTS)
Number of countries implementing DOTS (out of a total of 211 countries), 1991-2004
DOTS strategy, new patient had to be observed taking medication by medical team. To ensure complete treatment (expensive).
Changed, to e.g. family member.
DOTS = major results of improving control of TB.
Efficacy of DOTS on average = 85-90% globally.
Immune response in TB - good and bad points?
Good
Innate immunity: alveolar macrophages kill ingested bacilli
Th1 adoptive immune response: CD8 and CD4 T cells, IFN-gamma: essential for controlling infection
adaptive immune response = highly efficient.
Bad
Excessive immune response leads to overproduction of TNF-alpha and healthy tissue damage by macrophages (immunopathology of TB).
Killing health lung tissue – immunopathology, causes lesions.
What are the key components of protective immunity in TB?
Macrophages (kill bacteria within phagosomes)
Macrophage primary function = phagocytosis.
Role of macrophage in TB, kill bacteria, BUT also shelter them. TB Bacteria survive intracellularly.
Granuloma (containment)
Antigen presentation
CD8 cytotoxic T cells (direct killing of infected cells)
Th1 CD4 helper T cells (secrete IFN-gamma which activates macrophages)
role of Macrophages
Most efficient phagocyte for killing MTB, but also shelter for bacteria (because MTB evolved strategies for avoiding intracellular killing)
Phagocytosis of bacteria, cell membrane encircles it forms phagosome.
Fusion with lysosome (= phagolysosome), packed with enzymes. E.g proteases, hydrolases. Can damage bacterial cell wall.
Bactericidal agents produced within macrophage phagolysosome
acidification - bacteriostatic or cidal
toxic nitrogen oxides - NO
enzymes - lysozyme
antimicrobial peptides - defensins, can damage cell wall
how can TB manipulate phagosome?
manipulate phagosome so no fusion with lysosome occurs. Multiplies, breaks out of phagosome, multiples freely in cytosol. Kills cell.
what is a granuloma in TB?
containment of infection
Bacteria in middle.
Surrounding: Macrophages, lymphocytes.
Giant cells formed by fusion of several macrophages.
Acquired immune response:
Develops typically from 2 weeks onwards
Requires presentation of mycobacterial antigen-peptides to T cells
Dendritic cells are the most important antigen-presenting cells (other being macrophages and memory B cells)
Antigen Presentation to T cells: MHC
Antigens are presented to T cells as short peptide fragments bound to Major Histocompatibility (MHC) molecules.
Two types of MHC in humans and mice:
MHC I: presents an 8-10 amino acid peptide to CD8+ T cells.
MHC II: presents a longer peptide (13 aa or more) to CD4+ T cells.
‘Professional’ antigen presenting cells (APC): Dendritic cells (DC), macrophages and memory B cells
- Antigen presentation = essential for inducing effective immune response.
- Antigen needs to be processed before can present. Loaded to MHC and presented in complex.
- For MHC1, Peptide derived from cytosol of APC
- MHC2; peptide from phagolysosome. (so from different compartments)
Antigen presentation
MHC1 interact with CD8+ T cell. (peptide derived from cytosol) cd8+ = cytotoxic, kill infected cell.
In MHC2, peptide derived from phagosome. Induce CD4, also can kill BUT primary function is producing cytokines to help other cells. E.g. macrophage to kill infection
Functions of the different T cell types in TB
CD8+ cells:
Kill MTB infected cells
CD4+ cells:
TH1: Activate macrophages by production of IFN-gamma, to aggressively ingest antigen and to kill ingested MTB.
TH2: Stimulate B cells (via production of cytokines such as IL-4, IL-13 and also via cell-cell contact) to differentiate into antibody-producing plasma cells
Antibody responses in TB:
May contribute to protection (but insufficient on their own)
May also exacerbate infection
But prime defence is T cells, CD4 and CD8.
Vaccination for TB?
Bacillus Calmette–Guérin vaccine
Attenuated M. bovis Bacillus Calmette-Guerin
Attenuated bovine TB.
Grown in harsh enviroment, bile. For 10+ years, bacteria forced to shed virulence factors as unnecessary for survival, save energy, only important parts were retained.
The most heavily used vaccine in medical history
Given usually to infants or in early childhood
Protects against disseminated primary infection
Ineffective against reactivation adult TB
Why does BCG fail?
rotection ranges from 80% to zero in different parts of the world
Vaccination is given to infants but protection only lasts about 15 years.
strong protection against childhood TB little against the adult infectious form
Boost with BCG does not work
Enviromental hypothesis:
Environmental bacteria similar to TB, but not pathogenic to humans. E.g. Mycobacterium avium-intracellular, mycobacterium marina
These are similar to TB immunogenically. So, have immune response to mycobacteria but not disease.
Inject BCG, pre immunised with these bacteria. So existing immune response, eliminates BCG before can induce optimal response.
Takes 4 weeks for lesion to heal. Pre-existing immune response works against them.
Need new vaccine for e.g. post exposure
Difficulties in testing TB vaccines in animal models
human studies are unethical
monkeys closest to humans - expensive, also ethical issues
guinea pigs close in pathology - get cavitary lung lesions
mice are cheap and easier but does’t replicate the human disease v well
Types of new candidates
Attenuated M. tuberculosis - Attenuated M. tb, new vaccine based on human tb instead of bovine
Recombinant BCG (may increase efficiency)
Recombinant virus vector expressing MTB antigens
Protein subunit plus adjuvant
DNA
Prime-boost strategy for protection
Prime with BCG (or a recombinant BCG or a live TB variant)
Boost with recombinant fusion protein in adjuvant
Boost with a vectored vaccine
- recombinant MVA
- recombinant Adenovirus
- packaged DNA
