TUBERCULOSIS

Can the spread of

this killer disease be
halted?

TUBERCULOSIS

19th-century tuberculosis ward

Soil bacteria

Tuberculosis remains a global challenge

- can its spread be halted?
g

History

Tuberculosis (TB) is primarily a disease of the lungs

Methanogenic bacteria
Methanospirillum hungatii

In the late 1940s the incidence of TB fell further due

to the introduction of effective antibiotics to treat the
disease and the start of the BCG vaccination programme
to prevent the disease such as the one launched in
Britain in 1945.

caused by the bacterium Mycobacterium tuberculosis.

It is a very old disease. References to it in the Bible

Streptomycin was the first antibiotic to be

and other sources show that it was prevalent in ancient

successfully developed to treat TB. It was given to a

civilizations. The earliest known case of TB in Britain was

critically ill TB patient on 20 November 1944 who went

found in the spine of an Iron Age man who died in

on to make a rapid recovery. After that a succession of

Dorset around 300 BC.

anti-TB drugs started to emerge. The effect of this was

a decrease in TB in developed countries which could

TB was rife from 1600 1800. During the 17th and 18th

afford the drugs, but it was not reflected in developing

centuries, at the height of the epidemic, up to 30 % of

countries where the disease continued to thrive. It was a

deaths in Europe were caused by tuberculosis. During

case of out of sight, out of mind and there was huge

the 19th and 20th centuries deaths from TB started

optimism that the disease was a thing of the past, but

to decrease as living standards improved, due to better

sadly this was not the case.

diet, water quality and housing conditions. People

TB returns

became healthier and so their immune systems were

better at fighting infection. The only treatment for the

TB in the UK continued to decline steadily until 1988

disease at this time was the transfer of patients to

but since this date the number of reported cases has

sanatoria where it was hoped that the combination of

increased annually by approximately 2 % or more until

good food, plenty of rest and fresh air would result in a

2005 when numbers stabilised. However rates remain at

cure. This was often ineffective and many patients never

their highest since the late 1980s.

recovered. However removing infected patients from the

community also helped to reduce the spread of the

In 2007, 8417 cases were reported in the Annual

disease.

Report on Tuberculosis Surveillance in the UK. TB is now a

TUBERCULOSIS
problem in some UK cities and largely affects deprived
communities. In 2007 92 % of the cases reported in the
UK occurred in England; the largest proportion of these
cases, 39 %, was diagnosed in London. The majority of
cases occurred in young male adults aged between 15
and 44 years and among those born outside the UK
predominantly from South Asia and Sub-Saharan Africa.
There are three main reasons why there has been a

3
ORGANISM

HOST

M. tuberculosis

humans

M. africanum

humans (tropical Africa)

M. microti

voles & rodents

M. bovis

wide range of mammals

especially cattle

resurgence in the disease:

M. bovis can infect humans, probably through drinking

In the developing world TB never went away.

untreated milk.

Increased population movements due to global air

travel and immigration have helped to spread the

disease to more developed countries.

There has been an increase in the number of

people susceptible to TB (see section on TB and

HIV, page 8).

There has been an increase in the number of cases

of multi-drug resistant TB (see section on Drug

resistant TB, page 7).

Mycobacterium tuberculosis

In 1993 The World Health Organisation (WHO)

declared TB a global emergency. TB causes more deaths
than any other infectious disease. This means that 2-3
million people will die from TB each year, which is
approximately 1 death every 10 seconds. The WHO
reported that TB is spreading at a rate of one person per
second. Although 95 % of cases are in the developing
world, it is re-emerging in cities in the developed world.
The WHO predicts that between 2000 and 2020 nearly
1 billion people will be newly infected with TB,
200 million people will get sick and 35 million people
will die from the disease.

M. tuberculosis is an aerobe, consequently the

bacteria grow successfully in tissues with high oxygen

What causes TB?

concentrations such as the lungs. However the infection

Most mycobacteria are non-pathogenic and are found

can spread in the blood from the lungs to all organs in

in habitats such as soil or water. Some are opportunistic

the body such as the kidneys and spine. M. tuberculosis

pathogens of humans, for example Mycobacterium avium

has a complex thick waxy cell wall due to its high lipid

is a problem in AIDS patients. A few species are obligate

content; this acts as a barrier to antibiotics and is

pathogens of humans and animals. M.tuberculosis along

resistant to lysosomal enzymes, enabling the bacteria to

with M. bovis, M. africanum and M. microti all cause the

survive inside macrophages in the body. This waxy layer

disease tuberculosis and are members of the tuberculosis

also protects the bacilli from drying out so they may

complex. Although closely related, these bacteria have

survive many months in the air and dust as long as it is

different host ranges.

dark. Direct sunlight kills mycobacteria in 5 minutes.

TUBERCULOSIS

Transmission of TB

How is TB spread?

The minimum infectious dose is approximately 10

TB is spread from person to person through the

bacterial cells. Only a small number of people newly

air. When a person with active TB coughs, talks or

infected with TB will develop immediate symptoms of

sneezes, mucus and saliva loaded with the infectious

the disease. The majority will not become ill and cannot

organism are propelled into the air. The moisture quickly

transmit the bacteria. The mycobacteria remain

evaporates from these particles to leave droplet nuclei

inactive (latent infection) without causing the disease.

(dried microscopic pellets) that may remain airborne for

They can become reactivated at any time, even years

hours or days and can spread over long distances. Drop-

later, especially in people with a weakened immune

let nuclei are between 1 5 m in size and contain 1 3

system. Depressed immunity due to ageing, a poor diet,

infectious organisms each. Infection occurs if the inhaled

a low standard of living and over-crowding or infection

organism reaches the alveoli of the lungs. A single sneeze

with HIV, can lead to an increase in the likelihood of

will release millions of mycobacteria into the air; one

developing the disease.

person with active TB can go on to infect 10 15 people

throughout the year.

The immune response to TB

In the lung the bacteria are engulfed by macrophages

Once in the alveoli the organisms are engulfed by

but are relatively resistant to destruction by lysosomal

macrophages. The hosts cell-mediated immune response

enzymes. They are not destroyed by phagocytosis. Once

is activated and limits further multiplication and spread of

inside the macrophages M. tuberculosis can grow and

M. tuberculosis. However some bacilli may remain viable

multiply. This causes the macrophages to die and release

but dormant in the macrophages for many years after

bacterial cells that can infect further macrophages, setting

initial infection.

up a cycle of infection and multiplication.

TUBERCULOSIS
Latent TB Infection
People with latent infection
Have no symptoms
Dont feel unwell
Cant spread it to others
Usually have a positive skin test reaction
(see section on Vaccination, page 8)
Can develop TB disease in later life if
they dont receive preventative therapy
To prevent latent TB infection becoming
active TB disease
Treatment with the drug isoniazid prevents TB
infection developing into the disease because
it kills TB bacteria that are inactive in the body.

5
Active TB
People with the disease have the following
symptoms that get more severe over time
Bad cough for longer than 2 weeks
Pain in the chest
Greenish or bloody sputum
Weakness or fatigue
Weight loss (the gradual wasting of the
body gave the disease the name
consumption)
No appetite
Chills
Fever
Night sweats

Mechanism
Initial infection stimulates a cell-mediated response

lesions may become calcified (lung tissue is replaced by

that seals the bacilli inside nodules or tubercles and

calcium deposits). Calcified lesions show up clearly on

prevents them from spreading. A tubercle is a

chest X-rays. In other cases the tissue of the tubercle

granuloma (a tightly clustered organised collection

breaks down and becomes soft and crumbly like cheese.

of chronic inflammatory cells) consisting of a central

This is known as a caseous necrotic lesion. This necrosis

core containing mainly macrophages infected with

can spread to the bronchioles allowing liquified caseous

M. tuberculosis. An outer wall made of lymphocytes

material containing masses of bacilli to leak into the

and neutrophils surrounds the core.

bronchi. Surviving mycobacteria can multiply rapidly

under these optimum conditions; where there is oxygen

Neutrophils release lysosomal enzymes, which destroy

and plenty of nutrients. As well as destroying the lung

not only the bacilli but also the tubercle. Within the

tissue, this allows bacteria to spread to other parts of the

granuloma there is a battle between the host and the

lung. The patient will be infectious because mycobacteria

bacteria. In some cases the bacteria are killed and the

will be coughed up and transmitted to others.

Macrophage engulfing
M.bovis (orange)

Specimen of lung tissue

showing grey lesions
(tubercles) caused
by tuberculosis

TUBERCULOSIS

Cell mediated immunity

This type of immunity involves sensitised T cells and phagocytes rather than antibodies. After the
M. tuberculosis has been engulfed by the macrophages the mycobacterial antigens (proteins) are
digested into small peptide fragments. These fragments are inserted into the membrane of the
macrophage, which then acts as an antigen-presenting cell (APC).
T cells (T lymphocytes) are a type of white blood cell that are made in the bone marrow and mature in
the thymus gland. They are an essential component of the response against the mycobacteria. Each T
cell has a membrane receptor that recognises a specific mycobacterial antigenic peptide fragment when
it is located on the surface of the APC (macrophage).
T cells can be divided into:

CD4+ T cells. These are helper cells. Their role is to activate B cells which are responsible for the

production of antibodies and macrophages. CD4+ cells bind to the antigen presented by the

antigen-presenting cells. The CD4+ T cells then secrete cytokines which activate the macrophages.

Activated macrophages are able to kill bacteria. They also release chemokines that attract other cells

to the area resulting in inflammation of the tissues and the formation of granulomas.

CD8+ T cells. These are killer (cytotoxic) cells which specifically destroy mycobacteria-infected cells.

They secrete molecules that destroy the cell to which they have bound.
The way in which particular mycobacteria antigens have been processed and displayed on the
macrophage surface determines whether CD4+ or CD8+ T cells are activated. A combination of
both types of T cell appears to be important in protectiveSulfolobus
immunity
sp. against TB.

Diagnosis

there is hypersensitivity to the tuberculin protein. This

Diagnosis of tuberculosis relies on X-rays of the chest,

could be due to a previous infection (latent or active

clinical examination of the patient and microscopic and

disease) or it could be a false positive due to previous

microbiological examination of the sputum. Diagnosis

exposure to other mycobacteria or a BCG vaccination.

can also be made by a positive tuberculin skin test.

Prevention and control

Tuberculin, a partially purified protein extract obtained

from M. tuberculosis, is injected into the dermis of the

Drug therapy

forearm. If there is a strong reaction characterised by a

Current treatment involves 3 4 different kinds of

hardening and reddening of the area around the site of

antibiotics given in combination over 6 9 months.

the injection, which is larger than 10mm, it means that

Multi-antibiotics are necessary to prevent the emergence

Sputum samples on glass slides
These are to be stained and examined
for the presence of M. tuberculosis

Testing sputum
for the
presence of
M. tuberculosis

TUBERCULOSIS

Child preparing to
take DOTS tuberculosis
drugs

Antibiotics used to
treat tuberculosis

of drug resistance in the bacteria. A combination of

Emergence of drug resistant TB

isoniazid and rifampicin for 6 months with pyrazinamide

The publication Anti-Tuberculosis Drug Resistance in the

and ethambutol for the first 2 months is usually used,

World (2008), based on data collected between 2002

as this provides the highest antibacterial activity as

and 2006 on 90,000 TB patients in 81 countries reported

well as having the capacity to inhibit the development

that multi-drug resistance tuberculosis (MDR-TB),

of resistance. It results in a 90 % cure rate. Patients stop

(defined as resistance to isoniazid and rifampicin),

being infectious to others after 2 weeks. After 1 month

is at the highest rates ever. Extensively drug-resistant

patients should feel well and start to regain weight.

tuberculosis (XDR-TB), a virtually untreatable form of the

respiratory disease, (defined as resistance to isoniazid

A problem with treatment arises when patients stop

and rifampicin as well as fluroquinolones and at least

taking the drugs as soon as they feel better, because

one of the second-line anti-TB injectable drugs), is

of inconvenience or to save money. This is mainly

widespread with 45 countries having reported at least

seen in patients in poorer countries or those of low

one case.

socio-economic status in developed nations.

Badly supervised, incomplete or incorrect treatment

MDR-TB responds poorly to standard short-course

programmes may lead to recurrence of illness in the

chemotherapy; for it is both long (often lasting for 2

individual and the emergence of drug resistant strains

years) and also more toxic to patients as second line

of M. tuberculosis. Examination of the bacteria isolated

drugs are required. It is also extremely expensive due

from relapsed cases shows that 52 % are resistant to one

to the price of second line drugs and the extended

or more drugs. To combat the rise in resistant strains a

period for which they have to be taken. It can be 100

Directly Observed Treatment, Short Course (DOTS)

times dearer to treat MDR-TB than drug susceptible

programme has been implemented in many countries.

strains, which often makes it too expensive for

DOTS uses a nurse to make sure that each patient takes

developing countries with MDR-TB to treat the

their complete course of drugs.

disease successfully.

TUBERCULOSIS
Baby boy receiving
the BCG vaccine

Drug-resistant tuberculosis bacteria

Vaccination

and does not produce enough of an immune response to

The control of infectious disease through vaccination

protect against TB.

has been one of the most successful accomplishments

of public health in the 20th century, enabling the

In the UK BCG does not protect about 25 % of the

eradication of smallpox and virtual eradication of

people who receive it. Protection in the rest is

polio from the world. Today, vaccination remains our

thought to last for 10 to 15 years. A second

most effective and cost-effective tool in the fight against

vaccination with BCG has been shown to confer no

infectious disease and must be considered as an integral

further protection.

part of any global effort to control infections.

Vaccination with BCG is widely used because it is cheap,
In 1921 Albert Calmette and Camille Guerin of the

offers some degree of protection against TB meningitis

Pasteur Institute in Paris developed the BCG vaccine

in infants and also prevents leprosy. However a more

from a live attenuated strain of M. bovis which is used

effective vaccine for TB is needed as BCG does not

today, with around 388 million doses being administered

protect against lung TB in adults in the developing world.

world-wide each year. It took 13 years of subculturing

TB and HIV

M. bovis to produce a vaccine for tuberculosis. However,

the efficacy of BCG vaccine varies around the world and

TB and HIV form a deadly synergistic combination.

between populations, ranging from no protection to

When people are infected with both TB and HIV, TB

70 to 80 % protection.

is much more likely to become active because in AIDS

patients the immune system is weakened.

Genetic differences in populations and variations in

exposure to environmental mycobacteria are thought to

HIV is a virus so it needs a host cell to replicate in.

affect the efficacy of the BCG in different countries.

HIV uses CD 4+ cells as the host. The virus attaches and

Environmental mycobacteria prefer the habitats in

enters the CD4+ cell damaging it in the process so it is

tropical countries: this correlates with those countries

no longer able to function. This weakens the bodys

where the efficacy of BCG is lower, for example

defence mechanism to M. tuberculosis, making it

Malawi and some southern states of America. Exposure

more suseptible to infection. HIV also promotes the

to environmental mycobacteria results in a weaker

progression of latent TB infection to active disease

immune response to the BCG vaccine (partial immunity)

and the relapse of the disease in previously treated

TUBERCULOSIS

Tuberculosis colonies
(cream) on a
Petri dish in a
BCG vaccine study

patients. TB is the leading cause of illness in HIV-positive

Various vaccine strategies are being investigated and

individuals in many developing countries. In 2008 the

these include:

WHO reported that every year TB was taking the lives of

nearly a quarter of a million people living with HIV.
As more TB cases become active it means larger numbers
of people carry and spread TB to healthy populations.
TB also appears to speed up HIVs replication rate
although the mechanism is not fully understood.
g

Latest research

New advances in basic sciences, such as molecular

biology, immunology and genomics are altering the way
we design and make our vaccines. In 1998 scientists at

Heterologous prime-boost vaccines The BGC vaccine

is used as the priming vaccine and the boosting vaccine
candidate is either protein based, DNA based or viral
vector based. Each vaccine, the prime and the boost,
uses the same antigen from the pathogen that the
immune system will target and remember. The vaccines
are given separately. The advantage of this method is
that we can keep using the current BCG vaccine, which
does protect against TB meningitis in infants, and then
give our booster vaccine to protect children from
developing lung TB as adults.

The Sanger Centre and the Pasteur Institute sequenced

Modified BCG vaccines The BCG vaccine is genetically

the genome of M. tuberculosis. Researchers are now

modified to overexpress one or more of its proteins.

using this information to design novel vaccines and

The immune system will then make a stronger response

drugs and to identify parts of the organism most

to the overexpressed protein. There has been a clinical

suitable for targeting with drugs and vaccines.

trial with a BCG vaccine overexpressing antigen 85A but

10

TUBERCULOSIS

there was very little increase in immune response to this

Drug development

antigen and the developers have gone back to the

In October 2008 the Global Alliance for TB Drug

drawing board.

Development reported that scientists at Rutgers

Attenuated M. tuberculosis vaccines These vaccines

work on the hypothesis that a TB vaccine derived from
the human Mycobacterium tuberculosis bacterium would
offer better protection than the BCG vaccine which is
based on Mycobacterium bovis. Live attenuated mutants
of M. tuberculosis are currently being tested in animal
models but none have been tested in humans to date.

University had discovered how a group of antibiotic

compounds, myxopyronin, corallopyronin and ripostatin
kill bacteria. These antibiotics were first isolated more
than 10 years ago from microbes occurring naturally in
the soil. It is hoped that they will be able to treat
antibiotic-resistant tuberculosis as they attack a
different site within the bacteria from the antibiotics
currently used to treat infections.

DNA vaccines A DNA plasmid is designed to encode

for one or more protein antigens from M. tuberculosis.

The antibiotic compounds kill tuberculosis bacteria by

The DNA vaccine can then be used alone or in a

attacking an essential protein called RNA polymerase

heterologous prime-boost combination with another

(RNAP), which controls gene transcription in cells and is

vaccine. This strategy showed much promise in the

necessary for cell survival. Ebright, the lead study author,

mouse model. However, in humans the immune

compared the RNAP to a crabs claw. The claw opens and

reponse to DNA vaccines has been very poor and

closes to grab DNA and assemble the RNA, the first step

there is no DNA vaccine for TB in clinical trials.

in synthesising proteins. Ebright reported that Just as

Protein and adjuvant vaccines These vaccines are

based on purified mycobacterial proteins which are
administered in combination with an adjuvant.
Administering a protein alone only gives a weak
immune response but good immune reponses are seen
when proteins are given with complex molecules that we
call adjuvants. Protein+adjuvant vaccines can be used
alone or in heterologous prime-boost with other
vaccines. There are 2 protein+adjuvant vaccines for
TB in early clinical trials.

with a real crab claw, one pincer stays fixed and one pincer
moves opening and closing to keep the DNA in place.
The pincer that moves does so by rotating about a hinge.
Their studies have shown that all three antibiotics bind
to the hinge joint preventing it from moving. Importantly
the specific site where myxopyronin binds is different
in humans and bacteria implying that myxopyronin will
not damage the human version of RNAP. The researchers
hope that myxopyronin may be in human trials within
five years.

Viral vector vaccines These are the most advanced new

TB vaccines in terms of clinical development. Using a viral
vector to express an antigen has many advantages.
Viral vectors can generate strong cellular and humoral
immune responses without the need for an adjuvant,
are readily manufactured and can be used to target
specific immune cells. A modified vaccinia virus Ankara
expressing antigen 85A from M. tuberculosis (MVA85A)
has been in clinical trials for 6 years. This vaccine will be
used in a heterologous prime-boost regime, with BCG
as the priming vaccine, in infants in Cape Town, South
Africa in 2009. This is very exciting as it will be the first
efficacy trial of a TB vaccine since BCG was first tested in
humans more than 100 years ago.

Research into
novel antibiotics

TUBERCULOSIS

11

Key points
TB is caused by the bacterium Mycobacterium tuberculosis.
It is primarily a disease of the lungs.
TB is spread from person to person through the air.
People with latent TB infection have no symptoms and are not infectious.
People with TB disease have symptoms and may be infectious.
Treatment of TB disease involves a combination of 3-4 antibiotics given over a 6-9 month period.
Multi-drug resistant TB is defined as resistance to the antibiotics isoniazid and rifampicin.

Terms explained

Cell-mediated immunity A type of immune response brought about by T cells.

Epidemic An outbreak of a disease affecting a large number of individuals at the same time.

Lymphocyte A type of white blood cell made continuously in the bone marrow. If they continue to
mature in the bone marrow they become B cells. If they mature in the thymus they become T cells.


Macrophage A large white blood cell important in phagocytosis and in activating B and T cells.
They extend long pseudopodia that attach to the surface of a microbe and then engulf it.

Obligate pathogen An organism known to cause disease in humans and other animals.

Opportunistic pathogen A microbe that normally doesnt cause disease but can do so when the
immune system is suppressed.

Phagocytosis A non-specific defence mechanism. Micro-organisms that invade the body are
engulfed by certain types of white blood cells which release lysosomal enzymes. These digest the
microbes and destroy them.

Neutrophil A white blood cell which is important in phagocytosis. After the neutrophil has engulfed
and destroyed the microbe it self-destructs.

Further information

www.textbookofbacteriology.net/tuberculosis.html

www.hpa.org.uk/webw/HPAweb&Page&HPAwebAutoListName/Page/1191942150134

www.netdoctor.co.uk/diseases/facts/tuberculosis.htm

www.stoptb.org

www.tbalert.org

www.who.int/tb/publications/2008/drsreport4-26febo8.pdf Anti-Tuberculosis Drug Resistance in the World

Tuberculosis in the UK: Annual report on tuberculosis surveillance in the UK. London:

Health Protection Agency Centre for Infections, October 2008.

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TUBERCULOSIS
Can the spread of this killer disease be halted?
A resource for secondary schools
Written and designed by Dariel Burdass
Edited by Janet Hurst

Acknowledgements

Thanks are due to Dr Helen Fletcher (Jenner Institute, Oxford University) who supplied the text on the various
vaccine strategies that are currently under investigation. Thanks are also due to Professor Neil Stoker (Royal Veterinary
College) and Professor Stephen Gillespie (University College London) for their helpful comments on the text. Every
care has been taken to ensure that the information provided in this factfile is correct, but the author will be pleased to
learn of any errors that have remained undetected.

Picture credits
Front cover, Du Cane Medical Imaging Ltd/SPL*, p.2 upper, Library of Congress/SPL, p.3 middle right, A. Dowsett, Health Protection
Agency/SPL, p.4 upper, Mark Miller/SPL, p.5 lower left, SPL, p.5 lower right, CNRI/SPL, p.6 lower left, Arno Massee/SPL, p.6 lower
right, Andy Crump, TDR, WHO/SPL p.7 top left, Andy Crump, TDR, WHO/SPL, p.7 top right, Andy Crump, TDR, WHO/SPL, p.8
top left,Dr Kari Lounatmaa/SPL, p.8 top right, Mark Thomas/SPL, p.9 upper,H. Raguet, Eurelios/SPL, p.10 lower right, Geoff
Tompkinson/SPL, p.11,Du Cane Medical Imaging Ltd/SPL.
*SPL, Science Photo Library

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