M33: Mechanisms of Damage II: Immunopath (Mycobacteria) Flashcards Preview

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Flashcards in M33: Mechanisms of Damage II: Immunopath (Mycobacteria) Deck (31)
1

Tuberculosis:

1. Tuberculosis is caused by the bacterium _
- Infection with organism does not necessarily or even frequently lead to _, but a person can remain infected for life without _ or without being _

2. Disease can be _ (most common), _, or _.

3. Clinical aspects of disease
- _: 50% death rate
- Often a _ disease: lung destruction, hemoptysis
- _ (probably due to increased inflammatory response)
- _ manifestations

1. Mycobacterium tuberculosis
- disease
symptoms
contagious

2. pulmonary
extra-pulmonary
miliary

- Untreated
- pulmonary
- Wasting
- Extrapulmonary

2

Tuberculosis:
Spectrum of disease includes:

a. Primary: _ tuberculosis within 1-2 years of _ infection (PPD+)

b. Latent tuberculosis: M. tuberculosis infection without _; these people are not generally considered to be _. Most people infected with M. tuberculosis have a latent infection and are skin test (positive / negative) for mycobacterial infection (PPD(+/-)). This is a CLINICAL definition.

c. Reactivation tuberculosis: reactivation of a latent infection that results in _, _ tuberculosis. Reactivation usually occurs in the _, but can occur anywhere in the body

d. Factors responsible for reactivation: (5), etc

a. active
initial

b. clinical disease
contagious
positive (+)

c. active, contagious
lungs

d. immunosuppression due to age, steroids, HIV, malnutrition, alcohol or drug abuse

3

Tuberculosis:
Epidemiology

a. _: 1.5-2 million deaths per year, 8 million new cases each year.

b. In the United States:
• 20% increase in number of cases since 1985
• The numbers of cases had been steadily (increasing / decreasing) for 100 years

c. _ and _ infection significantly increase risk of active tuberculosis

d. _ of foreign born persons from TB-endemic areas increase TB in population

e. _ strains are emerging.

f. estimated 1/3 of world’s population infected with M. tuberculosis

a. Worldwide

b. decreasing

c. AIDS and HIV

d. Immigration

e. Drug resistant

4

Tuberculosis:

Transmission
a. Transmission is generally via the _ route
b. _ bacteria (droplet nuclei) are infectious particles
c. Multiple contacts with _ greatly increases risk
d. Only people with _ disease are contagious

The following factors contribute to susceptibility
a. poor _, crowding
b. _
c. compromised _ system
d. exposure potential (more exposure, more chance of _)
e. Some _ components contribute to susceptibility

a. respiratory
b. Aerosolized
c. infected person
d. active

a. living conditions
b. malnourishment
c. immune
d. getting infected
e. genetic

5

Pathogenesis of M. tuberculosis:
Microbial characteristics

a. _ bacilli: staining with _ (red phenolic dye) and destaining with _ gives red _ shaped organisms.

_ bind the dye. Most other bacteria will not retain red color when treated with _ (hence "_”). All mycobacteria are _ organisms.

b. M. tuberculosis is a (fast / _)-growing organism with an 18-24 hour doubling time (compared to 20-30 minutes for E. coli)

c. Like all mycobacteria, M. tuberculosis has a _ rich, hydrophobic "_" cell wall (which accounts for _ staining)—much more complex than usual Gram positive or Gram negative bacteria.

d. Various media allow growth of M. tuberculosis cultures in laboratory

a. acid-fast
carbolfuschin
acid-alcohol
rod

Lipids
acid-alcohol
acid-fast
acid-fast

b. slow

c. lipid
"waxy"
acid-fast

6

Pathogenesis of M. tuberculosis:
Virulence factors

a. Virulence factors include (6)

b. Major virulence determinants: allow survival and replication of M. tuberculosis within _

i. The organism enters via _, can use _ receptor and probably other receptors on cells.

c. Interaction with _ responsible for much of the pathology and _ seen during disease.

a. mycolic acids, lipids, lipoarabinomannan, cytolysin, adhesin/invasin genes, potential secretion systems (ESX loci)

b. macrophages

i. phagocytosis
complement

c. host immune system
tissue damage

7

Pathogenesis of M. tuberculosis:
Survival within macrophages and persistence within the host

a. M. tuberculosis inhibits _ - _ fusion within the _

b. _ (_) has little direct effect on M. tuberculosis (M. tuberculosis has a catalase gene, _)

c. _ produced by macrophages can kill M. tuberculosis.

d. Down-regulation of _ presentation—evade detection by CD4 T cells? 19kDa lipoprotein of M. tuberculosis binds to _, and down-regulates _ on chronically infected macrophages.

a. phagosome-lysosome
macrophage

b. Respiratory burst (reactive oxygen intermediates)
katG

c. Reactive nitrogen intermediates (e.g. nitric oxide)

d. MHC Class II
Toll-like receptor (TLR) 2
MHC Class II

8

Case study: A 71 year old female visited her local clinic complaining of with an illness of 2 months duration, which was characterized by low grade fever and cough. Despite prior injections of penicillin at the clinic, her cough had become more productive of thick yellow sputum. The patient had lived most her life in an urban setting under impoverished conditions.

Laboratory data obtained at the time her clinic visit: Gram stain of sputum showed many neutrophils, scattered gram positive cocci, a few gram negative cocci and rods; white cell count of 6300/mm3; normal urinalysis. Two blood cultures were negative for bacterial growth at 24 hours. Sputum cultures yielded a moderate growth of Pseudomonas species and a few colonies of Enterobacter aerogenes. A chest radiograph showed a dense infiltrate within the right upper lobe, within which could be discerned a "highlight" consistent with a cavity.

A _ skin test was ordered. Because of the normal leukocyte count and evidence of what appeared to be normal flora in sputum, antimicrobial therapy was not initiated at this visit. When she returned to the clinic 2 days later, the _ skin test showed 18mm induration. Acid-fast stains of sputum and sputum cultures for mycobacteria were ordered. Sputum stains revealed a moderate number of acid-fast bacilli and anti-_ therapy was initiated. Culture of each of the two sputum samples containing acid-fast bacilli was reported 21 days later to have yielded _.

tuberculin

tuberculin

tuberculous

Mycobacterium tuberculosis

9

M. tuberculosis:

a. Transmission: bacteria transmitted through _

b. Initial infection:

i. interaction of bacillus with _

ii. _ signals from infected cells

iii. hematogenous _

iv. recruitment of _ and _ to the lungs

v. formation of _

a. aerosolization

i. alveolar macrophages

ii. inflammatory

iii. spread of bacteria to other organs

iv. monocytes and lymphocytes

v. granuloma

10

M. tuberculosis:

c. Control of bacterial _ ("walled off" lesion in granuloma, not actively infectious) can result if the immune response is effective.

Alternatively, development of _ (_, _, _) can occur within 1-2 years of infection, if immune response is not effective at controlling bacteria.

d. In the majority of infected persons, bacteria are not completely _, resulting in _ infection (_)

e. Reactivation of latent infection can occur many years later to cause _, which is _ to others

f. Active tuberculosis is characterized by _ of lesion, _ of lung tissue, _ formation, large numbers of _, often released into _.

Often a _ disease, with weight loss, lethargy, etc ensues.

g. Host immune response to infection contributes to pathology.

c. replication

primary tuberculosis (replicating bacteria, active disease, infectious)

d. eliminated
latent
not infectious

e. active TB
infectious

f. liquefaction
necrosis
cavity
bacilli
airways


wasting

11

M. tuberculosis:
Diagnosis

a. Symptoms: (3)

b. _ skin test is used to screen for infection

i. Antigen mixture (_) from M. tuberculosis is injected under skin on forearm.

ii. _ immune response causes _ type hypersensitivity reaction to occur. Test is read 48-72 hr later.

iii. Positive test is determined by extent of _. Usually >10mm indicates a positive response.

iv. Positive test does not indicate _ disease, but indicates _

a. cough, fever, difficulty in breathing

b. Tuberculin

i. purified protein derivative = PPD

ii. Cell mediated (T cell) memory
delayed

iii. induration

iv. active
infection with Mycobacterium

12

M. tuberculosis:
Diagnosis

c. _ based immunoassays to distinguish _ infection from _ vaccinated or non-tuberculous mycobacteria sensitization

d. Chest X-rays: _ or _ indicates infection and disease

e. _ in sputum smear (red rods on blue background) is used to diagnose that the infection is mycobacterial in nature.

f. Cultivation of organisms from patient sample takes 3-8 weeks, using a Bactec machine, and unless the patient is treated, s/he is _ to others during this time.

g. Tuberculous infection may occur in organs other than _

c. IFN-g
Mtb
BCG

d. lesion or cavity

e. Acid-fast bacilli

f. infectious

g. lung

13

Immune Response to tuberculosis:
Cell mediated immunity required

a. Humoral response much (more / less) important than T cell responses.

b. (CD4 / CD8) T cells important, but (CD4 / CD8) T cells likely play a role also

c. _ production by T cells is essential to control of infection.

d. Lysis of infected _ by CD8 T cells may kill intracellular organisms or release them to be taken up by more activated _

a. less

b. CD4
CD8

c. Cytokine

d. macrophages
macrophages

14

Immune Response to tuberculosis:
Cytokines

a. _: important cytokine in control of infection, and is required for macrophage activation

b. _: required for control of infection, but also may be involved in tissue damaging reactions.

TNF is important in _ activation and _ formation. Treatment of _ diseases (such as rheumatoid arthritis or Crohn’s disease) with TNF neutralizing agents such as _ (an antibody against TNF) is a major reactivation risk for tuberculosis in humans.

c. Other T cell and macrophage cytokines (_, _) also play important roles in controlling infection.

a. IFN-g

b. TNF

macrophage
granuloma
inflammatory
infliximab

c. IL-12, IL-6

15

Immune Response to tuberculosis:
Macrophage activation: key to control of infection

a. _ macrophages cannot destroy M. tuberculosis bacilli, and the organisms _ well within the macrophages.

b. Activation of human macrophages for destruction of mycobacteria not well understood.

c. In murine macrophages, production of _ (_) participates in killing intracellular mycobacteria.

d. Macrophage activation is believed to involve interaction with _ cells and the cytokines produced by these cells (_, _)

a. Unactivated
replicate

c. reactive nitrogen intermediates (e.g. nitric oxide)

d. T
IFN-g, TNF-a

16

Immune Response to tuberculosis:
Granuloma formation is important in control/containment of infection

a. _ cells and _ involved in granuloma formation

b. _ also an important player in this process

c. Center of granuloma can be _ or _

d. _ are believed to reside within the granuloma for long periods of time

a. T cells and macrophages

b. TNF

c. necrotic or caseous

d. Persistent mycobacteria

17

Vaccines against tuberculosis:

a. _: efficacy is variable. Most effective against childhood TB. Does not prevent infection, but may prevent development of TB.

b. Future vaccines may include subunit proteins, _ mycobacteria, viral vectors expressing _ proteins, or (DNA / RNA) vaccines

Prevention measures include:
a. Effective _
b. improvement of _ conditions
c. _
d. _ of infected patients

a. BCG

b. recombinant
Mtb
DNA

a. treatment
b. social
c. screening
d. isolation

18

Treatment for tuberculosis:

Front line drugs for treatment (of drug sensitive organisms)

i. _ (inhibition of synthetic pathways of mycolic acids, also may inhibit catalase-peroxidase enzyme): used almost exclusively for mycobacterial infections

ii. _ inhibition of DNA-dependent RNA polymerase at beta subunit

iii. _ likely interferes with cell wall biosynthesis

iv. _ mechanism unknown

i. Isoniazid

ii. Rifampin

iii. Ethambutol

iv. Pyrazinamide

19

Treatment for tuberculosis:

Second line drugs (for treatment of drug resistant organisms)

Use first line drugs where sensitive, add second line drugs to regimen (6)

New drugs considered for use, especially in drug resistant cases

- Streptomycin (aminoglycoside) (must be injected)
- Fluoroquinolones (moxifloxacin)
- Capreomycin
- Ethionamide
- Cycloserine
- P-aminosalicylic acid (PAS)

- Linezolid
- TMC207 (Bedaquline)
- Nitroimidazoles

20

Treatment for tuberculosis:

c. (#) first-line mycobacteria-specific drugs used simultaneously for 2 months, then _ / _ for the remaining 4 months (or longer)

d. Drug _ testing very important

e. Treatment for (#)-(#) months

f. _ with treatment essential to avoid relapse and selection of drug resistant strains

g. Infected persons without active disease can be treated _ to reduce reactivation risk

h. Drug resistance (_ strains = _): resistant to two or more front line drugs: _ / _.

i. _: extensively or extremely drug resistant: MDR + resistant to three or more of the six classes of second-line drugs

c. four
INH / RIF

d. sensitivity

e. 6-12

f. Compliance

g. prophylatically

h. Multi-drug resistant (MDR)
INH / RIF

i. XDR

21

Leprosy (Hansen's Disease):
Etiology

a. Leprosy is caused by _

b. Route of transmission is not proven, but may be _. Mycobacteria are shed by the _ secretions of infected persons. This (is / is not) particularly contagious, and extended _ is usually required to contract leprosy.

c. There is an enormous _ attached to leprosy in most parts of the world, which affects patients quality of life, treatment, and choice to seek medical advice.

d. Leprosy is endemic in _, _, and parts of _. At least 6 million people worldwide have leprosy.

e. (animal) can be infected with M. leprae

a. Mycobacterium leprae

b. respiratory
nasal
is not
exposure

c. stigma

d. Africa, Asia, and parts of Latin America

e. Armadillos

22

Leprosy (Hansen's Disease):
Pathogenesis

a. The organism is similar to other pathogenic mycobacteria in that its cell wall consists of _, _, and other _. Dense lipid-rich outer “capsule” contains _

b. It is an _ bacterium. This is also a very (fast / slow) growing organism, and it replicates best a (higher / lower) temperatures (_).

c. M. leprae resides within _ and _ cells —tropism for peripheral nerves

d. M. leprae cannot be cultivated in the _, and therefore little is known about the virulence factors, pathogenesis, or survival mechanisms of these organisms.

e. There is no _ model, although (animal) footpads are sometimes used for infection, and (animal) are sometimes used as a source of bacteria.

a. lipoproteins, mycolic acids, and other lipids
phenolic glycolipid 1 (PGL-1)

b. acid fast
slow
lower (32-34°C)

c. macrophages and Schwann cells

d. laboratory

e. animal
mouse
armadillos

23

Leprosy (Hansen's Disease):
Clinical Manifestations

a. There is a spectrum of disease in leprosy which is characterized by the number of _ and the _ response, as well as the disease manifestations.

b. At one end of the spectrum is _ leprosy and the other end is _ leprosy. Many patients fall somewhere in the middle of the spectrum.

c. _ occur following infection. These are _, _, and _.

a. bacteria
immune

b. tuberculoid
lepromatous

c. Skin lesions
flat, depigmented, and anesthetic (numb to the touch)

24

Leprosy (Hansen's Disease):
Clinical Manifestations

d. Tuberculoid leprosy is characterized by _ and _.

i. Bacterial numbers in the lesions are very (high / low) and often _. The nerve damage is the result of _ in response to the infection

ii. Numerous _ are observed in the lesions of tuberculoid patients.

iii. Sensory nerve damage leads to loss of _ or _. _, _, and _ result from the loss of feeling in the extremities.

iv. _ are observed at lesion sites.

d. skin lesions and peripheral nerve damage

i. low
undetectable
inflammation

ii. lymphocytes

iii. fingers or toes
Skin ulcers, infection, and amputation

iv. Granulomata

25

Leprosy (Hansen's Disease):
Clinical Manifestations

e. Lepromatous leprosy is characterized by _, _, _, and in advanced cases, _ and _.

i. Bacterial numbers are very (high / low) in lesions of lepromatous patients, and fewer _ are seen. Instead, foamy _ are observed in the lesions, and these are heavily infected with bacteria.

ii. Well-formed granulomata (are / are not) observed.

iii. The (large / small) number of bacilli present makes lepromatous patients (more / less) infectious than tuberculoid patients

iv. Bacteria replicate in _ and cause _ damage

v. Complication of leprosy: _

e. skin lesions, sensory deficits, enlarged peripheral nerves
dermal edema and disfigurement of nose and face

i. high
lymphocytes
macrophages

ii. are not

iii. large
more

iv. Schwann cells
nerve

v. erythema nodosum leprosum

26

Immunology of leprosy:

a. The spectrum of disease is determined by the _

b. Tuberculoid leprosy is characterized by a _ mediated immune response

i. Type _ response, with CD4 and CD8 T cells producing type _ cytokines, such as _ and _ which can activate _.

ii. Bacterial numbers are very (high / low), although bacteria are still _

iii. The chronic inflammatory response contributes to the pathology of the disease by _ formation, which can cause _ damage.

iv. Patients have strong _ responses to a skin test antigen, _

v. CD4 (> /

a. host immune response

b. cell

i. 1
1
IFN-g and IL-2,
macrophages

ii. low
present

iii. granuloma
nerve

iv. DTH
lepromin

v. >

vi. +

27

Immunology of leprosy:

c. Lepromatous leprosy is characterized by a Type _ T cell profile.

i. T cells at the lesions are primarily (CD4 / CD8) T cells, with some (CD4 / CD8) T cells and produce Type _ cytokines (_, _).

ii. The Type _ cytokines produced favor an _ response, but the _ do not provide protection

iii. Bacterial numbers (are / are not) controlled

iv. Bacteria invade _ and _ near nerves and cause substantial _ damage

v. Lepromatous patients are _ (DTH(+/-)) to lepromin

c. 2

i. CD8
CD4
2
IL-4, IL-10

ii. 2
antibody
antibodies

iii. are not

iv. Schwann cells and macrophages
nerve

v. anergic
-

28

Immunology of leprosy:

d. Spectrum of disease differs geographically: In _ and _, 90% of patients are tuberculoid. In _, 50% are lepromatous and 50% are tuberculoid. In _, 90% are lepromatous. This suggests a _component, although other factors likely contribute.

e. Complication of leprosy: _

i. Occurs in 50% of borderline or (lepromatous / tuberculoid) patients

ii. Mostly after _ treatment

iii. Painful _, _

iv. probably _ complex driven

d. India and Africa
Southeast Asia
Mexico
genetic

e. Erythema nodusum leprosum

i. lepromatous

ii. antibiotic

iii. nodules, neuritis

iv. immune

29

Leprosy (Hansen's Disease):
Diagnosis and treatment

a. Diagnosis is by _, stained by _ and _ (to characterize the cells) and the "_" stain for acid fast bacilli

i. In early leprosy, clinical manifestations of lepromatous vs. tuberculoid can be (easy / difficult) to distinguish

ii. Diagnosis is made by _ and is based on numbers of _ and numbers of _ in the skin lesion

iii. High bacterial numbers with few lymphocytes but many "foamy" macrophages indicates (lepromatous / tuberculoid) leprosy, while low bacterial numbers and high lymphocytes (and granulomata) indicates (lepromatous / tuberculoid) leprosy

b. Treatment: antibiotics (_ and _) for 1.5-2 years.

Antibiotic therapy in tuberculoid patients usually resolves _, although _ damage is not reversed.

a. skin biopsy
hematoxylin and eosin
Fite

i. difficult

ii. skin biopsy
acid-fast bacilli (AFB)
lymphocytes

iii. lepromatous
tuberculoid

b. dapsone and rifampin

lesions
nerve

30

Other mycobacteria seen in clinical diseases:

1. Non-tuberculous mycobacteria (NTM)

a. _ organisms

b. grow (faster / slower) than M. tuberculosis, but still relatively (fast / slow)

c. primarily cause disease in _ patients

Most common NTM (5)

a. environmental

b. faster
slow

c. immunocompromised

M. avium-intracellulare
M. marinum
M. kansasii
M. ulcerans
M. fortuitum

31

Other mycobacteria seen in clinical diseases:

2. M. avium-intracellulare
- Most common NTM cause of _
- Common opportunistic pathogen in _ patients (systemic)

3. M. marinum
- _ organism
- _ / _

4. M. ulcerans
- Cause of _ ulcer
- Toxin _ skin
- Endemic in parts of _ and _

5. All NTM can be difficult to treat
- All are _ (_)

- chronic pulmonary disease
- AIDS

- Marine
- Swimmer’s granuloma/fish tank granuloma

- Buruli
- necrotizes
- Africa and Australia

- acid fast (mycobacteria)