Upload
others
View
13
Download
0
Embed Size (px)
Citation preview
1
Clicker Data
• 19 clicker questions to date
• Best students got 18 (94.7%) correct
• Class averages – steady improvement– 1st lecture = 65%
– 2nd lecture = 85%
– 3rd lecture = 91%
• Note: no response = incorrect response
Clickers must be returned at the end of Thursday’s 1:30 lecture
no clicker – no grade for VPM 201
Mycobacteria: Orientation
Slow-growing Mycobacteria
M Avium Complex (MAC)
M Tuberculosis Complex (MTBC)
Leprosy
Mycobacterium tuberculosis
A highly successful pathogen
A Global Problem
Most common infectious disease of humans in the world.M. tuberculosis infects one new person every second.
2.1 billion people are infected2 million deaths / year
2
Magnitude of the Problem
TB is #1 killer of women, > all causes of maternal mortality. TB creates more orphans than any other infectious disease. TB is the leading cause of death among HIV-positive individuals. TB is not on the decline. TB infects 7-8 million people every year. TB >25% of all preventable adult deaths in the developing world.
Clinical Signs
Cough for more than three weeks
Blood in the sputum
Chest pain for more than one month
Increasing weakness and loss of weight
Clinical Signs
Consumption
Coughing & Cachexia
Pathology
Mediastinal lymph node
Pathology
Lung: milliary tuberculosis
3
Pathogenesis Details
Novel cell wall structure & chemistry.Responsible for mycobacteria being:
Acid-fastAntibiotic resistant
Resistant to environmentResistant to intracellular killing
Mycolates
Lipoarabinomannan
Arabinogalactan
Slow Growth Strategy
Growth rate is linked with virulence.Rapid growers, e.g., M. phlei = non-pathogenicModerate growers, e.g., M. avium = low virulence.Slow growers, e.g., M. tuberculosis = most virulent.
TB Controls Host Cell
• Regulates phagosome environment– Sustains pH at growth optimum– Selectively allows delivery of molecules like
transferrin to phagosome by fusion with vesicles in early endosomal network.
• Suppresses immune response– Sequesters itself away from antigen-
processing machinery of host cell.– Suppress ability of infected macrophage to
stimulate CMI.– Over-produce cell wall lipids (pthiocerol
dimycocerasate) that leave infected cell by exocytosis to suppress neighboring macrophages.
Control
• Education
• Screening general public: skin test
• Confirmatory testing: X-ray & culture or PCR
• Treatment:– Observed to assure compliance
• BCG vaccination (in high-prevalence countries)
Human TB Diagnostics
Screen by skin test Confirm by X-ray
Delayed-type hypersensitivity response to PPD: Purified Protein Derivative of M. tuberculosis. PPD is a Mtb culture (synthetic medium) filtrate from which proteins are precipitated by trichloroacetic acid or ammonium sulfate and concentrated by ultrafiltration.
4
Diagnostic Microbiology
Acid-fast stain of sputum
Anti-Mycobacterial Drugs
BCG Vaccine
“…the only thing worse than BCG is nothing.”D. Russell, Nature Reviews, August 2001.
New Challenges
Resurgence in USA due to AIDS, IV drug use, and drug-resistant strains.
“…the incidence of TB will invariably increase in most areas of the world if the rate of HIV infection in the adult population is high (≥5%).”
“…in the presence of a significant proportion of untreated HIV infection among adults, TB incidence cannot be reduced with current technologies.”
T.R. Frieden, Int.J.Epidemiol., 2002.
Our Worst Fear
MDR-TB = Resistant to:Isoniazid and rifamycin
XDR-TB = Resistant to:Isoniazid and rifamycin +Any Fluoroquinolone +Any one of 3 injectable 2nd line TB drugs
(capreomycin, kanamycin, amikacin)
Our Worst Fear
MDR-TB = Resistant to:Isoniazid and rifamycin
XDR-TB = Resistant to:Isoniazid and rifamycin +Any Fluoroquinolone +Any one of 3 injectable 2nd line TB drugs
(capreomycin, kanamycin, amikacin)
XDR-TB is raising the specter of something we have been worried might happen for a decade – the possibility of a virtually untreatable TB.
Paul Nunn, World Health Organization
5
First Case He Doc! Glad we ran into you. Take a look at the inside of this deer and tell us if it is
OK to eat the meat.
Pleural surface
Acid-fast Stained Smear What is your diagnosis?
Tuberculosis
What’s the probable cause?
A. Rhodococcus equi
B. Mycobacterium bovis
C. Salmonella typhimurium
D. Mycobacterium paratuberculosis
What characteristic(s) of M. bovis are most responsible for its pathogenicity?
A. Thick waxy cell wall
B. Potent exotoxins
C. Spore formation
D. Intracellular survival
E. Two of the above
6
Which antibiotic(s) are best for treatment of tuberculosis in cattle?
A. Isoniazid
B. Fluoroquinolones
C. Penicillin
D. None of the above TB is not treated
Which of the following states are currently classified as free of bovine TB?
A. Minnesota
B. Wisconsin
C. Michigan
D. All of the above
In which Canadian provinces is bovine TB most likely to be discovered?
A. PEI
B. Manitoba
C. BC
D. Quebec
Animal Version of TB Story
M. bovisTechnically, Mycobacterium tuberculosis subsp. bovis
• Source: infected animal, cattle…or?• Contact or inhalation• Invasion through respiratory mucosa• Uptake by macrophages• Survives intracellularly
• Arrests phagosome development• Suppresses host immune response
• Disseminates to regional lymph nodes granuloma caseous necrosis escape from host in respiratory secretions possible bacteremia / dissemination
• Clinical signs: wasting (cachexia)• Diagnosis – culture or skin test• REPORTABLE DISEASE – notify State Veterinarian / CFIA
Key Elements of the Story
• If cattle found infected;• Quarantine herd• Test entire herd
• Slaughter test-positive cows,…or• Slaughter entire herd
• Trace forward and trace backward for other infected herds• Treatment: none• Prevention – biosecurity, interstate regulations; no vaccine• Transmissible to humans: Zoonotic
Key Elements of the Story
7
Pathogenesis Details
Novel cell wall structure & chemistry.Responsible for mycobacteria being:
Acid-fastAntibiotic resistant
Resistant to environmentResistant to intracellular killing
Mycolates
Lipoarabinomannan
Arabinogalactan
Key Concepts
Intracellular bacterial pathogensBacteriologist’s view:
T-cell-mediated host responseImmunologist’s view:
Granulomatous tissue responsePathologist’s view:
Tuberculosis (TB) – like lesionFood safety inspector’s view
Practitioner’s view: Vaccines do not work well &antibiotic therapy is difficult
Clinical signs - wasting
From 1923 book on TB First accurate illustration of pathology, 1838.
Pathology - granulomas
Caseous Necrosis
Mediastinal lymph node
Lung
Readily Disseminates Classical Lesions are Granulomas
Bovine Spleen
Bovine Liver
MonkeyKidney
Granuloma = Tubercle
Caseous necrosis
Mineralization
Mononuclear cell inflammation
Fibrinous wall
8
Diagnosis
Caudal fold skin test M. bovis PPDSwelling = positive
Measures CMI response
Comparative Cervical Test
0
2
4
6
8
10
12
0 2 4 6 8 10 12
M. bovis PPD reaction (mm)
M. a
viu
m P
PD
rea
ctio
n (
mm
)
M. avium PPD reactor
M. bovis PPD reactor
Diagnosis and RegulationFlow Chart
Comparative Cervical TestDTH reaction toM. avium PPD
andM. bovis PPD
Compared(skin thickness measured with a calipers)
Culture: Special media + special labs
M. bovis is Zoonotic1993 Reviews Article on M. bovis in Humans
Stomach of child that got M. bovis from drinking raw milk, 1923 book illustration.
Herd of TB-free cattleused by Boston Children’shospital 1914-1940.
In the 1920s, 20% of all human cases of TB in the U.S. were caused by M. bovis.
Close to Home & In The News
On July 12, 2005, the Minnesota Board of Animal Health in conjunction with the United States Department of Agriculture (USDA) announced the confirmation of a tuberculosis (TB) infected beef cattle herd in Roseau County. This was the first positive herd identified in Minnesota since 1971, when the state was declared free from tuberculosis.
October, 2006; 6th herd found. Minnesota lost accredited TB-free status. Every bovine leaving the state must be TB tested.
9
Biological & Political Challenges
http://www.bovinetb.com/
Outstanding website!
Deer feeding congregation M. bovis transmission
Since 1995, bovine TB has been diagnosed in 398 white-tailed deer out of more than 88,000 tested.
Canadian Conundrum
Manitoba
New Zealand
Brushtail Possum
The wild animal reservoir of TB in New Zealand.
United Kingdom
The wild animal reservoir of TB in the U.K.
Badger
Unique ChallengesAnthropozoonosis
TB lung Asian elephantTesting protocol
18 U.S. elephants were found infectedwith M. tuberculosis, originating from humans. These animals then pass the infection back to humans. All U.S. elephants must now be tested annually.Treatment costs for an elephant are roughly$50,000 – requires one full year.
10
Unique ChallengesWildlife Health
Kruger National Park
Avian Tuberculosis
Etiology:M. avium (17%)M. genavense (71%)
Enlarged liverWith granulomas
Common in psittacine birdsand zoos with aviaries.
Leprosy M. leprae Leprosy = Hansen’s Disease
Armauer Hansen1841-1912
First to discover the leprosy bacillus.
Global distribution
Hansen’s reputation was tarnished when it was learned that he inoculated infectious material from leprosy victims into nurses and patients in an attempt to study the disease.
M. leprae Attacks Nerves
Leprosy lesionwith abundant
acid-fast bacteria
Can not be cultured in vitro
Grows in cooler parts of the body
Classification of Leprosy
RESISTANCE
TuberculoidSkin-NerveNo or few bacilliTuberculoid granuloma
LepromatousSkin-Nerve-EyeInternal organs
Numerous bacilliFoam cell granuloma
NO RESISTANCE
INFECTION
INDETERMINATE
BORDERLINE
11
Leprosy Models
Mouse footpadand armadillo;only means of
cultivatingM. leprae.
Feline LeprosyM. lepraemurium
Erosive skin lesionsFig. 2-63 inSmall Animal DermatologyW.B. Saunders
Nicely described in Greene, 3rd ed. pp. 477-479.
Who’s Winning,The Host or the Pathogen?