TB Activist Toolkit - TB Basics [PowerPoint Slides]

Treatment Action Group

TB/HIV Advocacy Toolkit

MODULE ONE
TB Basic Science

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Topics to be covered
What is Tuberculosis? TB bacteria and what is unique about it.How is TB different from HIV?How is TB transmitted? Important players in the immune response.How does our immune system react to TB?The difference between latent TB infection and active TB diseaseChallenges to TB control in context of HIVAdvocacy priorities
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History of TB

Section 1 History of TB

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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

Robert Koch, March 24, 1882


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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 worlds population is infected the MTB and it is the leading killer of people with HIV, it is reasonable to think that this quote still holds true today.

A brief history of TB

TB has been found in the mummies of ancient Egyptians and Andean Indians demonstrating that it has been in humans for thousands of yearsWas first identified by
Dr. Robert Koch in 1882. Around the turn of the 20th century, TB was referred to as consumption.
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The distribution of TB in mummies in South America and North Africa shows that it has been geographically widespread since early human history.

Fundamental Concepts

Section 2 Fundamental Concepts

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What is TB?
The scientific name for the TB microbe is mycobacterium tuberculosis or MTBBeneath a microscope, it has a long rodlike shape and thick, waxy-looking coat.

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The MTB bacteria is named for both its appearance (myco meaning waxy in Latin) and the disease it causes (tuberculosis). TB bacilli are rod-shaped organisms -the term bacilli refers to the rod shape.

What is TB? (contd)
Bacteria are single-celled organisms which can exist either independently or as parasites (dependent upon another organism for life).TB is a type of mycobacteria
myco means waxy in Latin and refers to TBs waxy-looking cell wall.

There are 70 different types of mycobacteria.

Not all mycobacterias are harmful but MTB is the most harmful to humansMany nonharmful bacteria live in and on our bodies. In fact, there are around 10 times as many bacterial cells in a persons 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.

What is TB? (contd)
The thick waxy cell wall allows the germ to spread through the air and survive outside of the body.The nature of the cell wall means that it retains specific staining dyes after being washed in acidic solutions (acid-fast bacillus)
TB bacilli stained bright red using the Ziehl-Neelson stain (image copyright Dennis Kunkel Microscopy, Inc.)


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MTBs thick waxy cell wall is made primarily of mycolic acids and fat molecules called lipids.

TB reproduction
Unlike most bacteria, which divide within minutes or hours, TB splits in two once every 16 to 20 hours. This asexual process is known as binary fission. MTB has all the necessary genetic material to reproduce so it does not require a host.

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TB is a slow bacteria. Unlike most bacteria, which divide within minutes or hours, TB splits in two once every 16 to 20 hours.Binary fission is one of the properties of TB that make it difficult and slow to grow in the laboratory. This slow process can result in longer times in diagnosing TB.HIV, on the other hand, can reproduce millions of new viremia every day

Critical differences between TB and HIV

MTB is a huge bacteria made of a fatty cell wall, and many proteins.

stores its genetic material as DNA.

DNA is more stable than RNA because it has a proofreading mechanism that regulates its mutations.

TB is a relatively complex organism and has ~4,000 genes.

TB reproduces by dividing in two in a process called binary fission.

TB has been infecting humans for thousands of years.

HIV is a tiny retrovirus made of just a few proteins and a glycolipid (sugar-fat-protein) envelope.

stores its genetic material as RNA.

RNA has no regulating mechanism hence copies often contain changes or mutations.

HIV is a relatively simple organism and has nine genes.

HIV tricks our own cells genetic machinery to replicate.

HIV has been around for about 70 years.


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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 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 eg. drug-resistant TB (MDR-TB and XDR-TB)Note that humans have about 9,000 genes

How is TB transmitted?

Section 3 TB Transmission

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To start, lets look at some ways that TB is NOT spread: via blood, sperm, vaginal fluids, food or liquids, eating utensils, dust, dirt, or vehicle fumes. Ask participants how TB is transmitted?

How is TB transmitted?
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.

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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 from an infected person can generate more than 9,000 bacterium. A sneeze can produce triple that amount (or about 27,000 bacterium) and propel the germs up to 10 feet away.Not all persons exposed to TB become infected! Exposure to TB does not guarantee infection.What factors might impact the likelihood of infection?

Factors that may affect
TB transmission
Not all persons exposed to TB become infected!Factors related to the person with TB (index case):
whether they have sputum smear-positive (high or low baciliary load);

have cough;

are on AND adhering to their TB medication regimen
Factors related to the person being exposed to TB (contact):
Closeness and frequency of contact with index case

age of contact-young children and older adults may be at increased risk for transmission
Environmental factors:
ventilation;

size of room or space;

duration of exposure; and

sunlight or Ultraviolet (UV) light

After two to three weeks on treatment, persons with smear positive drug-sensitive TB are considered no longer infectiousthis is confirmed by smear negative test resultSunlight and UV light can kill TB bacteria

Whos who in the
immune response?

Section 4 Whos who in Immune Response

Our Immune response
Some of the players include...

ANTIGEN -PRESENTING CELLS - (macrophages and dendritic cells) patrol the body looking for germs.

CD4 T-CELLS - act as coordinator of the immune response instructing other ells to attack specific invading germs.

CD8 T-CELLS - are involved in cell-to-cell killing, when ordered by CD4 T cells they seeks out and destroy cells that have been infected by a specific germ.

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).

Adapted from CSTEP curriculum: Project Inform and A&PIWC


B-CELL
Dendritic cells are a type of antigen-presenting 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.Macrophages 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.

How does the immune system respond to TB?

The immune system sends out an army of immune cells. Chief among them are dendritic cells and macrophages.


Macrophage

Dendritic cell

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When TB gets into a persons body, the immune system will try and get rid of it.To do this, the immune system sends out an army of immune cells. The first wave of cells will include cells known as dendritic cells and macrophages. These cells are also 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. They patrol areas of the body where invading microbes are found, looking for anything that is not supposed to be there. Dendritic cells use long tentacles, called dendrites, to grab TB bacilli while macrophages engulf TB.Macrophages are large cells that eat microbes. Macro means large and phage means eat.

How does the body respond?

Dendritic cells and macrophages transport TB to the lymph nodes which act as the communication and meeting center for the
immune system.

In the lymph nodes, the cells chop up the TB bacilli and present it to the CD4 T cell which coordinates the immune response.


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Each of highlighted areas on this graphic are a component of the immune system.Other parts of the immune system include Skin, nails, hair, and eye lashes.

Immune Response

Bone Marrow

B-cells

Antibody Response

(or Humoral)
B-CellsAntibodiesAttacks germs
outside of cell
(e.g. germs in blood)

Cellular Response
CD8 T cellsCell-to-cell killingAttacks germs
inside of cells
(e.g. infected cells)
cytokines

cytokines

Thymus

CD8 T cells


Th2

Th1


CD4 T cell

B

B

B

B

T8

T8

T8

T4

T4

T4
This is a very basic explanation for the immune response to germs. These responses 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, to direct the CD8 T cell to recognize and eliminate infected cells. CD8 T cells are cells that are toxic to other cells. The thymus is a organ that is located behind the breastbone and produces immune system cells (CD4 and CD8 T cells).In the Th2 or antibody (humoral) response the CD4 T cell directs B cells to make antibodies that are proteins that stick to free floating germs preventing them from infecting new cells and marking them for destruction. Unfortunately, antibodies are largely ineffective against TB.Here is a good place to do an exercise: Have the participants work in groups to develop a way to teach the above immune response to others. They can act it out, draw it, make it into 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).

Immune response

Section 5 Immune response

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Before going any furtherwhat is the difference between latent TB infection and active TB disease?


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What is the difference between TB infection and TB disease?

Many people incorrectly use the terms TB infection
and TB disease interchangeably.

Latent TB infection (aka LTBI) refers to the period of
time when the immune system has been successful
in containing the TB and preventing disease.

Active TB disease refers to the time when TB breaks
out of latency and causes disease.


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Mixing up LTBI and active TB disease is a common and understandable mistake but needs to be cleared up.

Latent TB infection
TB-specific CD4 and CD8 T cells travel into the lung to contain TB bacilli and eliminate infected cells. Cytokines (cellular chemical messengers) released by these cells also activate macrophages in a way that helps them break down and dispose of TB (process known as phagocytosis).As a result, instead of being eliminated from the body, the TB microbe is encased in a hard shell, known as a tubercle.

tuberculosis tubercle

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One of most important reasons that TB is so widespread is it has developed ways of hijacking our bodys normal immune response.TB has figured out a way to block phagocytosis by blocking the chemical messenger that activates this process (see next slide).

Phagocytosis

a. Ingestion of the pathogen and the formation of a internal pocket called a phagosome.

b. Normally, a cytokine called interferon gamma (IFN-gamma) activates macrophages in a way that promotes the phagosome to fuse with another pocket called a lysosome (which contains substances capable of breaking down the pathogen) to create a phagolysosome that disposes of the pathogen.

TB has the ability to block this process in order to survive in the macrophages phagosome and prevent its transport to the lysosome for degradation and disposal.

c. Waste material is expelled


1. Pathogens
2. Phagosome
3. Lysosomes
4. Waste material
5. Cytoplasm
6. Cell membrane

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Note to facilitator: This process can be very difficult to explain and we do not consider it to be fundamental to understanding basic concepts of TB so do not feel that this slide must be included in your presentation.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 help them break down and dispose of TB. This process known as phagocytosis (remember phage means eat, and cyto refers to cell). However TB has evolved the ability to block those chemical messengers. So instead of being eliminated from the body, the TB microbe is encased in a hard shell, known as a tubercle. This tubercle protects and hides TB

Latent TB infection

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.

When in latency, TB bacilli change their diet so that
they require very little oxygen to survive and can
remain dormant or reproduce at very low levels.


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Granulomas can effectively contain TB in such a way that it may never make someone sick, or be transmitted to another person. On the other hand, it hides the infection from the immune system, allowing the bacteria to survive- possibly becoming active at a later time and making a person sick. If TB were unable to make this switch to needing little oxygen, the TB would die off inside of the granuloma, 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 switch to activate to disease.

Immunologic memory

In a matter of weeks after the initial infection, 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 die off in a process called apoptosis (cell suicide).


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Apoptosis is a part of a healthy immune response.See graphic on next slide

Immune Response
Once the germ has been dealt with the immune system slows down.
A small number of memory cells remain

If exposed to the same germ again - the memory cells will "remember" and mount a response that is more rapid than the first time the immune system responded to the germ.


Section 5: Immune response

Apoptosis

Memory cells

Memory immune response
In a matter of weeks after the initial exposure, TB is usually contained by the immune system. 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.

Immune response

In HIV-negative persons, the bodys immune system usually keeps TB infection under control. In fact, most people with latent TB infection never develop TB disease, 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 percent of developing TB disease. In other words, they have a 1 in 10 chance every year, of progressing to active disease

Section 5: Immune response
These statistics are based on pre-HAART data and does not account for the impact of HAART on reducing incidence of TB disease but highlights the increased risk of disease progression that people with HIV face.

How do LTBI progress to
Active Disease?

Latent TB infection can progress to active disease when the body becomes weak from disease, malnutrition, immune suppression, or even old age.

When the immune system is compromised, the tubercles may begin to multiply and break out of the granulomas damaging the lung tissue creating cavities.


Cavity

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In most people with a healthy immune system, this will never happen- the TB will stay latent, trapped inside of the granulomas. Cavities are enlarged air spaces in the lung caused by tubercles breaking out of granulomas.

Active TB disease
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. Pulmonary TB expels pus into the lungs, which a person with
TB may cough up in spit or sputumExtrapulmonary TB (EPTB) is rare in adults with healthy immune systems but occurs in up to 40% of TB cases among people with HIV (rarely involves a single organ) and children.

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Challenges to TB control
in TB/HIV coinfection

Section 6 Challenges

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Challenges: Extra-pulmonary TB (EPTB)
People with HIV are more likely to have extrapulmonary TB.
Sites that can be affected include:Miliary TB is TB disseminated throughout the body.Tuberculosis lymphadenitis is found in the lymph nodes, and is the most common form of EPTB.Pleural TB is found in the pleural cavity around the lungs and is the most common form of EPTB in people with HIV.Skeletal TB is found in the bones and joints .Tuberculosis meningitis is found in the central nervous system.Gastrointestinal TB is found in the gastrointestinal tract.Genitourinary TB is found in genitourinary tract.Tuberculosis peritonitis is found in the pelvic cavity.Tuberculosis pericarditis is infects the membrane around the heart (pericardium).

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TB disease can also develop outside of the lung, which is called extra-pulmonary TB (EPTB). This is normally rare but EPTB occurs in 4 -40% of TB cases in people with HIV.

Challenges: smear-negative TB

People with HIV and children have fewer TB bacteria in their sputum due to fewer functioning CD4 and CD8 T cells. In healthy immune systems CD4 and CD8 T cells expel TB into the sputum.

As CD4 T cells are lost and compromised due to HIV infection, CD8 T cells lose the directional support they need to do their job and become impaired in their ability to kill TB-infected cells.

When this happens, the chance of smear-negative TB increases because fewer TB bacilli are released in the sputum.

Up to 61% of people coinfected with HIV and TB generate smear-negative tests, meaning the sputum smear test comes up negative incorrectly indicating that the person does not have TB.


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Low baciliary count is also referred to as paucibaciliary disease.Remember the most common way for TB to be diagnosed is to look at a sample of sputum coughed up by a patient. Trouble is, people with HIV have fewer TB bacteria in their sputum, thanks to fewer CD4 and CD8 T cells, which in healthy bodies expel TB into the phlegm (or 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 and become impaired in their ability to kill TB-infected cells. When this happens, the chance of smear-negative TB increases because fewer TB bacilli are released in the sputum. Smear test results may also be reported as acid fast bacilli-positive (AFB +) or acid fast bacilli-negative (AFB-). Because of its waxy wall TB bacilli must be washed in an acidic solution in order to retain specific staining dyes so that it can be seen under a microscope, therefore it is referred to as an acid fast bacilli.

Advocacy priorities
The need for basic understanding of TB is essential for newer and better prevention and infection control strategies, vaccines, diagnostics, and treatments.The Global Plan to Stop Tuberculosis 2006-2015 is currently under revision and the new version is expected to include basic science research in its research priorities.High burden countries need to increase their investment in basic science research and programs.
Section 6 Advocacy

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The response to AIDS has shown the impact that diverse advocacy efforts can have in crafting the most effective response to public health challenges. Both TB and HIV disproportionately affect individuals, communities and nations lacking financial and other important resources.

The revised version of the research agenda of the GP2 is expected to be completed by the end of 2010.

A brief review
Name two differences between TB and 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 is the difference between latent TB infection and active TB disease?Why are people with HIV more likely to have smear-negative TB?Please note that this is not an exhaustive list of review questions 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.
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