Download TB Basics - Facilitator Notes

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The aim of the “TB Basics module” is to provide activists with fundamental
information about tuberculosis in order to strengthen advocacy and
scientific literacy around TB and TB/HIV . We hope that activists will use this
information to inform their advocacy and to develop community education
materials and sessions on TB. The facilitator notes and slide set are teaching
tools that can be used as is or modified to suit your needs and audience.
We estimate that it will take about two hours to complete this module using
the attached slide set. Time estimates have been included in each section of
the module for your reference but will vary based on the facilitator’s comfort
with the material and the participants’ understanding of the material. Please
use the time allotments as a planning guide rather than a rule.
The module is broken up into sections that can be taught as separate units or
in one workshop. The information in the facilitator notes is organized into five
main categories:
s Fundamental information provides further explanation of the
information on the slides and slide notes, and is what we consider to be
“need to know” information.
s Teaching points/exercises are optional and are meant to provide an
opportunity to reinforce information and/or stimulate discussion.
s Summary/review revisits key points of each section and provide an
opportunity for clarification or further explanation.
s Definitions provide explanation of commonly used and/or key terms.
These terms are italicized in the main text.
s “Nice-to-know” information is not considered necessary or
fundamental to understanding basics concepts of this module but
is “nice-to-know.” Please be careful before citing this information in
a workshop, as participants who are new to tuberculosis may get
overwhelmed by “too much information.”
These facilitator notes are meant to be used as a guide for and explanation
to the slide set. However, facilitators should feel free to develop their own
slide sets or teaching tools using the notes and/or modifying the slides
depending on their needs.
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The goal of this module is to provide participants with a foundation to
understand the key concepts of TB disease. At the end of this module
participants will
1. be familiar with the history of TB
2. be familiar with fundamental scientific concepts about Mycobaterium
tuberculosis (MTB)
3. be able to explain how TB is transmitted
4. be able to explain the difference between latent TB infection and active
TB disease
5. understand the immune response to TB
6. be familiar with some specific challenges to TB control in the context of
TB/HIV coinfection
7. be able to identify some of the most pressing issues for TB advocates
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S E C T I O N 1 History of TB (slides 3-5; 5 minutes)
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“If the importance of a disease for mankind is measured by the number
of fatalities it causes, then tuberculosis must be considered much more
important than those most feared infectious diseases.”
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NICE TO KNOW
In this same talk, Koch outlined what became known as,
“Koch’s Postulates,’” a set of criteria to determine if a
microbe is the cause of a disease. At the time Koch was
writing this piece, the idea that germs - tiny life forms
too small to see - were the cause of many diseases was
controversial. This idea, called germ theory, was contrary
to then widely held beliefs that “miasmas” or bad spirits
were the cause of most disease.
This quote is from a lecture entitled “The Etiology of TB,” which was first
presented at a meeting of the Physiological Society of Berlin in March
24, 1882 during which Dr. Robert Koch, one of the most influential early
microbiologists, announced the discovery of MTB as the cause of TB. Koch
was the first person to isolate the TB bacterium and detail its properties.
It is also interesting that Koch began this important talk with an effort to
convince his audience that TB should be counted among the most important
infectious diseases.
TEACHING POINT
ASK THE PARTICIPANTS TO DISCUSS WHETHER THEY THINK THIS QUOTE IS STILL RELEVANT
TODAY.
NOTE TO FACILITATOR: GIVEN THE FACT THAT ONE-THIRD OF THE WORLD’S POPULATION IS
INFECTED WITH MTB AND IT IS THE LEADING KILLER OF PEOPLE WITH HIV, IT IS REASONABLE
TO THINK THAT THIS QUOTE STILL HOLDS TRUE TODAY.
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TB has been found in the mummified bodies of ancient Egyptians and Andean
Indians, demonstrating that it has been infecting humans for thousands of years.
However, it was not until 1882 that Koch was able to isolate MTB as the cause
of TB. The disease was historically referred to as “consumption” during the late
1800’s and early 1900’s.
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s 4"WASlRSTISLOATEDANDIDENTIlEDBY2OBERT+OCHIN
s 4"HASBEENINFECTINGHUMANSFORTHOUSANDSOFYEARS
s 4HEREISARCHEOLOGICALEVIDENCEOF4"SGEOGRAPHICALDIVERSITYANDTHE
fact that it has been infecting humans for thousands of years from
mummies in Egypt and ancient Andean Indians in South America.
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Q:
A:
Q:
A:
How long has TB been infecting humans?
Thousands of years.
Who discovered TB?
Robert Koch.
Note to facilitator: If participants had difficulty with these
questions, return to the slides to reinforce points they did
n o t i d e n t i f y.
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S E C T I O N 2 Fundamental Concepts (slides 6-11; 20 minutes)
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The scientific name for the pathogen that causes tuberculosis is
Mycobacterium tuberculosis (also referred to as MTB for short). When viewed
with a microscope, it has a long rodlike shape and a thick, waxy-looking coat.
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!"#$%&#'()*+,-'+%()#+.$/*/, also referred to
as MTB, is a rod-shaped bacteria characterized by a
thick waxy coating, it is the bacteria that causes the
disease tuberculosis.
0&'1$2(3/-are any disease-causing substances
or agents, such as bacteria, viruses, and other
microbes.
TIP: Depending on the comfort level of your
audience with this informaton, it may be a good
idea to use less technical language and refer to
pathogens as germ, critter, or bug.
NICE TO KNOW
The word pathogens comes from patho meaning
“disease,” and gen refers to “creation” (like Genesis the
creation story in the Bible).
NICE TO KNOW
Bacteria are different from other microbes because they
lack a membrane-bound nucleus. The term for this is
prokaryotic. Algea and fungi are eukaryotic microbes,
meaning they have a nucleus that is protected by a
membrane.
4&#'()*& are single-celled microorganisms that are
found virtually everywhere on earth.
NICE TO KNOW
Tuberculosis may be referred to by a number of names or
acronyms in conversation and in writings, including: TB,
Mycobacterium tuberculosis, M. tuberculosis, MTB, M.
tb, M.TB, TB bacterium/bacteria (bacterium is singular
and bacteria is plural) or TB bacillus/bacilli (bacillus is
singular and bacilli is plural).
NICE TO KNOW
The prefix myco- can mean “fungi” (as in mycology, the
study of mushrooms and other fungi), or “waxy.” In the
case of MTB, it refers to the waxy coating of the cell wall.
NICE TO KNOW
The term bacilli refers to the rod shape. Other bacterial
shapes are cocci (round), spirochete (cork-screw), and
pleomorphic (having a mixed shape).
TB is a type of mycobacteria (myco means “waxy” in Latin). The TB
bacterium are named for both its appearance (myco) and the disease it
causes (tuberculosis).
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There are over 70 types of mycobacteria -not all of them are harmful.
However MTB is the most common in humans and the most harmful.
Many nonharmful bacteria live in and on our bodies. In fact, there are around
10 times as many bacterial cells in a person’s body than human cells. The
skin, the mouth, and the reproductive and digestive tracts all contain large
numbers of normal, healthy bacteria. Humans have trillions of bacteria in our
gut that help us digest food and synthesize vitamins and hormones.
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MTB’s thick waxy cell wall is made primarily of mycolic acids and fat
molecules called lipids.
The makeup of the cell wall is important for two reasons. First, it allows the
bacteria to live outside the body for a relatively long period of time, making it
more capable of passing from one person to another because the protective
structure allows the germ to spread through the air.
Second, it makes the bacteria difficult to stain and look at under a microscope.
The nature of the cell’s waxy wall requires specific staining dyes after being
washed in acidic solutions; therefore it is referred to as an “acid-fast bacillus.”
This special kind of staining process is called acid-fast testing, and strips the
bacterium of much of its cell wall through the acidic wash, making it more
receptive to traditional staining techniques.
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MTB reproduces very slowly compared to other bacteria through a process
known as binary fission. On average it will reproduce every 16-20 hours, in
contrast to many other bacteria that replicate in a matter of minutes, or an
hour or so at most. This makes diagnosis of TB more difficult as it takes
longer to detect TB in the body and to grow it in the laboratory. Because
MTB has all the necessary genetic material to reproduce it does not require
a host like HIV.
TB and HIV are two of the most important infectious diseases in the world
today. While they overlap in many important ways, they are also quite
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different. TB is a large and complex bacteria that has been infecting humans
since early civilization. HIV however is a tiny, relatively simple virus that
has been infecting humans for less than a century. The downside for TB
mutation in humans is that when they occur, they are more likely to become
fixed and stable over time as compared to HIV.
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Critical differences between TB and HIV
NICE TO KNOW
Unlike TB, most bacteria can be stained with a simple
technique called gram staining, which exposes the cell
wall to a couple of dyes that will either be absorbed
by the cell wall (gram positive) or not absorbed (gram
negative).
s-4"ISAHUGEBACTERIAMADEOF
DNA, a fatty cell wall, and many
proteins.
s$.!ISMORESTABLETHAN2.!
because it has a proofreading
mechanism that regulates its
mutations.
s()6ISATINYRETROVIRUSMADEOF
RNA with just a few proteins and
a glycolipid (sugar-fat-protein)
envelope.
s2.!HASNOREGULATINGMECHANISM
hence copies often contain changes
or mutations.
s4"ISARELATIVELYCOMPLEXORGANISM
and has ~4,000 genes.
s()6ISARELATIVELYSIMPLEOGANISM
and has nine genes.
s4"REPRODUCESBYDIVIDINGINTWO
in a process called binary fission.
s()6TRICKSOUROWNCELLSGENETIC
machinery to replicate.
s4"HASBEENINFECTINGHUMANS
for thousands of years.
s()6HASBEENAROUNDFORABOUT
years.
In summary, TB is a large and complex bacteria that has been infecting
humans for thousands of years while HIV is a tiny, relatively simple virus that
has been infecting humans for less than a century.
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!"#$%&'())"*# is the process by which most
bacteria reproduce. The bacterial DNA is replicated
(an exact copy is made) inside the cell, and each of
the two strands of DNA attaches itself to one end of
the inner cell wall. The cell then divides, leaving two
daughter cells.
s -4"ISARODSHAPEDBACTERIACHARACTERIZEDBYITTHICKWAXYWALLAND
slow rate of reproduction.
s 4HEMAKEUPOFTHECELLWALLISIMPORTANTFORTWOREASONS
–It allows the TB bacteria to survive inside and outside of the body.
–It makes it difficult to stain so that it can be detected under a
microscope.
s -4"REPRODUCESEVERYHOURSINANASEXUALPROCESSKNOWNAS
binary fission.
s 4"ISALARGEANDCOMPLEXBACTERIATHATHASBEENINFECTINGHUMANSFOR
thousands of years while HIV is a tiny, simple virus, relative to TB, that
has been infecting humans for less than a century.
NICE TO KNOW
In most cases the daughter cells are genetically identical
to the parent cell and to each other. The exception to
this is when changes arise due to spontaneous (random)
mutations. Most mutations harm the organism, either
rendering it nonviable (unable to reproduce) or less
capable of sustaining itself (compared to nonmutated
forms). However, sometimes this process can lead to
the changes that benefit the organism- for example
making it less susceptible to antibiotics. This is the same
process that drives all evolution, from simple one-celled
organisms to complex plants and animals.
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Q:
A:
Q:
A:
Q:
A:
What is the shape of the TB bacilli?
Rod-shaped.
What does myco- mean?
It means “waxy” in Latin and refers to the TB cell wall.
How does the “waxy” wall help MTB to survive?
It allows MTB to survive outside of the body.
5 5
NICE TO KNOW
TB has been found in the mummified bodies of ancient
Egyptians and Andean Indians, demonstrating that it has
been infecting humans for thousands of years. There is
strong evidence that HIV has been infecting humans for
about 70 years. The origins of HIV have been traced to
a species of nonhuman primate called pantroglodyte
troglodyte-a type of chimpanzee native to equatorial
Africa. Researchers found that a strain of Simian
Immunodeficiency Virus (SIV) infecting these chimps is
the likely source of all HIV-1 in humans, based on genetic
similarities. By comparing the genes of this strain of SIV
to HIV and comparing those differences to the rate at
which HIV is known to mutate (change), it is estimated
that the virus jumped from chimps to humans sometime
in the first half of the 20th century. While it is not known
exactly how the virus jumped from chimps to humans,
most think it happened when a SIV-infected chimp was
butchered by a human.
Q: What does “acid-fast bacilli’ refer to?
A: The acidic wash that is used to strip away the TB cell wall so that it can
be stained and viewed under a microscope.
Q: How often does TB reproduce?
A: It splits every 16-20 hours through binary fission
Q: Name two differences between HIV and TB
A: See list on page 4 for reference.
Note to facilitators: If participants had difficulty with these
questions, return to the slides to reinforce points they did
n o t i d e n t i f y.
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S E C T I O N 3 TB Transmission (slides 12–14; 15 minutes)
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TEACHING POINTS:
1. ASK PARTICIPANTS TO EXPLAIN HOW TB IS SPREAD.
A. TB IS SPREAD THROUGH INHALING TB BACILLI.
2. IF APPROPRIATE, ASK PARTICIPANTS TO DISCUSS HOW TB IS NOT TRANSMITTED.
A. VIA BLOOD, SPERM, VAGINAL FLUIDS, FOOD OR LIQUIDS, EATING UTENSILS, DUST, DIRT,
OR VEHICLE FUMES.
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56+'+, is the mucus or phlegm that is coughed
up from the lungs that is often examined for the
presence of TB bacilli.
7.8($.* are small air sacs in the lung. They are the
site where most oxygen is brought into-and carbon
dioxide is removed from-the lungs in a process that
is known as gas exchange.
TB is transmitted through the air from exposure to bacilli in the saliva of
infected persons and sputum coughed up from their lungs. Once inhaled, the
droplets can push their way into the lungs, settling in tiny air sacs known as
alveoli.
TB loves oxygen. So it often initially takes root in the oxygen-filled regions of
the lungs. To get inside the lungs, TB typically travels through the nose and
mouth. A single cough can generate more than 9,000 bacteria. A sneeze can
produce triple that amount and propel the germs up to 10 feet away.
Not all persons exposed to TB become infected! There are a number of
factors that increase or mitigate the likelihood of transmission.
EXCERCISE:
ASK THE PARTICIPANTS TO LIST SOME OF THE FACTORS THAT MAY INCREASE OR DECREASE THE
PROBABILITY OF INFECTION?
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Factors that may increase or decrease the risk of infection (this list is not
exhaustive):
s Factors related to the person with TB (index case): whether their sputum
is sputum smear positive (smear positive indicates a high level of MTB in
their sputum); have a cough; are adhering to their TB medication regimen
(after 2-3 weeks on treatment, persons with drug-susceptible TB are
considered no longer infectious).
s Factors related to the person being exposed to TB (contact): Proximity
and frequency of contact (how close one is to an infected person); age
of contact (young children and older adults may be at increased risk for
transmission).
s Environmental factors: ventilation; size of room or space; duration of
exposure; sunlight or ultraviolet (UV) light (which kills TB bacteria).
B ' = = A $ L<
s (OW4"ISNOTTRANSMITTED
Via blood, sperm, vaginal fluids, food or liquids, eating utensils, dust, dirt,
or vehicle fumes.
s 4"ISANAIRBORNEDISEASEANDISTRANSMITTEDTHROUGHINHALING4"BACILLI
through the nose or mouth:
s !SINGLECOUGHCANCONTAIN4"CONTAININGDROPLETS
s !SNEEZECANCONTAINMANYMORE
s 4ALKINGSINGINGSNEEZINGANDCOUGHINGCANINJECTBACILLIINTOTHEAIR
7 7
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Q:
A:
Q:
A:
Q:
What are three ways that TB is not passed from person to person?
See list on page 5 for answers
Name two factors that can impact the risk of infection.
See list on page 6 for answers
Can TB be passed from person-to-person through casual or close
contact?
A: Yes
Note to facilitators: If participants had difficulty with these
questions return to the slides to reinforce points they did
n o t i d e n t i f y.
8 8
S E C T I O N 4 Who’s Who in the Immune Response: Roles and
Responsibilities (slides 15-19; 30 minutes)
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EXERCISE:
ASK THE PARTICIPANTS “WHAT OUR BEST DEFENSE IS AGAINST INFECTION AND DISEASE?”
A. THE IMMUNE SYSTEM. THIS IS YOUR BEST DEFENSE SYSTEM AGAINST ANY PATHOGEN
(OR CRITTER, GERM, OR BUG).
ASK PARTICIPANTS TO LIST SOME PARTS OF THE IMMUNE SYSTEM.
A. SKIN, NAILS, HAIR, EYE LASHES, LYMPH NODES, CD4 CELLS, BONE MARROW, TONSILS,
THYMUS, ETC. (PLEASE NOTE THAT THIS LIST IS NOT EXHAUSTIVE.)
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When TB gets into a person’s body, the immune system will try and get rid of
it. Some of the important “players” in the body’s immune response to TB (and
HIV) are:
73*'2(3-6)(/(3'*32-#(../ are the immune
system’s first responders. They patrol the body
looking for cells and other materials that are foreign
(and potentially harmful) to the body.
ANTIGEN ­PRESENTING CELLS ­ (macrophages cells) patrol the body looking for germs.
CD4 T­CELLS ­ act as coordinator of the immune response instructing other ells
to attack specific invading germs.
!&#)$61&2(/ are a type of antigen-presenting
cell, they are large (macro) cells that engulf (phage
meaning “to eat”) invading organisms and bring
them to the coordinating cell of the immune system,
the CD4 T cell.
9(3:)*'*#-#(../ are also a type of antigenpresenting cell, and have long, stringlike projections
from their cell bodies called dendrites. These
dendrites act like the strings on a mop, grabbing a
hold of invading organisms to transport them to the
CD4 T cell.
and dendritic
CD8 T­CELLS ­ are involved in cell­to­cell killing, when ordered by CD4 T cells they
seeks out and destroy cells that have been infected by a specific germ.
)
B­CELL
B CELLS ­ are immune cells that when instructed by the CD4 T cells make antibodies.
ANTIBODIES ­ are sticky proteins that attach to germs marking
them for destruction by the immune system or hampering their ability to reproduce.
Antibodies are specific to the germ (bacteria, virus, or other harmful toxins).
!)&*+,-./)+-*01)2Q
The immune system sends out an army of immune cells to look for anything
that is not supposed to be there. The first wave of patrol cells are dendritic
cells and macrophages. These cells are known as antigen-presenting cells, and
guard against foreign invaders entering the body. Antigen-presenting cells can
be thought of as the “advance scouts” of the immune system, as they alert
the body to foreign invaders (pathogens or germs).
MACROPHAGE
DENDRITIC CELL
9 9
Dendritic cells use long tentacles, called dendrites, to grab TB bacilli while
macrophages engulf TB. Dendritic cells can be likened to string mops, with
the dendrites being like the strings on the mop. Macrophages are large cells
that eat microbes. Macro means “large” and phage means “eat.”
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Both of these cells transport TB to the lymph nodes, which act as the
communication and meeting center for the immune system. In the lymph
nodes, the antigen-presenting cells chop up the TB bacilli and present it to
the CD4 T cell (also known as the CD4 cell, T4 cell, T4 helper cell, or less
accurately as helper T cell, or T cell) which coordinates the immune response.
CD4 T cells are the coordinator cells of the immune system and are
responsible for sending out instructions to other immune system cells telling
them how to respond to a challenge.
Th2
B
;",61-3$:(/ are small, bean shaped structures
and are the work centers of the immune system.
They act as filters-trapping bacteria, viruses, and
other pathogens-and as meeting places for immune
system cells.
<9=->-#(../ act as coordinators of the immune
response instructing other cells (like B cells and
CD8 T cells) to attack specific invading pathogens.
Some alternative ways of explaining the role of the
CD4 T cell are as “the conductor of the immune
system orchestra” or “the general of the immune
system army” or “the boss of the immune system
workplace’”or “the brains of the immune system.’”
<"'$?*3(/ are proteins produced by certain
immune cells that act as chemical messengers
between cells. They can stimulate or inhibit the
growth and activity of various immune cells in
response to a specific pathogen or disease. CD4 T
cells use specific cytokines to direct CD8 T cells and
B cells.
<9@->-#(../ are immune system cells involved
in cell-to-cell killing. When instructed by a CD4 T
cell, they seek out and destroy cells that have been
infected by a specific pathogen. They are sometimes
called CTLs or cytotoxic T Lymphocytes, which
translates to “immune system cells that are toxic to
other cells.”
4-<(../ are white blood cells that when instructed
by CD4 T cells make antibodies.
73'*%$:*(/ are sticky proteins that attach to freefloating pathogens (those not inside a cell), marking
them for destruction and hampering their ability to
reproduce and attach to tissues and cells.
NICE TO KNOW
CD4 T cells are so called because their cell membranes
contain (or express) large amounts of a protein known as
CD4. The “CD” stands for cluster differentiation-a system
for classifying certain proteins.
B
B
Th1
cytokines
B
Antibody Response
(or Humoral
(or Humoral))
! B­Cells
! Antibodies
! Attacks germs
outside of cell
(e.g. germs in blood)
cytokines
CD4 T cell
Cellular Response
! CD8 T cells
! Cell­to­cell killing
! Attacks germs
inside of cells
CD8 T cells
T8
T8
T4
T4
T8
T4
(e.g. infected cells)
Thymus
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The immune responses to pathogens can be divided into two broad
categories: Th1 (cellular immunity) or Th2 (humoral or antibody response).
The Th1 or cellular response involves the CD4 T cell using cytokines, or
cellular messages (imagine SMS or text messages between cells), to direct
the CD8 T cell to recognize and eliminate infected cells. CD8 T cells are also
called cytotoxic T cells (CTLs). This means they are cells that are toxic to
other cells; in other words, they are cells that kill other infected cells.
In the Th2 or antibody (humoral) response, the CD4 T cell directs B cells to
make antibodies which are proteins that stick to free floating pathogens
preventing them from infecting new cells and marking them for destruction.
Unfortunately, antibodies are largely ineffective against TB.
TIP: It is helpful to come up with nonscientific ways to explain some of these
concepts. For instance, another way to describe the two immune responses
is:
! "! Cellular (or Th1) immune response: A robber (pathogen) breaks into a
house, so the police chief (CD4 T cell) tells the police officer (CD8 T cell)
to find the house where the robber is (infected cell) and set the house
on fire so that the robber is killed and the house is destroyed, thereby
stopping the robbery (or killing the infected cell).
! "! Antibody (or humoral or Th2) immune response: A robber (pathogen) is
walking on the street looking for a house to rob (a cell to infect) and the
1010
police officer (B cell) comes up to him and puts stickers (antibodies) all
over his body that say ‘robber’. Now the robber is unable to break into a
house because he has stickers all over his hands AND he will be noticed
and picked up by the police before he can break into a house (or killed by
patrolling immune cells) because they can see that he is a robber.
EXERCISE
ALLOW 10 MINUTES FOR GROUP WORK AND 5 MINUTES PER GROUP FOR PRESENTATION:
DEPENDING ON THE SIZE OF THE GROUP, BREAK PARTICIPANTS INTO GROUPS OF NO MORE
THAN EIGHT, AND ASK EACH OF THE GROUPS TO DEVELOP A WAY TO TEACH OTHERS ABOUT
THE IMMUNE RESPONSE. PARTICIPANTS CAN ACT IT OUT, DRAW IT, WRITE A SONG-WHATEVER
THEY WANT. IT SHOULD INCLUDE THE ROLES OF ANTIGEN-PRESENTING CELLS BOTH DENDRITIC
CELLS AND MACROPHAGES, CD4 T CELLS, CD8 T CELLS AND B CELLS. DEPENDING ON THE TIME
AVAILABLE AND ON THE SIZE OF THE GROUP, YOU MAY ASSIGN ONLY ONE TYPE OF IMMUNE
RESPONSE PER GROUP. GIVE THE GROUPS 10 MINUTES TO DEVELOP THEIR PRESENTATION, AND
THEN BRING THE GROUP BACK TOGETHER TO PRESENT.
The immune system has a mixed record in responding to TB infection. Many
healthy people will eliminate or at least control TB infection for life, keeping
it from ever making them sick. Some will not. People with compromised or
deteriorating immune systems from HIV infection, malnutrition, old age, or
other factors, or children with developing immune systems, are less able to
keep the infection in check. As previously mentioned, the antibody (or humoral
or Th2) response to TB seems largely ineffective.
B ' = = A $ L)
A generic immune response behaves something like this:
s !PATHOGENAVIRUSBACTERIAFUNGUSETCENTERSTHEBODY
s )TISlRSTDETECTEDBYANANTIGENPRESENTINGCELLEITHERAMACROPHAGEORA
dendritic cell.
s 4HEANTIGENPRESENTINGCELLGRABSTHEPATHOGENANDBRINGSITTOA#$4
cell, which is the coordinator cell of the immune system.
s 4HE#$4CELLCANINITIATETWOTYPESOFIMMUNERESPONSES4HAND4H
Some infections will illicit one type of response or the other, but most will
initiate both.
s )NTHECELLULARIMMUNERESPONSE4HTHE#$4CELLSSIGNALSANOTHER
type of T cell, called a CD8 T cell, to find and destroy any cells that are
infected by the pathogen.
s )NTHEANTIBODYORHUMORALOR4HIMMUNERESPONSETHE#$4CELL
signals another type of white blood cell, called a B cell, to produce
antibodies (sticky proteins) to bind to the pathogen so that it is unable to
infect cells and is marked for destruction. The antibody immune response
is ineffective in combating TB.
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Q: Describe a basic immune response. What role do the following cells play
in the response: CD4 cells, CD8 cells, B cells, antigen-presenting cells?
A: See explanations on page 9.
Q: What are other names for cellular and humoral immunity? Please explain
what happens in each response.
A: Cellular: Th1, and humoral: Th2 or antibody.
See explanations on page 9 to guide explanation of the each of these
responses.
1111
Q: What is an antibody?
A: A sticky protein produced by B cells that binds to a pathogen so that it
cannot infect a cell and mark it for destruction by other cells.
Q: Extra credit: What is a cytokine?
A: A cellular chemical messenger.
Note to facilitator: If participants had difficulty with these
questions return to the slides to reinforce points they did
n o t i d e n t i f y.
1212
S E C T I O N 5 Immune Response: Latent TB Infection (LTBI) versus
Active TB Disease (slides 20-30; 30 minutes)
!"&*+,-./)+-*01)CT
A)&3+.$,&/ are immunologic prisons made of TBspecific CD4 and CD8 T cells that enclose and trap
tubercles, keeping them from causing symptoms or
being passed on to other people.
>+%()#.(/ are TB bacilli contained within a hard
shell. Tubercles are the result of TB’s ability to
short circuit a normal immune system process
called phagocytosis the macrophage engulfs and
destroys an invading organism. By shutting off the
macrophage’s ability to break it down, the bacteria
is left inside the macrophage, protected from the
immune system. When TB is encased in a tubercle
it changes what it eats and how much oxygen it
needs. It also greatly slows down the speed at which
it reproduces. These changes allow it to survive for
long periods of time- in some cases an entire human
lifespan- inside the body
Many people incorrectly use the terms TB infection and TB disease
interchangeably. This mistake is both common and understandable, but needs
to be cleared up.
!"&*+,-./)+-*01)C2
EXERCISE:
ASK THE GROUP TO DESCRIBE THE DIFFERENCE BETWEEN LATENT TB INFECTION AND ACTIVE TB
DISEASE.
!"&*+,-./)+-*01)CC
Latent TB infection (LTBI) refers to the period of time when the immune
system has been successful in containing the TB bacilli and preventing
disease. Active TB disease refers to the time when TB breaks out of latency
and causes disease. In some cases, persons may progress to active disease
right after being infected with TB. In these cases, the immune system fails to
contain TB in granulomas (see below for further explanation) and is referred
to as progressive primary TB disease.
!"&*+,-./)+-*01)CI
“NICE TO KNOW” Numbered Parts of the Diagram
STEPS OF A PHAGOSOME INGESTING A PATHOGEN
1. Pathogens 2. Phagosomes 3. Lysosomes 4. Waste
material 5. Cytoplasm 6. Cell membrane
During latent TB infection, TB bacilii are captured and encased by
macrophages in a structure called a tubercle. The tubercles are in turn
walled off by other macrophages and white blood cells in a structure called a
granuloma. When in a latent state, TB changes its diet by requiring little to no
oxygen, and divides less often to survive inside the granuloma. It is important
to note that a person who is latently infected with TB is not contagious and
does not experience any symptoms of TB.
One of most important reasons that TB is so widespread is because it has
developed ways of hijacking our body’s normal immune response.
a. Ingestion of the pathogen through a process called
phagocytosis, followed by an internal pocket called a
phagosome being formed
b. Normally, the phagosome fuses with another pocket
called a lysosome (which contains substances capable
of breaking down or lysing the pathogen) to create a
phagolysosome. In a normal immune response, the
pathogen is broken down in preparation for disposal in
the phagolysosome. A cytokine called interferon gamma
(IFN-gamma) activates macrophages in a way that
promotes lysosome/phagosome fusion and the creation
of the phagolysosome.
Importantly, TB has the ability to block this process in
order to survive in the macrophage’s phagosome and
prevent its transport by cellular mechanisms to the
lysosome for degradation and disposal.
c. Waste material is expelled
!"&*+,-./)+-*01)CJ
1313
When TB enters the body, TB-specific CD4 and CD8 T cells move into the lung
to contain TB bacilli and eliminate infected cells. This is done to contain the
infection and keep it from spreading. In the next step, these immune cells try
to release cytokines (cellular chemical messengers) to activate macrophages
in a way that normally direct them to break down and dispose of TB. This
process known as phagocytosis. (Remember, that phage means “eat”; and
cyto means “cell”).
TB has evolved so that it can block cytokines (those chemical messengers).
So instead of being eliminated from the body, the TB microbe is encased in
the hard shell known as the tubercle. The tubercle protects and hides TB.
!"&*+,-./)+-*01)CK
The tubercles are contained by TB-specific CD4 and CD8 T cells in an
immunological prison called a granuloma that can keep TB from causing
disease and spreading it to other people. This can be thought of as both
good and bad. It is good in the sense that granulomas can effectively contain
TB in such a way that it may never make someone sick, or be transmitted to
another person. It is bad in the sense that this process hides the infection
from the immune system, allowing the bacteria to survive– possibly becoming
active at a later time and making a person sick.
By changing its diet when in latency and requiring very little oxygen to survive,
TB can remain dormant or reproduce at very low levels for an entire lifetime.
This ability to change from the active form that uses large amounts of oxygen
to a far less active state where very little oxygen is needed is one of the key
features of TB. If it were unable to make this switch, the TB would die off
inside of the granuloma, because it would be starved of the oxygen it would
need to survive.
Researchers are trying to figure out how TB is able to survive in this latent
form. Understanding this process better might lead to ways of stopping it or
figuring out ways to keep it from being able to activate to cause disease.
TEACHING POINT:
ASK PARTICIPANTS TO EXPLAIN THE DIFFERENCE BETWEEN A TUBERCLE AND A GRANULOMA.
!"&*+,-./)+-*01)CP
In a matter of weeks after the initial exposure, TB is usually contained by
the immune system. Most (about 90%) of the newly generated TB-specific
CD4 and CD8 T cells are no longer needed and they automatically die off in
a process called apoptosis (cell suicide). This is a normal part of a healthy
immune response.
TEACHING POINT
ASK PARTICIPANTS WHY THEY THINK MOST OF THESE CELLS MUST DIE.
ANSWER: THESE CELLS MUST UNDERGO APOPTOSIS BECAUSE THE BODY DOES NOT NEED THEM
ANYMORE, AND KEEPING THEM ALIVE WILL TAKE TOO MUCH ENERGY.
!"&*+,-./)+-*01)CQ
Apoptosis
Memory cells
Memory immune response
1414
The remaining TB-specific CD4 and CD8 T cells become “memory” cells
that continue to patrol for TB and are capable of responding rapidly if they
encounter TB again. Immunologic memory enables our immune systems to
respond to future challenges so quickly that infection cannot be established
in the body at all. This is what we call “immunity.” It is also how vaccines
work. It is important to note that these cells are specific to the pathogen
that they were first exposed to. In this case, these CD8 T cells generated in
response to TB will only be able to fight TB for the rest of their lives.
!"&*+,-./)+-*01)CR
In HIV-negative persons, the body’s immune system usually keeps TB infection
under control. In fact, people with latent TB infection never exhibit symptoms,
and only 1 in 10 cases progress to active TB. On the other hand, HIV-positive
persons with LTBI have an annual risk of about 10% of developing TB disease.
In other words, they have a 1 in 10 chance, every year of their lives, of
progressing to active disease.
What is the difference between someone having a 10% lifetime risk of
developing TB disease (for HIV-negative people) compared to a 10% annual
risk for people with HIV?
A 10% lifetime risk means that 1 in 10 HIV-negative people with LTBI will
develop TB disease over the course of their entire lives. So if you have a group
of 100 HIV-negative people with LTBI, 10 of these individuals will develop
active TB disease at some point in their lives, meaning that 90 will never get
sick with or be able to transmit TB. Most of those who develop TB disease
will do so within the first two years after infection.
However, people with HIV have about a 10% risk of developing TB disease
each year. So, imagine a group of 100 HIV-positive people who have LTBI.
After the first year, 10 of them will likely develop TB disease. Leaving 90 HIVpositive persons latently infected with TB. In the second year, 9 of these 90
people (or 10%) will likely develop TB disease, meaning a total of 19 out of
the original 100 HIV-positive persons latently infected with TB progressed
to active TB disease. After the third year another 8 (or 10% of the remaining
80 latently infected) people would be expected to progress to TB disease,
meaning that 27 out of 100 have developed TB disease in three years. The
math is a bit challenging, but after 10 years, 64 of the 100 people with HIV
who were latently infected with TB would be expected to progress from LTBI to
TB disease.
START WITH…
100 HIV-positive
people with LTBI
DURING YEAR 1…
DURING YEAR 2…
DURING YEAR 3…
90 HIV-positive
people will stay
latently infected
81 HIV-positive
people will stay
latently infected
73 HIV-positive
people will stay
latently infected
And so on….
Total who develop
active TB disease
during the year
10 (or 10% of 100)
will develop active
TB disease
9 (or 10% of 90)
will develop active
TB disease
8 (or 10% of 81)
will develop active
TB disease
Total with active
TB disease
10
19
27
Note to the facilitator:these statistics are based on
pre-HAART data.
1515
<&8*'*(/ are enlarged air spaces in the lung caused
by tubercles breaking out of granulomas.
Cavity
!"&*+,-./)+-*01)CS
Latent TB infection can progress to active disease when the body becomes
weak from disease, malnutrition, immune suppression, or even old age. In
most people with a healthy immune system, this may never happen-the TB
will stay latent, trapped inside of the granulomas. If the immune system
is compromised, the immunologic prison of the granulomas no longer
successfully contains the tubercles and they begin to multiply and break out
of the granulomas damaging the lung tissue and creating cavities.
!"&*+,-./)+-*01)IT
UG-E:3.4/)#@ refers to TB disease of the lungs.
?V74.,G-E:3.4/)#@ refers to TB disease outside
of the lungs.
Active TB disease may manifest in the lungs (pulmonary TB) and/or in other
parts of the body (extrapulmonary TB). Pulmonary TB is the most common
form of TB disease. As a result, many people mistakenly believe that TB is a
disease of the lungs only. Typically, pulmonary TB expels pus into the lungs,
which a patient may cough up in spit or sputum. In fact, the most common
way doctors diagnose TB is to look for the bacteria in sputum using a
microscope.
Extrapulmonary TB (EPTB) is normally rare, but occurs in up to 40% of TB
cases among people with HIV.
B ' = = A $ L<
Latent TB infection refers to the time when a person is infected with the
MTB bacteria, but the infection is contained by the immune system, and the
person is not sick or contagious. Active TB disease refers to the time when
a person’s TB infection breaks through the immune system’s control and
causes symptoms of disease and that person may be contagious. In fact,
HIV-negative persons have only a 10% chance that they will develop active TB
over the course of their lifetime, while people with HIV have a 10% chance of
developing active TB disease each year.
An HIV-positive person bears an increased risk of progressing to TB disease,
particularly as immune function decreases. Likewise, factors such as young
and old age, malnutrition, and other disease may increase an individual’s risk
of disease progression to active TB disease.
$?M!?N<
Q: What is the difference between latent TB infection and active TB disease?
A: Latent TB infection refers to the time when a person is infected with the
mycobacterium tuberculosis bacteria, but the infection is contained by
the immune system, and the person is not sick or contagious. Active TB
disease refers to the time when a person’s TB infection breaks through
the immune system’s control and causes symptoms of disease and that
person may be contagious.
Q: Is someone who is latently infected with TB at risk for transmitting TB to
another?
A: No.
Q: What is the risk for a latently TB infected HIV-negative person developing
active TB disease as compared to an HIV-positive person?
A: An HIV-negative person’s risk is about 10% over his or her lifetime and an
HIV-positive person’s risk is about 10% per year.
Note to the facilitator: If participants had difficulty with
these questions return to the slides to reinforce points
t h e y d i d n o t i d e n f i t y.
1616
S E C T I O N 6 Challenges to TB Control in TB/HIV Coinfection
(slides 31-33; 10 minutes)
!"&*+,-./)+-*01)I2
Extrapulmonary TB (EPTB)
Active TB disease often manifests in the lungs (pulmonary TB) but can also
be found in other parts of the body (extrapulmonary TB). Pulmonary TB is the
most common form of TB disease.
Extrapulmonary TB (EPTB) is normally rare but occurs in up to 40% of TB
cases among people with HIV and rarely involves only a single organ. TB’s
ability to cause disease in so many parts of the body helps to illustrate
how challenging it is. Extrapulmonary TB may attack one specific organ or
multiple of areas of the body. Because of this, many medical providers miss
diagnosing EPTB because of the many possible symptoms of this disease.
TEACHING POINT: ASK PARTICIPANTS TO NAME AREAS OF THE BODY WHERE THEY THINK TB CAN
CAUSE DISEASE.
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EPTB can be found in various parts of the body:
s -ILIARY4"IS4"DISSEMINATEDTHROUGHOUTTHEBODY
s 4UBERCULOSISLYMPHADENITISISFOUNDINTHELYMPHNODESANDISTHEMOST
common form of EPTB.
s 0LEURAL4"ISFOUNDINTHEPLEURALCAVITYAROUNDTHELUNGSANDISTHEMOST
common form of EPTB in people with HIV.
s 3KELETAL4"ISFOUNDINTHEBONESANDJOINTS
s 4UBERCULOSISMENINGITISISFOUNDINTHECENTRALNERVOUSSYSTEM
s 'ASTROINTESTINAL4"ISFOUNDINTHEGASTROINTESTINALTRACT
s 'ENITOURINARY4"ISFOUNDINGENITOURINARYTRACT
s 4UBERCULOSISPERITONITISISFOUNDINTHEPELVICCAVITY
s 4UBERCULOSISPERICARDITISINFECTSTHEMEMBRANEAROUNDTHEHEART
(pericardium).
!"&*+,-./)+-*01)II
Smear-negative TB (for more on this see “TB/HIV Impact” and “TB
Diagnostics” modules)
The most common test used to diagnose TB is sputum-smear microscopy.
Patients suspected of having TB provide a sputum sample (coughed up from
the lungs), which is washed in an acidic solution in order to retain specific
staining dyes so that the TB bacilli can be seen under a microscope (see
section 2). Smear test results may be reported as “acid fast bacilli-positive”
(AFB+) or “acid fast bacilli-negative” (AFB-), or more commonly known as
smear positive or smear negative. People with HIV have fewer TB bacteria
in their sputum, due to fewer CD4 and CD8 T cells, which in healthy bodies
expel TB into the sputum.
As CD4 T cells are lost due to and compromised by HIV infection, CD8 T cells
lose the directional support they need to do their job of killing TB-infected
cells because they are no longer being told to kill TB-infected cells. TB is
expelled into the sputum when TB-infected cells are killed. Therefore, the
chance of smear-negative TB increases because fewer TB bacilli are released
in the sputum. This means that TB is not being released into the sputum,
so despite the fact that someone may have TB in his or her system it is not
1717
detected using sputum-smear microscopy. Up to 61% of people coinfected
with HIV and TB generate smear-negative tests – in other words, an incorrect
diagnosis.
B ' = = A $ L<
People with HIV are more likely to have extrapulmonary and smear-negative
TB because of their impaired immune function. As a result, they are at risk for
being misdiagnosed as not having TB.
$?M!?N
Q: What is the difference between pulmonary and extrapulmonary TB?
A: Pulmonary TB refers to TB in the lungs, and extrapulmonary refers to TB
outside of the lungs.
Q: Name two types of extrapulmonary TB.
A: See list on page 14.
Q: Why are HIV-positive people at increased risk for smear-negative TB?
A: Because they are less likely to have functioning CD4 and CD8 cells that
kill the TB-infected cells thereby expeling TB into the sputum.
Note to facilitator: If participants had difficulty with these
questions return to the slides to reinforce points they did
n o t i d e n t i f y.
1818
S E C T I O N 7 Advocacy Issues (slide 34; 5 minutes)
!"&*+,-./)+-*01)IJ
Because new cases of TB occur most often in HIV-positive persons in most
high burden settings, there is tremendous overlap between the HIV and TB
epidemics. While the international community has begun making important
progress in expanding worldwide access to life saving HIV treatments, much
of this progress is threatened by the lack of attention to HIV/TB coinfection.
Until TB is more effectively addressed within the context of HIV, efforts to
combat HIV internationally will be less effective.
There are lessons to be learned from the HIV advocacy movement. HIV
activists have shown that concerted advocacy can shape an effective
response to public health challenges. HIV advocacy has also shown that a
good scientific understanding of the disease is crucial in both developing and
implementing advocacy priorities.
One of the most pressing issues for TB advocates in relation to basic
science is the urgent need for better understanding of TB, as this is
essential for newer and better prevention and infection control strategies,
vaccines, diagnostics, and treatments. Unfortunately, the Global Plan to
Stop Tuberculosis: 2006-2015 (http://www.stoptb.org/globalplan/) did not
originally account for basic science in its research priorities. However, the
research component of the Plan is going through a revision, and basic science
will be included in the research priorities. Additionally, the governments of
countries bearing a high TB burden need to increase their investment in basic
science research and programs. And given the challenges facing people with
HIV in TB control, national AIDS control programs need to include TB control
in their program activities.
=%&'>?)$?M!?N<
!"&*+,-./)+-*01)IK
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
How long has TB been infecting humans?
When was TB first isolated, and by whom?
Name two differences between TB and HIV.
Why are people with HIV at higher risk for TB?
What is the difference in risk for developing active TB disease for a
person with HIV versus a person who does not have HIV?
What is binary fission?
What does “AFB” refer to?
How is TB transmitted? Name one factor that may impact TB
transmission.
What are antigen-presenting cells?
What role do CD4 T cells play in the immune response?
What is the difference between latent TB infection and active TB disease?
Why are people with HIV more likely to have smear-negative TB?
Note to facilitator: Please note that this is not an
exhaustive list of review quesitons as it only touches on
some of the information discussed in this module, this
is meant to be a guide and facilitators are encouraged to
develop their own review questions.