as late as the 1800s, causes and cures of tb remained mysterious
TRANSCRIPT
As late as the 1800s, causes and cures of TB remained mysterious
Then along cameRobert Koch
December 11, 1843-May 27, 1910
You may not remember me butI’ll bet you’ve heard of my Postulates
I developed tests to determinewhether an infectious agent
causes a given disease
1.The microorganism must be found in abundance in all organisms suffering from the disease, but not in healthy organisms.
1.The microorganism must be found in abundance in all organisms suffering from the disease, but not in healthy organisms.
2.The microorganism must be isolated from a diseased organism and grown in pure culture
1.The microorganism must be found in abundance in all organisms suffering from the disease, but not in healthy organisms.
2.The microorganism must be isolated from a diseased organism and grown in pure culture
3.The cultured microorganism should cause disease when introduced into a healthy organism.
1.The microorganism must be found in abundance in all organisms suffering from the disease, but not in healthy organisms.
2.The microorganism must be isolated from a diseased organism and grown in pure culture
3.The cultured microorganism should cause disease when introduced into a healthy organism.
4.The microorganism must be re-isolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent.
In 1882 while working in BerlinI discovered the tuberculosis bacteriaand the means of culturing it
I know it’s a hard act to follow,but I wasn’t done yet
Nobelprize.org
The Nobel Prize in Physiology or Medicine 1905
Mycobacterium Tuberculosis (scanning EM)
Mycobacterium Tuberculosis on Lowenstein-Jensen medium
Images from CDC
Aren’t I pretty?
Our star: Mycobacterium Tuberculosis
Mycobacterium Tuberculosis (scanning EM)
Mycobacterium Tuberculosis on Lowenstein-Jensen medium
Images from CDC
But I am very hard to grow
Mycobacterium Tuberculosis (scanning EM)
Mycobacterium Tuberculosis on Lowenstein-Jensen medium
Images from CDC
I am an Obligate aerobe and grow very slowly
15-20 hour doubling vs. 30 minutes for E. coli
I require 6-8 weeks to grow on plates!
Mycobacterium Tuberculosis (scanning EM)
Mycobacterium Tuberculosis on Lowenstein-Jensen medium
Images from CDC
I am ‘acid-fast” so you can ID me using special stains
Mycobacterium tuberculosis (stained red) in tissue (blue).
Acid-fastness refers to resistance to decolorization by acids during staining procedures
The most common staining technique is Ziehl-Neelsen stain,in which the bacteria are stained bright red.
Mycobacterium tuberculosis (stained red) in sputum
Red is my favorite color!
Here’s my family tree
E. coli
Staph. aureus
TB bug
Genome Research 12, 1080-1090 (2002)
We’re distant cousins
You
E. coli
Staph. aureus
TB bug
Genome Research 12, 1080-1090 (2002)
Mycobacterial relatives of the TB bug cause other diseases
Mycobacterium leprae causes Leprosy (Hansen’s disease)
Mycobacterium africanum: causes ~30% of TB in West Africa. Milder in non-immunocompromised patient
Mycobacterial relatives of the TB bug cause other diseases
Mycobacterium bovis. Causes Bovine TB. Killed manyfarm animals in early 1900s. Destroyed by pasteurization. Causes TB in developing world.
Mycobacterium avium. Causes TB in birds. Alsoaffects HIV patients and other immunocompromised people
Left untreated, a person with active TBwill infect 10-15 other people per year
World Lung Foundation (2008) and http://pathport.vbi.vt.edu/pathinfo/pathogens/Tuberculosis_2.html
Here’s how it usually starts
TB lives INSIDE human cells!
It takes advantage of our bodiesown “first-responders”
Macrophage
Macrophages EAT bacteria and other foreign cells andActivate other immune cells
Macrophage
Bacteria
www.nyas.org/.../ images/carroll3_small.jpg
Macrophages love to “eat” bacteria
Yum-yum!
www.nyas.org/.../ images/carroll3_small.jpg
Cool people call that phagocytosis
Yum-yum!
Normally ingested bacteria andother things get sentto the “lysosome”for destruction by low pH andproteolysis
bacterium
Uh oh!
Ahhhhhhh…..
But the TB bacteriumhas a better idea--It remodels the lysosome to be itsnew home!
Very cozy
Avoiding the lysosomealso reduces exposure of the bacteriato the immune system
Very cozy
The infected macrophage calls for help,generating a granuloma
www.nyas.org/.../ images/carroll3_small.jpg
Let’s look at that in a bit more detail
Infected macrophages send signals that recruit nearby lymphocytes
Uninfected macrophages and Lymphocytes surround the infected cells
They encase the infected cells in a “cage” of “extracellular matrix” proteins
where they can stay for years!
We’re quite good at keeping TB at bayonly 30% of exposed patients
will become infected and only 3-5% develop TB in the first year
Clin Microbiol Rev. 2003 July; 16(3): 463–496.
We can harness the immune response To help fight TB
Albert Calmette Camille Guérin
We can harness the immune response To help fight TB
Bacillus Calmette-Guérin = BCG!
Albert Calmette Camille Guérin
Bacillus Calmette-Guérin = BCG!
An “attenuated” strain of M tuberculosis that does not Cause disease but can stimulate the immune response
http://www.cheng.cam.ac.uk/
Bacillus Calmette-Guérin = BCG!
Interestingly, all “attentuated” strains have a common deletionIn the bacteria’s genome, removing at least one known “virulence” gene
Clin Microbiol Rev. 2003 July; 16(3): 463–496.
Bacillus Calmette-Guérin = BCG!
BCG is clearly effective against miliary TB and TB meningitisBut its effectiveness against pulmonary TB is controversial
http://www.cheng.cam.ac.uk/
New attenuated strain vaccines and recombinant versions ofBCG are now in Phase II and Phase III clinical trials
Image from University of Oxford
Even without vaccination, in mostotherwise healthy people
the immune system keeps TB at bay
But if the immune system is compromisedby malnutrition, HIV or old age….
What happens next and why does TB Kill people?
There is still much to be learned!
“What makes M. tuberculosis virulent? Unfortunately, there is no simple answer yet, despite the knowledge obtained in the last 100 or more years”
Clin Microbiol Rev. 2003 July; 16(3): 463–496.
We do know certain things
Clin Microbiol Rev. 2003 July; 16(3): 463–496.
1. Uncontrolled M. tuberculosis growth is associated with extensive lung damage that ultimately causes death by suffocation.
We do know certain things
Clin Microbiol Rev. 2003 July; 16(3): 463–496.
1. Uncontrolled M. tuberculosis growth is associated with extensive lung damage that ultimately causes death by suffocation.
2. Inflammatory responses are important in pathogenesisin brain and bone.