M33: Mechanisms of Damage II: Immunopath (Mycobacteria) Flashcards
Tuberculosis:
- 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 _ - Disease can be _ (most common), _, or _.
- Clinical aspects of disease
- _: 50% death rate
- Often a _ disease: lung destruction, hemoptysis
- _ (probably due to increased inflammatory response)
- _ manifestations
- Mycobacterium tuberculosis
- disease
symptoms
contagious - pulmonary
extra-pulmonary
miliary
- Untreated
- pulmonary
- Wasting
- Extrapulmonary
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
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
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
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
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
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
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
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
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
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
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
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
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
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
