1. As late as the 1800s, causes and cures of TB remained mysterious

2. Then along came Robert Koch
December 11, 1843-
May 27, 1910

3. You may not remember me but I’ll bet you’ve heard of my Postulates

4. I developed tests to determine whether an infectious agent
causes a given disease

5. 1.The microorganism must be found in abundance
in all organisms suffering from the disease,
but not in healthy organisms.

6. 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

7. 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.

8. 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.

9. I know it’s a hard act to follow,
but I wasn’t done yet
In 1882 while working in Berlin
I discovered the tuberculosis bacteria
and the means of culturing it

10. The Nobel Prize in Physiology or Medicine
1905
In 1882 while working in Berlin
I discovered the tuberculosis bacteria
and the means of culturing it
Nobelprize.org

11. Aren’t I pretty? Our star: Mycobacterium Tuberculosis
Mycobacterium Tuberculosis on Lowenstein-Jensen medium
Mycobacterium Tuberculosis (scanning EM)
Images from CDC

12. But I am very hard to grow
Mycobacterium Tuberculosis on Lowenstein-Jensen medium
Mycobacterium Tuberculosis (scanning EM)
Images from CDC

13. 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 on Lowenstein-Jensen medium
Mycobacterium Tuberculosis (scanning EM)
Images from CDC

14. I am ‘acid-fast” so you can ID me using special stains
Mycobacterium Tuberculosis on Lowenstein-Jensen medium
Mycobacterium Tuberculosis (scanning EM)
Images from CDC

15. 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.
Red is my favorite color!
Mycobacterium tuberculosis (stained red) in tissue (blue).
Mycobacterium tuberculosis (stained red) in sputum

16. Here’s my family tree Staph. aureus TB bug E. coli
Genome Research 12, (2002)

17. We’re distant cousins Staph. aureus TB bug E. coli You
Genome Research 12, (2002)

18. Mycobacterial relatives of the TB bug cause other diseases
Mycobacterium africanum: causes up to one-third
of TB cases in West Africa.
Milder in non-immunocompromised patient
Mycobacterium leprae causes Leprosy (Hansen’s disease)

19. Mycobacterial relatives of the TB bug cause other diseases
Mycobacterium africanum: causes up to one-third
Of TB cases in West Africa.
Milder in non-immunocompromised patient
Mycobacterium leprae causes Leprosy (Hansen’s disease)
Mycobacterium bovis. Causes Bovine TB. Killed many
farm animals inn first half of 20th century.
Destroyed by pasteurization. Causes TB in developing world.
Mycobacterium avium. Causes TB in birds. Also
affects HIV patients and other immunocompromised people

20. Here’s how it usually starts
Left untreated, a person with active TB
will infect other people per year
World Lung Foundation (2008) and

21. TB lives INSIDE human cells!

22. It takes advantage of our bodies own “first-responders”
Macrophage

23. Macrophages are responsible for Phagocytosis of bacteria
and other foreign cells and for activation
of other immune cells
Macrophage
Bacteria

24. Macrophages love to “eat” bacteria
Yum-yum!
images/carroll3_small.jpg

25. Macrophages bind to mannosyl oligosaccharide residues
on the bacterial cell surface using their
cell surface mannose receptors
Yum-yum!
Clin Microbiol Rev July; 16(3): 463–496.

26. Normally ingested bacteria and other things get sent to the lysosome
for destruction
by low pH and
proteolysis
Uh oh!
bacterium
Ahhhhhhh…..

27. But the TB bacterium has a better idea-- It remodels the
endosome to be its
new home!
Very cozy

28. also reduces presentation of bacterial peptides
Avoiding the lysosome
also reduces presentation
of bacterial peptides
to the immune system by
the MHC proteins
Very cozy

29. The infected macrophage calls for help, generating a granuloma
images/carroll3_small.jpg

30. Let’s look at that in a
bit more detail

31. Infected macrophages send signals that recruit nearby lymphocytes

32. Uninfected macrophages and Lymphocytes surround the infected cells

33. They encase the infected cells in a
“cage” of “extracellular matrix” proteins
where they can stay for years!

34. We’re actually quite good at keeping TB at bay
only one-third of exposed patients
will become infected and only 3-5%
develop TB in the first year
Clin Microbiol Rev July; 16(3): 463–496.

35. We can harness the immune response
To help fight TB
Albert Calmette
Camille Guérin

36. We can harness the immune response
To help fight TB
Bacillus Calmette-Guérin = BCG!
Albert Calmette
Camille Guérin

37. Bacillus Calmette-Guérin = BCG!
An “attenuated” strain of M tuberculosis that does not
Cause disease but can stimulate the immune response

38. Bacillus Calmette-Guérin = BCG!
Interestingly, all “attentuated” strains have a common deletion
In the genome, removing at least one known “virulence” gene
Clin Microbiol Rev July; 16(3): 463–496.

39. Bacillus Calmette-Guérin = BCG!
BCG is clearly effective against miliary TB and TB meningitis
But its effectiveness against pulmonary TB is controversial

40. New attenuated strain vaccines and recombinant versions of
BCG are now in Phase II and Phase III clinical trials
Image from University of Oxford

41. Even without vaccination, in most otherwise healthy people
the immune system keeps TB at bay

42. But if the immune system is compromised
by malnutrition, HIV or old age….

43. What happens next and why does TB
Kill people?

44. 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 July; 16(3): 463–496.

45. We do know certain things
Uncontrolled M. tuberculosis growth is associated
with extensive lung damage that ultimately causes
death by suffocation.
Clin Microbiol Rev July; 16(3): 463–496.

46. We do know certain things
Uncontrolled M. tuberculosis growth is associated
with extensive lung damage that ultimately causes
death by suffocation.
Inflammatory responses are important in pathogenesis
in brain and bone.
Clin Microbiol Rev July; 16(3): 463–496.